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Hsu YSO, Hsu RH, Liau JY, Lee NC, Chien YH, Liao YH. Pseudoxanthoma Elasticum-Like Phenotype With a Novel MGP Variant. JAMA Dermatol 2025:2834546. [PMID: 40397434 DOI: 10.1001/jamadermatol.2025.1019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
This case report describes a patient with pseudoxanthoma elasticum–like phenotype associated with a novel MGP gene variant.
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Affiliation(s)
| | - Rai-Hseng Hsu
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jau-Yu Liau
- Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ni-Chung Lee
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yin-Hsiu Chien
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
- Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Hua Liao
- Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan
- Department of Dermatology, National Taiwan University College of Medicine, Taipei, Taiwan
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2
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Kaesler N, Kaushik S, Frisch J, Ziegler S, Grommes J, Gombert A, Roma LP, Kuppe C, Jankowski J, Floege J, de la Puente‐Secades S, Kramann R, Jankowski V. Vitamin K preserves gamma-glutamyl carboxylase activity against carbamylations in uremia: Implications for vascular calcification and adjunct therapies. Acta Physiol (Oxf) 2025; 241:e70040. [PMID: 40202064 PMCID: PMC11979876 DOI: 10.1111/apha.70040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 02/28/2025] [Accepted: 03/20/2025] [Indexed: 04/10/2025]
Abstract
AIM Vascular calcification contributes to morbidity and mortality in aging and is accelerated in diabetes and in chronic kidney disease. Matrix Gla Protein is a potent inhibitor of vascular calcification, which is activated by the vitamin K-dependent gamma-glutamyl carboxylase (GGCX). However, through a currently unidentified mechanism, the activity of GGCX is reduced in experimental uremia, thereby contributing to the promotion of vascular calcifications. In this study, we aim to identify the cause of these functional alterations and to stimulate the enzyme activity by potential GGCX binding compounds as a new avenue of therapy. METHODS Two rodent models of experimental uremia and human carotid plaques were assessed for GGCX activity and modifications, as well as calcification. In silico compound screening via BindScope identified potential binding partners of GGCX which were further validated in functional assays for enzymatic activity changes and for in vitro calcification. Mass spectrometry was applied to monitor molecular mass changes of the GGCX. RESULTS Mass spectrometry analysis revealed post-translational modifications of the GGCX in uremic rats and mice, as well as in calcified human carotid plaques. Functional assays showed that the post-translational carbamylation of GGCX reduced the enzyme activity, which was prevented by vitamin K2. Chrysin, identified by compound screening, stimulated GGCX activity, reduced calcium deposition in VSMCs, and oxidized GGCX at lysine 517. CONCLUSION In conclusion, this study clearly demonstrates that the vitamin K-dependent enzyme GGCX plays a significant role in uremic calcification and may be modulated to help prevent pathological changes.
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Affiliation(s)
- Nadine Kaesler
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
| | - Suresh Kaushik
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
- BiosciencesCardiff UniversityCardiffUK
| | - Janina Frisch
- Institute of Biophysics, Center of Human and Molecular Biology (ZHMB), Center for Gender‐Specific Biology and Medicine (CGBM)Saarland UniversityHomburgGermany
| | - Susanne Ziegler
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
| | - Jochen Grommes
- Marienhospital AachenClinic for Vascular SurgeryAachenGermany
| | - Alexander Gombert
- Clinic for Vascular SurgeryUniversity Hospital of the RWTH AachenAachenGermany
| | - Leticia Prates Roma
- Institute of Biophysics, Center of Human and Molecular Biology (ZHMB), Center for Gender‐Specific Biology and Medicine (CGBM)Saarland UniversityHomburgGermany
| | - Christoph Kuppe
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
| | - Joachim Jankowski
- Institute of Molecular Cardiovascular Research (IMCAR)University Hospital of the RWTH AachenAachenGermany
- Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM)University of MaastrichtMaastrichtThe Netherlands
- Aachen‐Maastricht Institute for CardioRenal Disease (AMICARE)University Hospital RWTH AachenAachenGermany
| | - Jürgen Floege
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
| | - Sofia de la Puente‐Secades
- Institute of Molecular Cardiovascular Research (IMCAR)University Hospital of the RWTH AachenAachenGermany
| | - Rafael Kramann
- Medical Clinic IIUniversity Hospital of the RWTH AachenAachenGermany
| | - Vera Jankowski
- Institute of Molecular Cardiovascular Research (IMCAR)University Hospital of the RWTH AachenAachenGermany
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Perrone S, Raso S, Napolitano M. Clinical, Laboratory, and Molecular Characteristics of Inherited Vitamin K-Dependent Coagulation Factors Deficiency. Semin Thromb Hemost 2025; 51:170-179. [PMID: 39496305 DOI: 10.1055/s-0044-1792031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2024]
Abstract
Vitamin K-dependent coagulation factors deficiency (VKCFD) is a rare autosomal recessive genetic disease characterized by impaired levels of multiple coagulation factors (II, VII, IX, and X) and natural anticoagulants (proteins C and S). VKCFD is part of familial multiple coagulation factor deficiencies, reporting overall 50 affected families thus far. Disease manifestations are quite heterogeneous, bleeding symptoms may vary, and even, although generally mild, some patients may succumb to fatal outcomes. VKCFD diagnosis may be delayed because the disease phenotype simulates the most frequently acquired deficiencies of vitamin K. First-line coagulation assays, prothrombin time/international normalized ratio (PT/INR) and activated partial thromboplastin time (aPTT), are both prolonged; mixing test typically normalizes the clotting times; and vitamin K-dependent coagulation factors will be variably decreased. Molecularly, VKCFD is associated with mutations in γ-glutamyl-carboxylase (GGCX) or vitamin K epoxide reductase complex subunit 1 (VKORC1) genes. Vitamin K is involved not only in the biosynthesis of coagulation proteins but also in bone metabolism and cell proliferation. Therapeutic options are based on vitamin K supplementation, coagulation factors (prothrombin complex), and fresh frozen plasma, in case of severe bleeding episodes. Two case studies here illustrate the diagnostic challenges of VKCFD: case 1 depicts a woman with a history of bleeding episodes, diagnosed, only in her third decade of life with inherited homozygous GGCX gene mutation. Case 2 shows a man with an acquired vitamin K deficiency caused by Crohn's disease. Better understanding of GGCX and VKORC1 mutations aids in prognosis and treatment planning, with emerging insights suggesting potential limitations in the effectiveness of vitamin K supplementation in certain mutations.
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Affiliation(s)
- Salvatore Perrone
- Department of Hematology, S. M. Goretti Hospital, Polo Universitario Pontino, Latina, Italy
| | - Simona Raso
- Department of Hematology and Rare Diseases, V Cervello Hospital, Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy
| | - Mariasanta Napolitano
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
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Liu K, Li S, Tong J, Jiang N, Hong M, Gu Y, Chen L, Liang D, Jin Y, Zhao Y, Hou D, Huang J, Tie JK, Hao Z. Structural and Functional Insights into GGCX-FIX Interaction: Implications for Vitamin K-Dependent Bleeding Disorders. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.18.638829. [PMID: 40027771 PMCID: PMC11870592 DOI: 10.1101/2025.02.18.638829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Gamma-carboxylation, catalyzed by γ-glutamyl carboxylase (GGCX), is a critical post-translational modification essential for the biological activity of vitamin K-dependent proteins (VKDPs). Mutations in GGCX, depending on their specific location, result in vitamin K-dependent coagulation factor deficiency type 1 (VKCFD1), which encompasses a broad spectrum of clinical manifestations ranging from mild to severe, including bleeding disorders, osteoporosis, and vascular calcification. The limited knowledge of GGCX's structure and functional regions hinders our understanding of the consequences of GGCX mutations and the treatment for VKCFD1. This study aimed to identify key functional regions of GGCX and their interactions with VKDPs to better elucidate the molecular mechanisms underlying these diverse clinical symptoms. Using AlphaFold 3 and molecular dynamics simulations, we developed a complex binding model of GGCX, FIX, and reduced vitamin K, which revealed critical regions and residues involved in their interaction. Site-directed mutagenesis and cell-based assays further validated the model, confirming that multisite and regional cooperative binding of FIX to GGCX plays a key role in modulating γ-carboxylation efficiency. Additionally, novel residues (I296, M303, M401, M402) were identified as essential for GGCX's dual enzymatic activities: carboxylation and vitamin K epoxidation. We further demonstrated that the spatial proximity of these active sites supports the hypothesis that GGCX's carboxylation and vitamin K epoxidation centers are interconnected, ensuring the efficient coupling of these processes. Our GGCX-FIX binding and carboxylation model aligns with known pathogenic GGCX mutations, providing valuable insights into the molecular basis of coagulation disorders caused by GGCX mutants.
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Berkner KL, Hallgren KW, Rishavy MA, Runge KW. Cellular and biochemical approaches to define GGCX carboxylation of vitamin K-dependent proteins. Methods Enzymol 2024; 708:175-205. [PMID: 39572139 DOI: 10.1016/bs.mie.2024.10.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2025]
Abstract
The gamma-glutamyl carboxylase (GGCX) generates clusters of carboxylated glutamic acid residues in vitamin K-dependent (VKD) proteins, which is required for their diverse functions including hemostasis and regulation of calcification. The GGCX modifies a VKD protein using several substrates and cofactors, and has regulatory mechanisms like processivity that ensures full carboxylation of VKD proteins. The GGCX mechanism is incompletely understood. GGCX mutations cause disease: vitamin K clotting factor deficiency (VKCFD1) associated with severe bleeding and pseudoxanthoma elasticum (PXE)-like, where bleeding is mild but calcification is excessive. Why mutations cause disease has only been revealed for a few GGCX mutants. The chapter describes biochemical and cellular assays developed to define GGCX mechanism and determine why GGCX mutations cause disease. Multiple components are important to VKD protein carboxylation. GGCX requires reduced vitamin K generated by the vitamin K epoxide reductase (VKORC1), which is activated by redox protein(s). GGCX activity is also supported by the reductases VKORC1-like and ferroptosis suppressor protein-1 (FSP1). Carboxylation occurs in the endoplasmic reticulum during VKD protein secretion and is impacted by quality control mechanisms. This chapter emphasizes the importance in maintaining an appropriate stoichiometry of the components when studying recombinant (r-) r-GGCX function in cells. Also emphasized is the essentiality in using both cellular and biochemical approaches to study r-GGCX function, as cellular analysis can detect altered VKD protein carboxylation by r-GGCX mutants but cannot explain the r-GGCX defects. This point is illustrated by studies on a GGCX mutant that causes the PXE-like disease, where biochemical analysis was necessary for revealing mutant dysfunction, i.e. impaired processivity.
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Affiliation(s)
- Kathleen L Berkner
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States.
| | - Kevin W Hallgren
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States
| | - Mark A Rishavy
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States
| | - Kurt W Runge
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH, United States
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Li Q, Troutman C, Peckiconis M, Wurst T, Terry SF. Inorganic pyrophosphate plasma levels in patients with GGCX-associated PXE-like phenotypes. Front Genet 2024; 15:1429320. [PMID: 39399214 PMCID: PMC11466855 DOI: 10.3389/fgene.2024.1429320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 09/16/2024] [Indexed: 10/15/2024] Open
Abstract
Introduction Pseudoxanthoma elasticum (PXE) is an autosomal recessive ectopic calcification disorder clinically affecting the skin, eyes, and vascular system. Most cases of PXE are caused by inactivating pathogenic variants in the ABCC6 gene encoding a hepatic transmembrane efflux transporter, which facilitates the extracellular release of ATP, the precursor of inorganic pyrophosphate (PPi), a potent endogenous inhibitor of calcification. Pathogenic variants in GGCX, encoding γ-glutamyl carboxylase required for activation of vitamin K-dependent coagulation factors as well as matrix Gla protein (MGP) and Gla-rich protein (GRP), two inhibitors of ectopic calcification, have also been reported to cause cutaneous changes like those seen in PXE. While ectopic calcification in ABCC6 deficiency has been associated with reduced plasma levels of PPi due to loss of ABCC6 transport activity in the liver, plasma PPi levels have not been reported in patients with GGCX-associated phenotypes. Methods We analyzed five patients from three unrelated families on their clinical, laboratory, and molecular findings who carry biallelic variants in GGCX and present with phenotypic characteristics associated with PXE. The variants were identified using a next-generation sequencing panel consisting of 29 genes associated with ectopic calcification. Results and conclusion This study demonstrates that in addition to ABCC6, GGCX variants can cause the PXE phenotype, expanding PXE and perhaps other heritable ectopic calcification disorders' clinical and genetic heterogeneity. The results also show that the plasma concentrations of PPi in these patients are not reduced compared to healthy control individuals, suggesting that plasma PPi does not govern ectopic calcification in GGCX deficiency.
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Affiliation(s)
- Qiaoli Li
- Department of Biochemistry and Molecular Biology, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States
- PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA, United States
| | | | | | - Tamara Wurst
- PXE International, Inc., Damascus, MD, United States
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Clauser S, Calmette L. [How to interpret and pursue a prolonged quick time or APTT]. Rev Med Interne 2024; 45:549-558. [PMID: 38811304 DOI: 10.1016/j.revmed.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 03/20/2024] [Accepted: 05/02/2024] [Indexed: 05/31/2024]
Abstract
The standard hemostasis workup [quick time (QT), and activated partial thrombin time (APTT)] is very commonly prescribed but its interpretation is often difficult for practitioners who are not specialized in hemostasis. Here, we review the principles of the diagnostic approach to these tests. Only a very basic knowledge of the coagulation cascade is necessary to identify which clotting factor tests to prescribe and to interpret the results. Deficiency in several clotting factors suggests liver dysfunction, disseminated intravascular coagulation (DIC) or vitamin K deficiency. If a single factor is deficient, we review the different causes of acquired deficiencies and briefly discuss the characteristics of the different congenital defects, which generally require specialized management. Lupus anticoagulant is a common and generally benign cause of prolonged APTT to be aware of, which is not related to a hemorrhagic risk. A good knowledge of the diagnostic approach to abnormal QT or APTT generally allows the resolution of the most common situations.
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Affiliation(s)
- S Clauser
- Service d'hématologie-immunologie-transfusion, hôpital Ambroise-Paré, AP-HP, 9, avenue Charles-de-Gaulle, 92104 Boulogne-Billancourt cedex, France; UFR des sciences de la santé Simone-Veil, université de Versailles Saint-Quentin-en-Yvelines, 2, avenue de la Source-de-la-Bièvre, 78180 Montigny-le-Bretonneux, France.
| | - L Calmette
- Service d'hématologie-immunologie-transfusion, hôpital Ambroise-Paré, AP-HP, 9, avenue Charles-de-Gaulle, 92104 Boulogne-Billancourt cedex, France
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Rubera I, Clotaire L, Laurain A, Destere A, Martin L, Duranton C, Leftheriotis G. A Plasma Pyrophosphate Cutoff Value for Diagnosing Pseudoxanthoma Elasticum. Int J Mol Sci 2024; 25:6502. [PMID: 38928212 PMCID: PMC11203691 DOI: 10.3390/ijms25126502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/03/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024] Open
Abstract
Pseudoxanthoma elasticum (PXE) is a rare inherited systemic disease responsible for a juvenile peripheral arterial calcification disease. The clinical diagnosis of PXE is only based on a complex multi-organ phenotypic score and/or genetical analysis. Reduced plasma inorganic pyrophosphate concentration [PPi]p has been linked to PXE. In this study, we used a novel and accurate method to measure [PPi]p in one of the largest cohorts of PXE patients, and we reported the valuable contribution of a cutoff value to PXE diagnosis. Plasma samples and clinical records from two French reference centers for PXE (PXE Consultation Center, Angers, and FAVA-MULTI South Competent Center, Nice) were assessed. Plasma PPi were measured in 153 PXE and 46 non-PXE patients. The PPi concentrations in the plasma samples were determined by a new method combining enzymatic and ion chromatography approaches. The best match between the sensitivity and specificity (Youden index) for diagnosing PXE was determined by ROC analysis. [PPi]p were lower in PXE patients (0.92 ± 0.30 µmol/L) than in non-PXE patients (1.61 ± 0.33 µmol/L, p < 0.0001), corresponding to a mean reduction of 43 ± 19% (SD). The PPi cutoff value for diagnosing PXE in all patients was 1.2 µmol/L, with a sensitivity of 83.3% and a specificity of 91.1% (AUC = 0.93), without sex differences. In patients aged <50 years (i.e., the age period for PXE diagnosis), the cutoff PPi was 1.2 µmol/L (sensitivity, specificity, and AUC of 93%, 96%, and 0.97, respectively). The [PPi]p shows high accuracy for diagnosing PXE; thus, quantifying plasma PPi represents the first blood assay for diagnosing PXE.
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Affiliation(s)
- Isabelle Rubera
- University Côte d’Azur, CNRS, LP2M, Labex ICST, 06107 Nice, France; (I.R.); (L.C.); (A.L.); (G.L.)
| | - Laetitia Clotaire
- University Côte d’Azur, CNRS, LP2M, Labex ICST, 06107 Nice, France; (I.R.); (L.C.); (A.L.); (G.L.)
| | - Audrey Laurain
- University Côte d’Azur, CNRS, LP2M, Labex ICST, 06107 Nice, France; (I.R.); (L.C.); (A.L.); (G.L.)
| | - Alexandre Destere
- Pharmacology Department, Nice University Hospital, 06000 Nice, France
- FAVA-MULTI South Competence Center for Rare Arterial Calcifying Disease, Nice University Hospital, 06000 Nice, France
| | - Ludovic Martin
- PXE Reference Center, MAGEC Nord, Angers University Hospital, 49000 Angers, France;
| | - Christophe Duranton
- University Côte d’Azur, CNRS, LP2M, Labex ICST, 06107 Nice, France; (I.R.); (L.C.); (A.L.); (G.L.)
| | - Georges Leftheriotis
- University Côte d’Azur, CNRS, LP2M, Labex ICST, 06107 Nice, France; (I.R.); (L.C.); (A.L.); (G.L.)
- FAVA-MULTI South Competence Center for Rare Arterial Calcifying Disease, Nice University Hospital, 06000 Nice, France
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Kauffenstein G, Martin L, Le Saux O. The Purinergic Nature of Pseudoxanthoma Elasticum. BIOLOGY 2024; 13:74. [PMID: 38392293 PMCID: PMC10886499 DOI: 10.3390/biology13020074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/13/2024] [Accepted: 01/19/2024] [Indexed: 02/24/2024]
Abstract
Pseudoxanthoma Elasticum (PXE) is an inherited disease characterized by elastic fiber calcification in the eyes, the skin and the cardiovascular system. PXE results from mutations in ABCC6 that encodes an ABC transporter primarily expressed in the liver and kidneys. It took nearly 15 years after identifying the gene to better understand the etiology of PXE. ABCC6 function facilitates the efflux of ATP, which is sequentially hydrolyzed by the ectonucleotidases ENPP1 and CD73 into pyrophosphate (PPi) and adenosine, both inhibitors of calcification. PXE, together with General Arterial Calcification of Infancy (GACI caused by ENPP1 mutations) as well as Calcification of Joints and Arteries (CALJA caused by NT5E/CD73 mutations), forms a disease continuum with overlapping phenotypes and shares steps of the same molecular pathway. The explanation of these phenotypes place ABCC6 as an upstream regulator of a purinergic pathway (ABCC6 → ENPP1 → CD73 → TNAP) that notably inhibits mineralization by maintaining a physiological Pi/PPi ratio in connective tissues. Based on a review of the literature and our recent experimental data, we suggest that PXE (and GACI/CALJA) be considered as an authentic "purinergic disease". In this article, we recapitulate the pathobiology of PXE and review molecular and physiological data showing that, beyond PPi deficiency and ectopic calcification, PXE is associated with wide and complex alterations of purinergic systems. Finally, we speculate on the future prospects regarding purinergic signaling and other aspects of this disease.
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Affiliation(s)
- Gilles Kauffenstein
- UMR INSERM 1260, Regenerative Nanomedicine, University of Strasbourg, 67084 Strasbourg, France
| | - Ludovic Martin
- PXE Consultation Center, MAGEC Nord Reference Center for Rare Skin Diseases, Angers University Hospital, 49000 Angers, France
- MITOVASC-UMR CNRS 6015 INSERM 1083, University of Angers, 49000 Angers, France
| | - Olivier Le Saux
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96822, USA
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Xia Z, Yang Y, Liu Z. Progressive Generalized Skin Laxity in a Young Woman. JAMA Dermatol 2023; 159:880-881. [PMID: 37405727 DOI: 10.1001/jamadermatol.2023.1671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/06/2023]
Abstract
A Chinese woman in her late 20s presented with a 20-year history of progressive skin laxity. What is your diagnosis?
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Affiliation(s)
- Zenan Xia
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuyan Yang
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China
| | - Zhifei Liu
- Department of Plastic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Manole S, Rancea R, Vulturar R, Simon SP, Molnar A, Damian L. Frail Silk: Is the Hughes-Stovin Syndrome a Behçet Syndrome Subtype with Aneurysm-Involved Gene Variants? Int J Mol Sci 2023; 24:ijms24043160. [PMID: 36834577 PMCID: PMC9968083 DOI: 10.3390/ijms24043160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/21/2023] [Accepted: 01/31/2023] [Indexed: 02/08/2023] Open
Abstract
Hughes-Stovin syndrome is a rare disease characterized by thrombophlebitis and multiple pulmonary and/or bronchial aneurysms. The etiology and pathogenesis of HSS are incompletely known. The current consensus is that vasculitis underlies the pathogenic process, and pulmonary thrombosis follows arterial wall inflammation. As such, Hughes-Stovin syndrome may belong to the vascular cluster with lung involvement of Behçet syndrome, although oral aphtae, arthritis, and uveitis are rarely found. Behçet syndrome is a multifactorial polygenic disease with genetic, epigenetic, environmental, and mostly immunological contributors. The different Behçet syndrome phenotypes are presumably based upon different genetic determinants involving more than one pathogenic pathway. Hughes-Stovin syndrome may have common pathways with fibromuscular dysplasias and other diseases evolving with vascular aneurysms. We describe a Hughes-Stovin syndrome case fulfilling the Behçet syndrome criteria. A MYLK variant of unknown significance was detected, along with other heterozygous mutations in genes that may impact angiogenesis pathways. We discuss the possible involvement of these genetic findings, as well as other potential common determinants of Behçet/Hughes-Stovin syndrome and aneurysms in vascular Behçet syndrome. Recent advances in diagnostic techniques, including genetic testing, could help diagnose a specific Behçet syndrome subtype and other associated conditions to personalize the disease management.
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Affiliation(s)
- Simona Manole
- Department of Radiology, “Niculae Stăncioiu” Heart Institute, 19-21 Calea Moților Street, 400001 Cluj-Napoca, Romania
- Department of Radiology, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Raluca Rancea
- Cardiology Department, Heart Institute “Niculae Stăncioiu”, 19-21 Calea Moților Street, 400001 Cluj-Napoca, Romania
| | - Romana Vulturar
- Department of Molecular Sciences, “Iuliu Hatieganu” University of Medicine and Pharmacy 6, Pasteur, 400349 Cluj-Napoca, Romania
- Cognitive Neuroscience Laboratory, University Babes-Bolyai, 30, Fântânele Street, 400294 Cluj-Napoca, Romania
- Correspondence:
| | - Siao-Pin Simon
- Department of Rheumatology, Emergency Clinical County Hospital Cluj, Centre for Rare Autoimmune and Autoinflammatory Diseases (ERN-ReCONNET), 2-4 Clinicilor Street, 400347 Cluj-Napoca, Romania
- Discipline of Rheumatology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400347 Cluj-Napoca, Romania
| | - Adrian Molnar
- Department of Cardiovascular Surgery, Heart Institute “Niculae Stăncioiu”, 19-21 Calea Moților Street, 400001 Cluj-Napoca, Romania
- Department of Cardiovascular and Thoracic Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania
| | - Laura Damian
- Department of Rheumatology, Emergency Clinical County Hospital Cluj, Centre for Rare Autoimmune and Autoinflammatory Diseases (ERN-ReCONNET), 2-4 Clinicilor Street, 400347 Cluj-Napoca, Romania
- CMI Reumatologie Dr. Damian, 6-8 Petru Maior Street, 400002 Cluj-Napoca, Romania
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Zarkasi KA, Abdullah N, Abdul Murad NA, Ahmad N, Jamal R. Genetic Factors for Coronary Heart Disease and Their Mechanisms: A Meta-Analysis and Comprehensive Review of Common Variants from Genome-Wide Association Studies. Diagnostics (Basel) 2022; 12:2561. [PMID: 36292250 PMCID: PMC9601486 DOI: 10.3390/diagnostics12102561] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/18/2022] [Accepted: 10/20/2022] [Indexed: 11/17/2022] Open
Abstract
Genome-wide association studies (GWAS) have discovered 163 loci related to coronary heart disease (CHD). Most GWAS have emphasized pathways related to single-nucleotide polymorphisms (SNPs) that reached genome-wide significance in their reports, while identification of CHD pathways based on the combination of all published GWAS involving various ethnicities has yet to be performed. We conducted a systematic search for articles with comprehensive GWAS data in the GWAS Catalog and PubMed, followed by a meta-analysis of the top recurring SNPs from ≥2 different articles using random or fixed-effect models according to Cochran Q and I2 statistics, and pathway enrichment analysis. Meta-analyses showed significance for 265 of 309 recurring SNPs. Enrichment analysis returned 107 significant pathways, including lipoprotein and lipid metabolisms (rs7412, rs6511720, rs11591147, rs1412444, rs11172113, rs11057830, rs4299376), atherogenesis (rs7500448, rs6504218, rs3918226, rs7623687), shared cardiovascular pathways (rs72689147, rs1800449, rs7568458), diabetes-related pathways (rs200787930, rs12146487, rs6129767), hepatitis C virus infection/hepatocellular carcinoma (rs73045269/rs8108632, rs56062135, rs188378669, rs4845625, rs11838776), and miR-29b-3p pathways (rs116843064, rs11617955, rs146092501, rs11838776, rs73045269/rs8108632). In this meta-analysis, the identification of various genetic factors and their associated pathways associated with CHD denotes the complexity of the disease. This provides an opportunity for the future development of novel CHD genetic risk scores relevant to personalized and precision medicine.
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Affiliation(s)
- Khairul Anwar Zarkasi
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Biochemistry Unit, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (UPNM), Kuala Lumpur 57000, Malaysia
| | - Noraidatulakma Abdullah
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
- Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Nor Azian Abdul Murad
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Norfazilah Ahmad
- Epidemiology and Statistics Unit, Department of Community Health, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia
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13
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Rishavy MA, Hallgren KW, Wilson LA, Hiznay JM, Runge KW, Berkner KL. GGCX mutants that impair hemostasis reveal the importance of processivity and full carboxylation to VKD protein function. Blood 2022; 140:1710-1722. [PMID: 35767717 PMCID: PMC9707401 DOI: 10.1182/blood.2021014275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 06/09/2022] [Indexed: 12/14/2022] Open
Abstract
γ-Glutamyl carboxylase (GGCX) generates multiple carboxylated Glus (Glas) in vitamin K-dependent (VKD) proteins that are required for their functions. GGCX is processive, remaining bound to VKD proteins throughout multiple Glu carboxylations, and this study reveals the essentiality of processivity to VKD protein function. GGCX mutants (V255M and S300F) whose combined heterozygosity in a patient causes defective clotting and calcification were studied using a novel assay that mimics in vivo carboxylation. Complexes between variant carboxylases and VKD proteins important to hemostasis (factor IX [FIX]) or calcification (matrix Gla protein [MGP]) were reacted in the presence of a challenge VKD protein that could potentially interfere with carboxylation of the VKD protein in the complex. The VKD protein in the complex with wild-type carboxylase was carboxylated before challenge protein carboxylation occurred and became fully carboxylated. In contrast, the V255M mutant carboxylated both forms at the same time and did not completely carboxylate FIX in the complex. S300F carboxylation was poor with both FIX and MGP. Additional studies analyzed FIX- and MGP-derived peptides containing the Gla domain linked to sequences that mediate carboxylase binding. The total amount of carboxylated peptide generated by the V255M mutant was higher than that of wild-type GGCX; however, the individual peptides were partially carboxylated. Analysis of the V255M mutant in FIX HEK293 cells lacking endogenous GGCX revealed poor FIX clotting activity. This study shows that disrupted processivity causes disease and explains the defect in the patient. Kinetic analyses also suggest that disrupted processivity may occur in wild-type carboxylase under some conditions (eg, warfarin therapy or vitamin K deficiency).
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Affiliation(s)
- Mark A. Rishavy
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
| | - Kevin W. Hallgren
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
| | - Lee A. Wilson
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
| | - James M. Hiznay
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
| | - Kurt W. Runge
- Department of Inflammation and Immunity, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
| | - Kathleen L. Berkner
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH
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14
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Berkner KL, Runge KW. Vitamin K-Dependent Protein Activation: Normal Gamma-Glutamyl Carboxylation and Disruption in Disease. Int J Mol Sci 2022; 23:5759. [PMID: 35628569 PMCID: PMC9146348 DOI: 10.3390/ijms23105759] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 05/11/2022] [Accepted: 05/14/2022] [Indexed: 12/12/2022] Open
Abstract
Vitamin K-dependent (VKD) proteins undergo an unusual post-translational modification, which is the conversion of specific Glu residues to carboxylated Glu (Gla). Gla generation is required for the activation of VKD proteins, and occurs in the endoplasmic reticulum during their secretion to either the cell surface or from the cell. The gamma-glutamyl carboxylase produces Gla using reduced vitamin K, which becomes oxygenated to vitamin K epoxide. Reduced vitamin K is then regenerated by a vitamin K oxidoreductase (VKORC1), and this interconversion of oxygenated and reduced vitamin K is referred to as the vitamin K cycle. Many of the VKD proteins support hemostasis, which is suppressed during therapy with warfarin that inhibits VKORC1 activity. VKD proteins also impact a broad range of physiologies beyond hemostasis, which includes regulation of calcification, apoptosis, complement, growth control, signal transduction and angiogenesis. The review covers the roles of VKD proteins, how they become activated, and how disruption of carboxylation can lead to disease. VKD proteins contain clusters of Gla residues that form a calcium-binding module important for activity, and carboxylase processivity allows the generation of multiple Glas. The review discusses how impaired carboxylase processivity results in the pseudoxanthoma elasticum-like disease.
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Affiliation(s)
- Kathleen L. Berkner
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH 44195, USA
| | - Kurt W. Runge
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Lerner College of Medicine at CWRU, Cleveland, OH 44195, USA;
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15
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Ghosh S, Oldenburg J, Czogalla-Nitsche KJ. The Role of GRP and MGP in the Development of Non-Hemorrhagic VKCFD1 Phenotypes. Int J Mol Sci 2022; 23:798. [PMID: 35054981 PMCID: PMC8775833 DOI: 10.3390/ijms23020798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/05/2022] [Accepted: 01/08/2022] [Indexed: 11/21/2022] Open
Abstract
Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-Glutamyl carboxylase (GGCX) gene. The GGCX enzyme catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins, which have function in blood coagulation, calcification, and cell signaling. Therefore, in addition to bleedings, some VKCFD1 patients develop diverse non-hemorrhagic phenotypes such as skin hyper-laxity, skeletal dysmorphologies, and/or cardiac defects. Recent studies showed that GGCX mutations differentially effect γ-carboxylation of VKD proteins, where clotting factors are sufficiently γ-carboxylated, but not certain non-hemostatic VKD proteins. This could be one reason for the development of diverse phenotypes. The major manifestation of non-hemorrhagic phenotypes in VKCFD1 patients are mineralization defects. Therefore, the mechanism of regulation of calcification by specific VKD proteins as matrix Gla protein (MGP) and Gla-rich protein (GRP) in physiological and pathological conditions is of high interest. This will also help to understand the patho-mechanism of VKCFD1 phenotypes and to deduce new treatment strategies. In the present review article, we have summarized the recent findings on the function of GRP and MGP and how these proteins influence the development of non-hemorrhagic phenotypes in VKCFD1 patients.
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Affiliation(s)
- Suvoshree Ghosh
- Institute of Experimental Haematology and Transfusion Medicine, Venusberg Campus 1, University Clinic Bonn, 53127 Bonn, Germany; (S.G.); (J.O.)
| | - Johannes Oldenburg
- Institute of Experimental Haematology and Transfusion Medicine, Venusberg Campus 1, University Clinic Bonn, 53127 Bonn, Germany; (S.G.); (J.O.)
- Center for Rare Diseases Bonn, Venusberg Campus 1, University Clinic Bonn, 53127 Bonn, Germany
| | - Katrin J. Czogalla-Nitsche
- Institute of Experimental Haematology and Transfusion Medicine, Venusberg Campus 1, University Clinic Bonn, 53127 Bonn, Germany; (S.G.); (J.O.)
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16
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Bus K, Szterk A. Relationship between Structure and Biological Activity of Various Vitamin K Forms. Foods 2021; 10:foods10123136. [PMID: 34945687 PMCID: PMC8701896 DOI: 10.3390/foods10123136] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 01/06/2023] Open
Abstract
Vitamin K is involved many biological processes, such as the regulation of blood coagulation, prevention of vascular calcification, bone metabolism and modulation of cell proliferation. Menaquinones (MK) and phylloquinone vary in biological activity, showing different bioavailability, half-life and transport mechanisms. Vitamin K1 and MK-4 remain present in the plasma for 8–24 h, whereas long-chain menaquinones can be detected up to 96 h after administration. Geometric structure is also an important factor that conditions their properties. Cis-phylloquinone shows nearly no biological activity. An equivalent study for menaquinone is not available. The effective dose to decrease uncarboxylated osteocalcin was six times lower for MK-7 than for MK-4. Similarly, MK-7 affected blood coagulation system at dose three to four times lower than vitamin K1. Both vitamin K1 and MK-7 inhibited the decline in bone mineral density, however benefits for the occurrence of cardiovascular diseases have been observed only for long-chain menaquinones. There are currently no guidelines for the recommended doses and forms of vitamin K in the prevention of osteoporosis, atherosclerosis and other cardiovascular disorders. Due to the presence of isomers with unknown biological properties in some dietary supplements, quality and safety of that products may be questioned.
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Affiliation(s)
- Katarzyna Bus
- Department of Spectrometric Methods, National Medicines Institute, 30/34 Chełmska, 00-725 Warsaw, Poland
- Correspondence:
| | - Arkadiusz Szterk
- Center for Translational Medicine, Warsaw University of Life Sciences, Nowoursynowska 100, 02-797 Warsaw, Poland;
- Transfer of Science Sp. z o.o., Strzygłowska 15, 04-866 Warsaw, Poland
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17
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Therapy of Pseudoxanthoma Elasticum: Current Knowledge and Future Perspectives. Biomedicines 2021; 9:biomedicines9121895. [PMID: 34944710 PMCID: PMC8698611 DOI: 10.3390/biomedicines9121895] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/05/2021] [Accepted: 12/07/2021] [Indexed: 12/24/2022] Open
Abstract
Pseudoxanthoma elasticum (PXE) is a rare, genetic, metabolic disease with an estimated prevalence of between 1 per 25,000 and 56,000. Its main hallmarks are characteristic skin lesions, development of choroidal neovascularization, and early-onset arterial calcification accompanied by a severe reduction in quality-of-life. Underlying the pathology are recessively transmitted pathogenic variants of the ABCC6 gene, which results in a deficiency of ABCC6 protein. This results in reduced levels of peripheral pyrophosphate, a strong inhibitor of peripheral calcification, but also dysregulation of blood lipids. Although various treatment options have emerged during the last 20 years, many are either already outdated or not yet ready to be applied generally. Clinical physicians often are left stranded while patients suffer from the consequences of outdated therapies, or feel unrecognized by their attending doctors who may feel uncertain about using new therapeutic approaches or not even know about them. In this review, we summarize the broad spectrum of treatment options for PXE, focusing on currently available clinical options, the latest research and development, and future perspectives.
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18
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Ghosh S, Kraus K, Biswas A, Müller J, Forin F, Singer H, Höning K, Hornung V, Watzka M, Oldenburg J, Czogalla-Nitsche KJ. GGCX variants leading to biallelic deficiency to γ-carboxylate GRP cause skin laxity in VKCFD1 patients. Hum Mutat 2021; 43:42-55. [PMID: 34816548 DOI: 10.1002/humu.24300] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 09/06/2021] [Accepted: 10/19/2021] [Indexed: 12/17/2022]
Abstract
γ-Glutamyl carboxylase (GGCX) catalyzes the γ-carboxylation of 15 different vitamin K dependent (VKD) proteins. Pathogenic variants in GGCX cause a rare hereditary bleeding disorder called Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1). In addition to bleedings, some VKCFD1 patients develop skin laxity and skeletal dysmorphologies. However, the pathophysiological mechanisms underlying these non-hemorrhagic phenotypes remain elusive. Therefore, we have analyzed 20 pathogenic GGCX variants on their ability to γ-carboxylate six non-hemostatic VKD proteins in an in vitro assay, where GGCX variants were expressed in GGCX-/- cells and levels of γ-carboxylated co-expressed VKD proteins were detected by a functional ELISA. We observed that GGCX variants causing markedly reduced γ-carboxylation of Gla rich protein (GRP) in vitro were reported in patients with skin laxity. Reduced levels of γ-carboxylated Matrix gla protein (MGP) are not exclusive for causing skeletal dysmorphologies in VKCFD1 patients. In silico docking of vitamin K hydroquinone on a GGCX model revealed a binding site, which was validated by in vitro assays. GGCX variants affecting this site result in disability to γ-carboxylate VKD proteins and hence are involved in the most severe phenotypes. This genotype-phenotype analysis will help to understand the development of non-hemorrhagic phenotypes and hence improve treatment in VKCFD1 patients.
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Affiliation(s)
- Suvoshree Ghosh
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Katrin Kraus
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Arijit Biswas
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Jens Müller
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Francesco Forin
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Heike Singer
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Klara Höning
- Unit for Clinical Biochemistry, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany
| | - Veit Hornung
- Unit for Clinical Biochemistry, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital, University of Bonn, Bonn, Germany.,GeneCenter and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Matthias Watzka
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.,Center for Rare Diseases Bonn, University Clinic Bonn, Bonn, Germany
| | - Johannes Oldenburg
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.,Center for Rare Diseases Bonn, University Clinic Bonn, Bonn, Germany
| | - Katrin J Czogalla-Nitsche
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
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19
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Beyens A, Pottie L, Sips P, Callewaert B. Clinical and Molecular Delineation of Cutis Laxa Syndromes: Paradigms for Homeostasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:273-309. [PMID: 34807425 DOI: 10.1007/978-3-030-80614-9_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Cutis laxa (CL) syndromes are a large and heterogeneous group of rare connective tissue disorders that share loose redundant skin as a hallmark clinical feature, which reflects dermal elastic fiber fragmentation. Both acquired and congenital-Mendelian- forms exist. Acquired forms are progressive and often preceded by inflammatory triggers in the skin, but may show systemic elastolysis. Mendelian forms are often pleiotropic in nature and classified upon systemic manifestations and mode of inheritance. Though impaired elastogenesis is a common denominator in all Mendelian forms of CL, the underlying gene defects are diverse and affect structural components of the elastic fiber or impair metabolic pathways interfering with cellular trafficking, proline synthesis, or mitochondrial functioning. In this chapter we provide a detailed overview of the clinical and molecular characteristics of the different cutis laxa types and review the latest insights on elastic fiber assembly and homeostasis from both human and animal studies.
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Affiliation(s)
- Aude Beyens
- Center for Medical Genetics Ghent, Department of Dermatology, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium
| | - Lore Pottie
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Patrick Sips
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Bert Callewaert
- Center for Medical Genetics Ghent, Department of Biomolecular Medicine, Ghent University Hospital, Ghent University, Ghent, Belgium.
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20
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Mathonnet A, Cunat S, Allias F, Caillot S, Thonnon C, Till M, Attié-Bitach T, Touraine R, Meunier S, Cartellier C, Rossi M, Attia J, Putoux A. GGCX-related congenital combined vitamin K-dependent clotting factors deficiency-1: Description of a fetus with chondrodysplasia punctata. Am J Med Genet A 2021; 188:314-318. [PMID: 34558179 DOI: 10.1002/ajmg.a.62503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 07/01/2021] [Accepted: 08/05/2021] [Indexed: 11/06/2022]
Abstract
Congenital combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare autosomal recessive disease resulting in hemorrhagic symptoms usually associated with developmental disorders and bone abnormalities. Pathogenic variants in two genes encoding enzymes of the vitamin K cycle, GGCX and VKORC1, can lead to this disorder. We present the case of a male fetus with a brachytelephalangic chondrodysplasia punctata (CDP), absence of nasal bone, growth restriction, and bilateral ventriculomegaly at 18 weeks of gestation. Pathological examination showed a Binder phenotype, hypoplastic distal phalanges, stippled epiphyses, and brain abnormalities suggestive of a brain hemorrhage. Two GGCX pathogenic variants inherited respectively from the mother and the father were identified. To our knowledge, this is the first prenatal description of VKCFD. Even if it remains a rare etiology, which is mostly described in children or adult patients, VKCFD should be considered in fetuses with CDP.
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Affiliation(s)
- Alix Mathonnet
- Hospices Civils de Lyon, Centre Pluridisciplinaire de Diagnostic Prénatal, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Séverine Cunat
- Département d'Hématologie Biologique, Hôpital Saint Eloi, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Fabienne Allias
- Hospices Civils de Lyon, Service d'Anatomo-Pathologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Sandrine Caillot
- Hospices Civils de Lyon, Centre Pluridisciplinaire de Diagnostic Prénatal, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Cyrielle Thonnon
- Hospices Civils de Lyon, Centre Pluridisciplinaire de Diagnostic Prénatal, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Marianne Till
- Hospices Civils de Lyon, Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétence Maladies Osseuses Constitutionnelles, Groupement Hospitalier Est, Bron, France
| | - Tania Attié-Bitach
- Service d'Histologie-Embryologie-Cytogenetique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.,INSERM UMR1163, Imagine Institute, Université de Paris, Paris, France
| | | | - Sandrine Meunier
- Hospices Civils de Lyon, Unité d'Hémostase Clinique, Centre de Référence Maladies Hémorragiques Constitutionnelles (CR-MHC), Hôpital Cardiologique, Bron, France
| | - Charline Cartellier
- Hospices Civils de Lyon, Centre Pluridisciplinaire de Diagnostic Prénatal, Hôpital Femme Mère Enfant, Bron, France
| | - Massimiliano Rossi
- Hospices Civils de Lyon, Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétence Maladies Osseuses Constitutionnelles, Groupement Hospitalier Est, Bron, France.,Équipe GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028 CNRS UMR5292, Université Claude Bernard Lyon 1, Lyon, France
| | - Jocelyne Attia
- Hospices Civils de Lyon, Centre Pluridisciplinaire de Diagnostic Prénatal, Centre Hospitalier Lyon Sud, Pierre Bénite, France
| | - Audrey Putoux
- Hospices Civils de Lyon, Service de Génétique, Centre de Référence Anomalies du Développement et Centre de Compétence Maladies Osseuses Constitutionnelles, Groupement Hospitalier Est, Bron, France.,Équipe GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028 CNRS UMR5292, Université Claude Bernard Lyon 1, Lyon, France
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21
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Ghosh S, Kraus K, Biswas A, Müller J, Buhl AL, Forin F, Singer H, Höning K, Hornung V, Watzka M, Czogalla-Nitsche KJ, Oldenburg J. GGCX mutations show different responses to vitamin K thereby determining the severity of the hemorrhagic phenotype in VKCFD1 patients. J Thromb Haemost 2021; 19:1412-1424. [PMID: 33590680 DOI: 10.1111/jth.15238] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/22/2020] [Accepted: 01/04/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND Vitamin K dependent coagulation factor deficiency type 1 (VKCFD1) is a rare hereditary bleeding disorder caused by mutations in γ-glutamyl carboxylase (GGCX). VKCFD1 patients are treated life-long with high doses of vitamin K in order to correct the bleeding phenotype. However, normalization of clotting factor activities cannot be achieved for all VKCFD1 patients. OBJECTIVE The current study aims to investigate the responsiveness to vitamin K for all reported GGCX mutations with respect to clotting factors in order to optimize treatment. METHODS This study developed an assay using genetically engineered GGCX-/- cells, in which GGCX mutations were analyzed with respect to their ability to γ-carboxylate vitamin K dependent pro-coagulatory and anti-coagulatory clotting factors by ELISA. Additionally, factor VII activity was measured in order to proof protein functionality. For specific GGCX mutations immunofluorescent staining was performed to assess the intracellular localization of clotting factors with respect to GGCX wild-type and mutations. RESULTS All GGCX mutations were categorized into responder and low responder mutations, thereby determining the efficiency of vitamin K supplementation. Most VKCFD1 patients have at least one vitamin K responsive GGCX allele that is able to γ-carboxylate clotting factors. In few patients, the hemorrhagic phenotype cannot be reversed by vitamin K administration because GGCX mutations on both alleles affect either structural or catalytically important sites thereby resulting in residual ability to γ-carboxylate clotting factors. CONCLUSION With these new functional data we can predict the hemorrhagic outcome of each VKCFD1 genotype, thus recommending treatments with either vitamin K or prothrombin complex concentrate.
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Affiliation(s)
- Suvoshree Ghosh
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Katrin Kraus
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Arijit Biswas
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Jens Müller
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Anna-Lena Buhl
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Francesco Forin
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Heike Singer
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Klara Höning
- Institute for Clinical Chemistry and Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, Bonn, Germany
| | - Veit Hornung
- Institute for Clinical Chemistry and Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, Bonn, Germany
- GeneCenter and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Matthias Watzka
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
- Center for Rare Diseases Bonn, University Clinic Bonn, Bonn, Germany
| | - Katrin J Czogalla-Nitsche
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
| | - Johannes Oldenburg
- Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany
- Center for Rare Diseases Bonn, University Clinic Bonn, Bonn, Germany
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22
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Shimada BK, Pomozi V, Zoll J, Kuo S, Martin L, Le Saux O. ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions. Int J Mol Sci 2021; 22:ijms22094555. [PMID: 33925341 PMCID: PMC8123679 DOI: 10.3390/ijms22094555] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022] Open
Abstract
Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.
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Affiliation(s)
- Briana K Shimada
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96817, USA
| | - Viola Pomozi
- Institute of Enzymology, RCNS, Hungarian Academy of Sciences, 1117 Budapest, Hungary
| | - Janna Zoll
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96817, USA
| | - Sheree Kuo
- Department of Pediatrics, Kapi'olani Medical Center for Women and Children, University of Hawaii, Honolulu, HI 96826, USA
| | - Ludovic Martin
- PXE Consultation Center, MAGEC Reference Center for Rare Skin Diseases, Angers University Hospital, 49100 Angers, France
- BNMI, CNRS 6214/INSERM 1083, University Bretagne-Loire, 49100 Angers, France
| | - Olivier Le Saux
- Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96817, USA
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23
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Steyaert W, Verschuere S, Coucke PJ, Vanakker OM. Comprehensive validation of a diagnostic strategy for sequencing genes with one or multiple pseudogenes using pseudoxanthoma elasticum as a model. J Genet Genomics 2021; 48:289-299. [PMID: 34049798 DOI: 10.1016/j.jgg.2021.02.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/03/2021] [Accepted: 02/09/2021] [Indexed: 10/21/2022]
Abstract
Pseudogenes are frequently encountered noncoding sequences with a high sequence similarity to their protein-coding paralogue. For this reason, their presence is often considered troublesome in molecular diagnostics. In pseudoxanthoma elasticum (PXE), a disease predominantly caused by mutations in ATP-binding cassette family C member 6 (ABCC6), the presence of two pseudogenes complicates the analysis of sequence data. With whole-exome sequencing (WES) becoming the standard of care in molecular diagnostics, we wanted to evaluate whether this technique is as reliable as gene-specific targeted enrichment analysis for the analysis of ABCC6. We established a PCR-based targeted enrichment and next-generation sequencing testing approach and demonstrated that the ABCC6-specific enrichment combined with the applied mapping algorithm overcomes the complication of ABCC6 pseudogene aspecificities, contrary to WES. We propose a time- and cost-efficient diagnostic strategy for comprehensive and accurate molecular genetic testing of PXE, which is highly automatable.
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Affiliation(s)
- Wouter Steyaert
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Shana Verschuere
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Paul J Coucke
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Olivier M Vanakker
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
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24
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Hao Z, Jin DY, Chen X, Schurgers LJ, Stafford DW, Tie JK. γ-Glutamyl carboxylase mutations differentially affect the biological function of vitamin K-dependent proteins. Blood 2021; 137:533-543. [PMID: 33507293 PMCID: PMC7845004 DOI: 10.1182/blood.2020006329] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/28/2020] [Indexed: 12/14/2022] Open
Abstract
γ-Glutamyl carboxylase (GGCX) is an integral membrane protein that catalyzes posttranslational carboxylation of a number of vitamin K-dependent (VKD) proteins involved in a wide variety of physiologic processes, including blood coagulation, vascular calcification, and bone metabolism. Naturally occurring GGCX mutations are associated with multiple distinct clinical phenotypes. However, the genotype-phenotype correlation of GGCX remains elusive. Here, we systematically examined the effect of all naturally occurring GGCX mutations on the carboxylation of 3 structure-function distinct VKD proteins in a cellular environment. GGCX mutations were transiently introduced into GGCX-deficient human embryonic kidney 293 cells stably expressing chimeric coagulation factor, matrix Gla protein (MGP), or osteocalcin as VKD reporter proteins, and then the carboxylation efficiency of these reporter proteins was evaluated. Our results show that GGCX mutations differentially affect the carboxylation of these reporter proteins and the efficiency of using vitamin K as a cofactor. Carboxylation of these reporter proteins by a C-terminal truncation mutation (R704X) implies that GGCX's C terminus plays a critical role in the binding of osteocalcin but not in the binding of coagulation factors and MGP. This has been confirmed by probing the protein-protein interaction between GGCX and its protein substrates in live cells using bimolecular fluorescence complementation and chemical cross-linking assays. Additionally, using a minigene splicing assay, we demonstrated that several GGCX missense mutations affect GGCX's pre-messenger RNA splicing rather than altering the corresponding amino acid residues. Results from this study interpreted the correlation of GGCX's genotype and its clinical phenotypes and clarified why vitamin K administration rectified bleeding disorders but not nonbleeding disorders.
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Affiliation(s)
- Zhenyu Hao
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and
| | - Da-Yun Jin
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and
| | - Xuejie Chen
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and
| | - Leon J Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands
| | - Darrel W Stafford
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and
| | - Jian-Ke Tie
- Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC; and
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25
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Molecular Genetics and Modifier Genes in Pseudoxanthoma Elasticum, a Heritable Multisystem Ectopic Mineralization Disorder. J Invest Dermatol 2020; 141:1148-1156. [PMID: 33341249 DOI: 10.1016/j.jid.2020.10.013] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/19/2020] [Accepted: 10/23/2020] [Indexed: 01/08/2023]
Abstract
In the past two decades, there has been great progress in identifying the molecular basis and pathomechanistic details in pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic mineralization disorder. Although the identification of pathogenic variants in ABCC6 has been critical for understanding the disease process, genetic modifiers have been disclosed that explain the phenotypic heterogeneity of PXE. Adding to the genetic complexity of PXE are PXE-like phenotypes caused by pathogenic variants in other ectopic mineralization-associated genes. This review summarizes the current knowledge of the genetics and candidate modifier genes in PXE, a multifactorial disease at the genome-environment interface.
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26
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Naima J, Abir RA, Hosen MJ. Homology Modeling and Virtual Screening of Proteins Related to PXE and PXE-like Diseases: Insights for Overlapping Metabolites. Curr Pharm Biotechnol 2020; 21:1470-1478. [DOI: 10.2174/1389201021666200519115032] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/28/2020] [Accepted: 05/20/2020] [Indexed: 11/22/2022]
Abstract
Background:
The molecular etiology of Pseudoxanthoma Elasticum (PXE), an autosomal
recessive connective tissue disorder, has become increasingly complex as not only mutations in the
ABCC6, but also in ENPP1 and GGCX, can cause resembling phenotypes.
Methods:
To get insights on the common pathway, the overlapping metabolites for these three proteins
were predicted through 3D homology modeling and virtual screening. 3D homology models of
ABCC6, ENPP1, and GGCX were generated by the MODELLER program, which were further validated
using RAMPAGE and ERRAT servers. Substrate binding sites of ABCC6 were predicted using
blind docking of reported in vitro substrates.
Results:
Virtual screening against the substrate binding site of ABCC6 using metabolites listed in Human
Metabolome Databases (HMDB) revealed the best possible substrate of ABCC6. Those listed metabolites
were further docked against predicted substrate binding sites of GGCX and ENPP1. Molecular
docking and virtual screening revealed a list of 133 overlapping metabolites of these three proteins.
Most of them are Phosphatidylinositol (PI), Phosphatidylserine (PS), Diacylglycerol (DAG), phosphatidic
acid, oleanolic acid metabolites and were found to have links with calcification.
Conclusion:
These predicted overlapping metabolites may give novel insights for searching common
pathomechanism for PXE and PXE-like diseases.
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Affiliation(s)
- Jannatul Naima
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science & Technology, Sylhet, Bangladesh
| | - Ruhshan A. Abir
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science & Technology, Sylhet, Bangladesh
| | - Mohammad J. Hosen
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science & Technology, Sylhet, Bangladesh
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27
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Verschuere S, Van Gils M, Nollet L, Vanakker OM. From membrane to mineralization: the curious case of the ABCC6 transporter. FEBS Lett 2020; 594:4109-4133. [PMID: 33131056 DOI: 10.1002/1873-3468.13981] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 12/13/2022]
Abstract
ATP-binding cassette subfamily C member 6 gene/protein (ABCC6) is an ATP-dependent transmembrane transporter predominantly expressed in the liver and the kidney. ABCC6 first came to attention in human medicine when it was discovered in 2000 that mutations in its encoding gene, ABCC6, caused the autosomal recessive multisystemic mineralization disease pseudoxanthoma elasticum (PXE). Since then, the physiological and pathological roles of ABCC6 have been the subject of intense research. In the last 20 years, significant findings have clarified ABCC6 structure as well as its physiological role in mineralization homeostasis in humans and animal models. Yet, several facets of ABCC6 biology remain currently incompletely understood, ranging from the precise nature of its substrate(s) to the increasingly complex molecular genetics. Nonetheless, advances in our understanding of pathophysiological mechanisms causing mineralization lead to several treatment options being suggested or already tested in pilot clinical trials for ABCC6 deficiency. This review highlights current knowledge of ABCC6 and the challenges ahead, particularly the attempts to translate basic science into clinical practice.
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Affiliation(s)
- Shana Verschuere
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Matthias Van Gils
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Lukas Nollet
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
| | - Olivier M Vanakker
- Center for Medical Genetics, Ghent University Hospital, Belgium.,Department of Biomolecular Medicine, Ghent University, Belgium.,Ectopic Mineralization Research Group Ghent, Ghent, Belgium
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28
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Beyens A, Boel A, Symoens S, Callewaert B. Cutis laxa: A comprehensive overview of clinical characteristics and pathophysiology. Clin Genet 2020; 99:53-66. [PMID: 33058140 DOI: 10.1111/cge.13865] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 09/17/2020] [Accepted: 10/07/2020] [Indexed: 12/20/2022]
Abstract
Cutis laxa (CL) syndromes comprise a rare group of multisystem disorders that share loose redundant skin folds as hallmark clinical feature. CL results from impaired elastic fiber assembly and homeostasis, and the known underlying gene defects affect different extracellular matrix proteins, intracellular trafficking, or cellular metabolism. Due to the underlying clinical and molecular heterogeneity, the diagnostic work-up of CL patients is often challenging. In this review, we provide a practical approach to the broad differential diagnosis of CL syndromes, provide an overview of the molecular pathogenesis of the different subtypes, and suggest general management guidelines.
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Affiliation(s)
- Aude Beyens
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Annekatrien Boel
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Sofie Symoens
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Bert Callewaert
- Center for Medical Genetics Ghent, Ghent University Hospital, Ghent, Belgium.,Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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29
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Li D, Ryu E, Saeidian AH, Youssefian L, Oliphant E, Terry SF, Tong PL, Uitto J, Haass NK, Li Q. GGCX mutations in a patient with overlapping pseudoxanthoma elasticum/cutis laxa-like phenotype. Br J Dermatol 2020; 184:1170-1174. [PMID: 33000479 DOI: 10.1111/bjd.19576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/15/2022]
Abstract
Pseudoxanthoma elasticum (PXE) is a multisystem disorder characterized by ectopic mineralization of connective tissues with primary manifestations in the skin, eyes and the cardiovascular system. The classic forms of PXE are caused by mutations in the ABCC6 gene encoding the ABCC6 protein, expressed primarily in the liver. Cutis laxa (CL) manifests with loose and sagging skin with loss of recoil. In 2009 we investigated a 19-year-old patient with overlapping cutaneous features of PXE and CL, together with alpha thalassaemia. Genetic analysis failed to identify pathogenic mutations in ABCC6. More recently we developed a gene-targeted panel of next-generation sequencing technology. This panel has 29 genes, 22 of which, including ABCC6 and GGCX, are associated with ectopic mineralization phenotypes. Mutation analysis in the patient identified two heterozygous GGCX mutations: c.200_201delTT in exon 2 and c.763G>A, p.V255M in exon 7. The GGCX gene encodes a γ-glutamyl carboxylase necessary for activation of blood coagulation factors in the liver. The p.V255M mutation was previously reported to result in reduced γ-glutamyl carboxylase activity in vitro, while the c.200_201delTT mutation is novel. Previous studies reported that mutations in GGCX cause overlapping PXE/CL skin phenotypes in association with or without multiple vitamin K-dependent coagulation factor deficiency. Our patient had loose redundant skin, moderate-to-severe angioid streaks and characteristic calcification of elastic structures in the mid dermis, consistent with PXE/CL overlap, but no coagulation abnormalities. Our studies expand the GGCX mutation landscape in patients with PXE-like phenotypes.
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Affiliation(s)
- D Li
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - E Ryu
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - A H Saeidian
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA.,Genetics, Genomics and Cancer Biology PhD Program, Thomas Jefferson University, Philadelphia, PA, USA
| | - L Youssefian
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - E Oliphant
- PXE International, Inc, Washington, DC, 20008, USA
| | - S F Terry
- PXE International, Inc, Washington, DC, 20008, USA
| | - P L Tong
- Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia.,Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - J Uitto
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - N K Haass
- Discipline of Dermatology, University of Sydney, Camperdown, NSW, Australia.,Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.,The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Q Li
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, and PXE International Center of Excellence in Research and Clinical Care, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, 19107, USA
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30
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Guillen-Climent S, García-Vázquez A, Silva E, Estebanez A, Cuesta Peredo A, Rengel Ruiz MD, Monteagudo C, Ramón Quiles MD. Pseudoxanthoma elasticum-like syndrome with coagulation deficiency associated with carotid artery hypoplasia and a novel gamma-glutamyl carboxylase gene mutation. Int J Dermatol 2020; 60:e13-e15. [PMID: 32808310 DOI: 10.1111/ijd.15147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 07/21/2020] [Accepted: 07/27/2020] [Indexed: 11/28/2022]
Affiliation(s)
| | | | - Esmeralda Silva
- Department of Dermatology, Clinical University Hospital of Valencia, Valencia, Spain
| | - Andrea Estebanez
- Department of Dermatology, Clinical University Hospital of Valencia, Valencia, Spain
| | - Ana Cuesta Peredo
- Department of Genetics, Clinical University Hospital of Valencia, Valencia, Spain
| | | | - Carlos Monteagudo
- Department of Pathology, Clinical University Hospital of Valencia, Valencia, Spain.,Department of Pathology, University of Valencia, Valencia, Spain
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31
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Nonlinear optical microscopy is a novel tool for the analysis of cutaneous alterations in pseudoxanthoma elasticum. Lasers Med Sci 2020; 35:1821-1830. [PMID: 32372237 PMCID: PMC7505829 DOI: 10.1007/s10103-020-03027-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 04/16/2020] [Indexed: 01/10/2023]
Abstract
Pseudoxanthoma elasticum (PXE, OMIM 264800) is a rare autosomal recessive disorder with ectopic mineralization and fragmentation of elastin fibers. It is caused by mutations of the ABCC6 gene that leads to decreased serum levels of inorganic pyrophosphate (PPi) anti-mineralization factor. The occurrence of severe complications among PXE patients highlights the importance of early diagnosis so that prompt multidisciplinary care can be provided to patients. We aimed to examine dermal connective tissue with nonlinear optical (NLO) techniques, as collagen emits second-harmonic generation (SHG) signal, while elastin can be excited by two-photon excitation fluorescence (TPF). We performed molecular genetic analysis, ophthalmological and cardiovascular assessment, plasma PPi measurement, conventional histopathological examination, and ex vivo SHG and TPF imaging in five patients with PXE and five age- and gender-matched healthy controls. Pathological mutations including one new variant were found in the ABCC6 gene in all PXE patients and their plasma PPi level was significantly lower compared with controls. Degradation and mineralization of elastin fibers and extensive calcium deposition in the mid-dermis was visualized and quantified together with the alterations of the collagen structure in PXE. Our data suggests that NLO provides high-resolution imaging of the specific histopathological features of PXE-affected skin. In vivo NLO may be a promising tool in the assessment of PXE, promoting early diagnosis and follow-up.
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32
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Quaglino D, Boraldi F, Lofaro FD. The biology of vascular calcification. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 354:261-353. [PMID: 32475476 DOI: 10.1016/bs.ircmb.2020.02.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Vascular calcification (VC), characterized by different mineral deposits (i.e., carbonate apatite, whitlockite and hydroxyapatite) accumulating in blood vessels and valves, represents a relevant pathological process for the aging population and a life-threatening complication in acquired and in genetic diseases. Similarly to bone remodeling, VC is an actively regulated process in which many cells and molecules play a pivotal role. This review aims at: (i) describing the role of resident and circulating cells, of the extracellular environment and of positive and negative factors in driving the mineralization process; (ii) detailing the types of VC (i.e., intimal, medial and cardiac valve calcification); (iii) analyzing rare genetic diseases underlining the importance of altered pyrophosphate-dependent regulatory mechanisms; (iv) providing therapeutic options and perspectives.
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Affiliation(s)
- Daniela Quaglino
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
| | - Federica Boraldi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
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33
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Al-Doory S, Radaideh M, Saleh S, Al Sabbah M. Congenital Vitamin K-Dependent Clotting Factors Deficiency Type 1: A Rare Bleeding Disorder. DUBAI MEDICAL JOURNAL 2020. [DOI: 10.1159/000506457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Combined deficiency of vitamin K-dependent clotting factors is usually an acquired clinical problem, often resulting from liver disease, malabsorption or warfarin overdose. However, an inherited form of the disease is very rare. Here we report a 4-month-old girl who presented with a 2-week history of multiple bruises and a 1-day history of right thigh swelling after receiving her 4th month vaccine. Laboratory investigations showed anemia (Hb 6.0 g/dL) with extremely prolonged PT and APTT. Factor assay revealed deficiency of vitamin K-dependent clotting factors II, VII, IX, X as well as protein C and protein S. Whole-exome sequencing detected a novel homozygous mutation (c.44-5T>A p.(?)) in the γ-glutamyl carboxylase (GGCX) gene responsible for the autosomal recessive combined vitamin K-dependent clotting factors deficiency type 1.
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34
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Mititelu R, Cheung LW, Sasseville D. Cutaneous polyarteritis nodosa and concurrent pseudoxanthoma elasticum–like phenotype: A case report. SAGE Open Med Case Rep 2020; 8:2050313X20953110. [PMID: 35154765 PMCID: PMC8825631 DOI: 10.1177/2050313x20953110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
We report a unique case of a patient presenting with histologically confirmed pseudoxanthoma elasticum–like phenotype and cutaneous polyarteritis nodosa. Cardiac, gastroenterological, and ophthalmologic evaluations were within normal limits. Genetic evaluation was pertinent for absent ABCC6, ENPP1, and GGCX mutations and a normal array comparative genomic hybridization. Extensive workup revealed skin-limited cutaneous polyarteritis nodosa, and further genetic testing for ADA2 deficiency was negative. The cutaneous polyarteritis nodosa lesions had an excellent response to hydroxychloroquine and methotrexate. Pseudoxanthoma elasticum and polyarteritis nodosa are relatively uncommon, and our patient is among the first reported cases presenting with both pseudoxanthoma elasticum–like and polyarteritis nodosa. Furthermore, this case emphasizes the importance of a thorough cutaneous exam, as the patient had the lesions consistent with pseudoxanthoma elasticum–like since childhood and had previously gone undiagnosed.
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Affiliation(s)
- Roxana Mititelu
- Division of Dermatology, McGill University Health Center, Montreal, QC, Canada
| | - Larry W Cheung
- Division of Dermatology, McGill University Health Center, Montreal, QC, Canada
| | - Denis Sasseville
- Division of Dermatology, McGill University Health Center, Montreal, QC, Canada
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35
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Hassan MO, Gassim DA, Albakrye AM, Elnasri HA, Khaier MA. In silico analysis of likely pathogenic variants in human GGCX gene. INFORMATICS IN MEDICINE UNLOCKED 2020. [DOI: 10.1016/j.imu.2020.100337] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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36
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Daamen WF, Quaglino D. Signaling pathways in elastic tissues. Cell Signal 2019; 63:109364. [DOI: 10.1016/j.cellsig.2019.109364] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 07/22/2019] [Indexed: 02/06/2023]
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37
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Periumbilical Papule: Answer. Am J Dermatopathol 2019; 41:531-532. [PMID: 31232737 DOI: 10.1097/dad.0000000000001124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Quantitative Trait Locus and Integrative Genomics Revealed Candidate Modifier Genes for Ectopic Mineralization in Mouse Models of Pseudoxanthoma Elasticum. J Invest Dermatol 2019; 139:2447-2457.e7. [PMID: 31207231 DOI: 10.1016/j.jid.2019.04.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 03/28/2019] [Accepted: 04/26/2019] [Indexed: 02/06/2023]
Abstract
Pseudoxanthoma elasticum, a prototype of heritable multisystem ectopic mineralization disorders, is caused by mutations in the ABCC6 gene encoding a putative efflux transporter, ABCC6. The phenotypic spectrum of pseudoxanthoma elasticum varies, and the correlation between genotype and phenotype has not been established. To identify genetic modifiers, we performed quantitative trait locus analysis in inbred mouse strains that carry the same hypomorphic allele in Abcc6 yet with highly variable ectopic mineralization phenotypes of pseudoxanthoma elasticum. Abcc6 was confirmed as a major determinant for ectopic mineralization in multiple tissues. Integrative analysis using functional genomics tools that included GeneWeaver, String, and Mouse Genome Informatics identified a total of nine additional candidate modifier genes that could influence the organ-specific ectopic mineralization phenotypes. Integration of the candidate genes into the existing ectopic mineralization gene network expands the current knowledge on the complexity of the network that, as a whole, governs ectopic mineralization in soft connective tissues.
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Sun Q, Wang W, Wu L, Cheng L, Tong X, Xu X. Unexpected ABCC6 mRNA splicing in a Chinese family with pseudoxanthoma elasticum. Acta Ophthalmol 2019; 97:e381-e389. [PMID: 30328268 DOI: 10.1111/aos.13819] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 04/13/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE To identify the clinical characteristics and pathogenic genes among a Chinese family with angioid streaks and to assess a novel splicing mutation at the transcriptional and translational levels. METHODS Consenting family members were clinically evaluated, and blood samples were collected for targeted exome capture sequencing and/or Sanger sequencing. The two affected siblings were assessed by multimodal fundus imaging. ABCC6 splicing patterns were analysed by RNA identification and quantification using the proband's peripheral blood mononuclear cells. Minigene experiments were performed to verify the university. Plasmids expressing the transcripts were transfected into HEK293 cells to assess protein translation. Bioinformatic analyses were also performed to predict the splicing patterns and the functional consequences of the mutation. RESULTS The two siblings were trans-compound heterozygous pseudoxanthoma elasticum (PXE) patients with the same genotype (c.3703C>T and c.1177-2A>G for ABCC6) but different phenotypes. We identified several ABCC6 alternative splicing transcripts that were not previously reported. The novel splicing mutation c.1177-2A>G led to the upregulation of three transcripts, one using a cryptic splice acceptor in the upstream region of the intron, another using a cryptic splice acceptor in the downstream exon, and the third stimulating non-canonical U12-type splicing. All the transcripts were successfully translated in vitro. CONCLUSION The genotype-phenotype correlation of PXE is poorly understood. The novel ABCC6 splicing mutation c.1177-2A>G results in multiple splicing patterns. Endogenous U2 to U12 conversion may occur in humans in a disease state. Peripheral blood mononuclear cells can be reliably used to study ABCC6 RNA.
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Affiliation(s)
- Qiao Sun
- Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University Shanghai China
- Shanghai Key Laboratory of Fundus Disease Shanghai China
| | - Weijun Wang
- Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University Shanghai China
- Shanghai Key Laboratory of Fundus Disease Shanghai China
| | - Lifang Wu
- Department of Biochemistry and Molecular Cell Biology Shanghai Key Laboratory of Tumor Microenvironment and Inflammation Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Lu Cheng
- Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University Shanghai China
- Shanghai Key Laboratory of Fundus Disease Shanghai China
| | - Xuemei Tong
- Department of Biochemistry and Molecular Cell Biology Shanghai Key Laboratory of Tumor Microenvironment and Inflammation Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education Shanghai Jiao Tong University School of Medicine Shanghai China
| | - Xun Xu
- Department of Ophthalmology Shanghai General Hospital Shanghai Jiao Tong University Shanghai China
- Shanghai Key Laboratory of Fundus Disease Shanghai China
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Nollet L, Van Gils M, Verschuere S, Vanakker O. The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders. Int J Mol Sci 2019; 20:E2142. [PMID: 31052252 PMCID: PMC6540172 DOI: 10.3390/ijms20092142] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 04/24/2019] [Accepted: 04/24/2019] [Indexed: 12/11/2022] Open
Abstract
Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.
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Affiliation(s)
- Lukas Nollet
- Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
| | - Matthias Van Gils
- Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
| | - Shana Verschuere
- Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
| | - Olivier Vanakker
- Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium.
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Van Gils M, Nollet L, Verly E, Deianova N, Vanakker OM. Cellular signaling in pseudoxanthoma elasticum: an update. Cell Signal 2019; 55:119-129. [PMID: 30615970 DOI: 10.1016/j.cellsig.2018.12.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 12/20/2018] [Accepted: 12/20/2018] [Indexed: 12/27/2022]
Abstract
Pseudoxanthoma elasticum is an autosomal recessive genodermatosis with variable expression, due to mutations in the ABCC6 or ENPP1 gene. It is characterized by elastic fiber mineralization and fragmentation, resulting in skin, eye and cardiovascular symptoms. Significant advances have been made in the last 20 years with respect to the phenotypic characterization and pathophysiological mechanisms leading to elastic fiber mineralization. Nonetheless, the substrates of the ABCC6 transporter - the main cause of PXE - remain currently unknown. Though the precise mechanisms linking the ABCC6 transporter to mineralization of the extracellular matrix are unclear, several studies have looked into the cellular consequences of ABCC6 deficiency in PXE patients and/or animal models. In this paper, we compile the evidence on cellular signaling in PXE, which seems to revolve mainly around TGF-βs, BMPs and inorganic pyrophosphate signaling cascades. Where conflicting results or fragmented data are present, we address these with novel signaling data. This way, we aim to better understand the up- and down-stream signaling of TGF-βs and BMPs in PXE and we demonstrate that ANKH deficiency can be an additional mechanism contributing to decreased serum PPi levels in PXE patients.
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Affiliation(s)
- M Van Gils
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Belgium
| | - L Nollet
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - E Verly
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - N Deianova
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
| | - O M Vanakker
- Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Belgium.
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Borst P, Váradi A, van de Wetering K. PXE, a Mysterious Inborn Error Clarified. Trends Biochem Sci 2018; 44:125-140. [PMID: 30446375 DOI: 10.1016/j.tibs.2018.10.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/07/2018] [Accepted: 10/15/2018] [Indexed: 12/15/2022]
Abstract
Ever since Garrod deduced the existence of inborn errors in 1901, a vast array of metabolic diseases has been identified and characterized in molecular terms. In 2018 it is difficult to imagine that there is any uncharted backyard left in the metabolic disease landscape. Nevertheless, it took until 2013 to identify the cause of a relatively frequent inborn error, pseudoxanthoma elasticum (PXE), a disorder resulting in aberrant calcification. The mechanism found was not only biochemically interesting but also points to possible new treatments for PXE, a disease that has remained untreatable. In this review we sketch the tortuous road that led to the biochemical understanding of PXE and to new ideas for treatment. We also discuss some of the controversies still haunting the field.
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Affiliation(s)
- Piet Borst
- Division of Oncogenetics, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
| | - András Váradi
- Institute of Enzymology, Research Center for Natural Sciences (RCNS), Hungarian Academy of Sciences, 1117 Budapest, Hungary
| | - Koen van de Wetering
- Department of Dermatology and Cutaneous Biology and PXE International Center of Excellence in Research and Clinical Care, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Li Q, van de Wetering K, Uitto J. Pseudoxanthoma Elasticum as a Paradigm of Heritable Ectopic Mineralization Disorders: Pathomechanisms and Treatment Development. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:216-225. [PMID: 30414410 DOI: 10.1016/j.ajpath.2018.09.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 08/17/2018] [Accepted: 09/26/2018] [Indexed: 12/24/2022]
Abstract
Ectopic mineralization is a global problem and leading cause of morbidity and mortality. The pathomechanisms of ectopic mineralization are poorly understood. Recent studies on heritable ectopic mineralization disorders with defined gene defects have been helpful in elucidation of the mechanisms of ectopic mineralization in general. The prototype of such disorders is pseudoxanthoma elasticum (PXE), a late-onset, slowly progressing disorder with multisystem clinical manifestations. Other conditions include generalized arterial calcification of infancy (GACI), characterized by severe, early-onset mineralization of the cardiovascular system, often with early postnatal demise. In addition, arterial calcification due to CD73 deficiency (ACDC) occurs late in life, mostly affecting arteries in the lower extremities in elderly individuals. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6, ENPP1, and NT5E, respectively, are characterized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Because PPi is a powerful antimineralization factor, it has been postulated that reduced PPi is a major determinant for ectopic mineralization in these conditions. These and related observations on complementary mechanisms of ectopic mineralization have resulted in development of potential treatment modalities for PXE, including administration of bisphosphonates, stable PPi analogs with antimineralization activity. It is conceivable that efficient treatments may soon become available for heritable ectopic mineralization disorders with application to common calcification disorders.
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Affiliation(s)
- Qiaoli Li
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, the PXE International Center of Excellence in Research and Clinical Care, and the Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
| | - Koen van de Wetering
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, the PXE International Center of Excellence in Research and Clinical Care, and the Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jouni Uitto
- Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, the PXE International Center of Excellence in Research and Clinical Care, and the Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
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Legrand A, Benistan K, Mazzella JM, Adham S, Frank M, Jeunemaitre X, Albuisson J. Clinical utility gene card: for pseudoxanthoma elasticum. Eur J Hum Genet 2018; 26:919-924. [PMID: 29487417 DOI: 10.1038/s41431-017-0090-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/21/2017] [Accepted: 12/05/2017] [Indexed: 11/09/2022] Open
Affiliation(s)
- Anne Legrand
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France. .,Paris centre de Recherche Cardiovasculaire-PARCC, INSERM, U970, Paris, France. .,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
| | - Karelle Benistan
- Département de Génétique, AP-HP, Hôpital Raymond Poincaré, Garches, France
| | - Jean Michael Mazzella
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Salma Adham
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Michael Frank
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Xavier Jeunemaitre
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.,Paris centre de Recherche Cardiovasculaire-PARCC, INSERM, U970, Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Juliette Albuisson
- Département de Génétique, Service de Médecine Vasculaire et Centre de Référence des Maladies Vasculaires Rares, AP-HP, Hôpital Européen Georges Pompidou, Paris, France.,Paris centre de Recherche Cardiovasculaire-PARCC, INSERM, U970, Paris, France.,Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
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Dordoni C, Gatti M, Venturini M, Zanca A, Cinquina V, Santoro G, Battocchio S, Calzavara-Pinton P, Ritelli M, Colombi M. Characterization of a Pseudoxanthoma elasticum-like patient with coagulation deficiency, cutaneous calcinosis and GGCX compound heterozygosity. J Dermatol Sci 2017; 89:201-204. [PMID: 29175035 DOI: 10.1016/j.jdermsci.2017.11.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 10/19/2017] [Accepted: 11/21/2017] [Indexed: 11/19/2022]
Affiliation(s)
- Chiara Dordoni
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy
| | - Marta Gatti
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy
| | - Marina Venturini
- Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, Brescia, Italy
| | - Arianna Zanca
- Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, Brescia, Italy
| | - Valeria Cinquina
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy
| | - Graziano Santoro
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy
| | - Simonetta Battocchio
- Pathology Unit, Department of Molecular and Translational Medicine, University of Brescia, Spedali Civili, Italy
| | - Piergiacomo Calzavara-Pinton
- Division of Dermatology, Department of Clinical and Experimental Sciences, Spedali Civili University Hospital, Brescia, Italy
| | - Marco Ritelli
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy
| | - Marina Colombi
- Division of Biology and Genetics, Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Italy.
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Favre G, Laurain A, Aranyi T, Szeri F, Fulop K, Le Saux O, Duranton C, Kauffenstein G, Martin L, Lefthériotis G. The ABCC6 Transporter: A New Player in Biomineralization. Int J Mol Sci 2017; 18:ijms18091941. [PMID: 28891970 PMCID: PMC5618590 DOI: 10.3390/ijms18091941] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/02/2017] [Accepted: 09/05/2017] [Indexed: 12/16/2022] Open
Abstract
Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.
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Affiliation(s)
- Guillaume Favre
- FINSERM, U 1081, Aging and Diabetes Team, Institute for Research on Cancer and Aging of Nice (IRCAN), 06107 Nice, France.
- CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), 06107 Nice, France.
- Faculty of Medicine, University of Nice-Sophia Antipolis, 06107 Nice, France.
- Nephrology Department, University Hospital, 06107 Nice, France.
| | - Audrey Laurain
- Nephrology Department, University Hospital, 06107 Nice, France.
| | - Tamas Aranyi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
| | - Flora Szeri
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
| | - Krisztina Fulop
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary.
| | - Olivier Le Saux
- Department Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA.
| | - Christophe Duranton
- Laboratory of Physiology and Molecular Medicine (LP2M) UMR CNRS 7073, 06107 Nice, France.
| | - Gilles Kauffenstein
- UMR CNRS 6015-Inserm 1083, School of Medicine, Bretagne Loire University, 49045 Angers, France.
- PXE Health and Research Center, University Hospital of Angers, 49045 Angers, France.
| | - Ludovic Martin
- UMR CNRS 6015-Inserm 1083, School of Medicine, Bretagne Loire University, 49045 Angers, France.
- PXE Health and Research Center, University Hospital of Angers, 49045 Angers, France.
| | - Georges Lefthériotis
- Faculty of Medicine, University of Nice-Sophia Antipolis, 06107 Nice, France.
- Laboratory of Physiology and Molecular Medicine (LP2M) UMR CNRS 7073, 06107 Nice, France.
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Jiang NX, Xu YH, Xia JW, Jiang B, Li YS. Impact of GGCX polymorphisms on warfarin dose requirements in atrial fibrillation patients. Turk J Med Sci 2017; 47:1239-1246. [PMID: 29156869 DOI: 10.3906/sag-1609-26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype. Results: In 215 AF patients, there were 104 cases of wild-type GG genotype (48.4%), 92 cases of GA genotype (42.8%), and 19 cases of AA genotype (8.8%). Patients with the GGCX rs699664 A allele (GA or AA genotypes) needed higher warfarin doses than those with the GG genotype (P < 0.05). A warfarin dosing algorithm showed that age, height, CYP2C9, VKORC1, and GGCX genotype were the best variables for estimating warfarin dose (R2 = 41.2%). Another independent cohort of 60 AF patients showed a significant linear correlation between predicted warfarin maintenance dose and actual dose (R = 0.660, P < 0.01). Conclusion: AF patients with the GA and AA genotypes in GGCX rs699664 required significantly higher warfarin doses. GGCX rs699664 is a potential predictor for the warfarin dose of AF patients.
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Molecular basis of the first reported clinical case of congenital combined deficiency of coagulation factors. Blood 2017; 130:948-951. [PMID: 28679738 DOI: 10.1182/blood-2017-05-782367] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Okubo Y, Masuyama R, Iwanaga A, Koike Y, Kuwatsuka Y, Ogi T, Yamamoto Y, Endo Y, Tamura H, Utani A. Calcification in dermal fibroblasts from a patient with GGCX syndrome accompanied by upregulation of osteogenic molecules. PLoS One 2017; 12:e0177375. [PMID: 28494010 PMCID: PMC5426700 DOI: 10.1371/journal.pone.0177375] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2016] [Accepted: 04/26/2017] [Indexed: 12/21/2022] Open
Abstract
Gamma-glutamyl carboxylase (GGCX) gene mutation causes GGCX syndrome (OMIM: 137167), which is characterized by pseudoxanthoma elasticum (PXE)-like symptoms and coagulation impairment. Here, we present a 55-year-old male with a novel homozygous deletion mutation, c.2,221delT, p.S741LfsX100, in the GGCX gene. Histopathological examination revealed calcium deposits in elastic fibers and vessel walls, and collagen accumulation in the mid-dermis. Studies of dermal fibroblasts from the patient (GGCX dermal fibroblasts) demonstrated that the mutated GGCX protein was larger, but its expression level and intracellular distribution were indistinguishable from those of the wild-type GGCX protein. Immunostaining and an enzyme-linked immunosorbent assay showed an increase in undercarboxylated matrix gamma-carboxyglutamic acid protein (ucMGP), a representative substrate of GGCX and a potent calcification inhibitor, indicating that mutated GGCX was enzymatically inactive. Under osteogenic conditions, calcium deposition was exclusively observed in GGCX dermal fibroblasts. Furthermore, GGCX dermal fibroblast cultures contained 23- and 7.7-fold more alkaline phosphatase (ALP)-positive cells than normal dermal fibroblast cultures (n = 3), without and with osteogenic induction, respectively. Expression and activity of ALP were higher in GGCX dermal fibroblasts than in normal dermal fibroblasts upon osteogenic induction. mRNA levels of other osteogenic markers were also higher in GGCX dermal fibroblasts than in normal dermal fibroblasts, which including bone morphogenetic protein 6, runt-related transcription factor 2, and periostin (POSTN) without osteogenic induction; and osterix, collagen type I alpha 2, and POSTN with osteogenic induction. Together, these data indicate that GGCX dermal fibroblasts trans-differentiate into the osteogenic lineage. This study proposes another mechanism underlying aberrant calcification in patients with GGCX syndrome.
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Affiliation(s)
- Yumi Okubo
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Research and Clinical Center for Yusho and Dioxin (ReCYD), Kyushu University Hospital, Fukuoka, Japan
| | - Ritsuko Masuyama
- Department of Molecular Bone Biology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Akira Iwanaga
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuta Koike
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yutaka Kuwatsuka
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomoo Ogi
- Department of Genetics, Research Institute of Environmental Medicine (RIeM), Nagoya University, Aichi, Japan
| | - Yosuke Yamamoto
- Department of Healthcare Epidemiology Research, Graduate School of Medicine Kyoto University, Kyoto, Japan
- Department of Dermatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Yuichiro Endo
- Department of Dermatology, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Hiroshi Tamura
- Department of Ophthalmology and Visual Sciences, Graduate School of Medicine Kyoto University, Kyoto, Japan
| | - Atsushi Utani
- Department of Dermatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Abstract
Pseudoxanthoma elasticum (PXE) is a genetic metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. The lack of functional ABCC6 protein leads to ectopic mineralization that is most apparent in the elastic tissues of the skin, eyes and blood vessels. The clinical prevalence of PXE has been estimated at between 1 per 100,000 and 1 per 25,000, with slight female predominance. The first clinical sign of PXE is almost always small yellow papules on the nape and sides of the neck and in flexural areas. The papules coalesce, and the skin becomes loose and wrinkled. The mid-dermal elastic fibers are short, fragmented, clumped and calcified. Dystrophic calcification of Bruch's membrane, revealed by angioid streaks, may trigger choroidal neovascularization and, ultimately, loss of central vision and blindness in late-stage disease. Lesions in small and medium-sized artery walls may result in intermittent claudication and peripheral artery disease. Cardiac complications (myocardial infarction, angina pectoris) are thought to be relatively rare but merit thorough investigation. Ischemic strokes have been reported. PXE is a metabolic disease in which circulating levels of an anti-mineralization factor are low. There is good evidence to suggest that the factor is inorganic pyrophosphate (PPi), and that the circulating low levels of PPi and decreased PPi/Pi ratio result from the lack of ATP release by hepatocytes harboring the mutant ABCC6 protein. However, the substrate(s) bound, transported or modulated by the ABCC6 protein remain unknown. More than 300 sequence variants of the ABCC6 gene have been identified. There is no cure for PXE; the main symptomatic treatments are vascular endothelial growth factor inhibitor therapy (for ophthalmic manifestations), lifestyle, lipid-lowering and dietary measures (for reducing vascular risk factors), and vascular surgery (for severe cardiovascular manifestations). Future treatment options may include gene therapy/editing and pharmacologic chaperone therapy.
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Affiliation(s)
- Dominique P Germain
- Division of Medical Genetics, University of Versailles - Saint Quentin en Yvelines, Paris-Saclay University, 2 avenue de la source de la Bièvre, F-78180, Montigny, France.
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