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1
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Sun Q, Ren Y, Cao Y, Zheng W, Su G, Wang X, Wang H. Identification of a novel missense variant in the LMX1B gene associated with nail-patella syndrome in a Chinese family. Front Genet 2025; 16:1574076. [PMID: 40421384 PMCID: PMC12104052 DOI: 10.3389/fgene.2025.1574076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Accepted: 04/02/2025] [Indexed: 05/28/2025] Open
Abstract
Background Nail-patella syndrome (NPS) is an autosomal dominant disorder caused by the variants of the LMX1B gene, affecting several systems, including musculoskeletal, renal, and ocular systems. Despite the well-established genetic basis, the complicated relationship between genotype and phenotype still remains unclear. This study aimed to identify the genetic cause of NPS in a Chinese family and elucidate its potential contribution to the disease's phenotypic spectrum. Methods Clinical data and peripheral blood samples were collected from the affected family. Whole-exome sequencing (WES) was conducted to identify potential pathogenic variants, followed by Sanger sequencing to validate the candidate variant. Bioinformatic tools were employed to predict the 3D structure alterations and pathogenicity of the variant. Wild-type and mutant LMX1B overexpression plasmids were constructed to investigate the functional consequences of the variant. Western blotting and immunofluorescence were conducted to measure the expression and localization of the protein. Results The proband presented with clinical manifestations, including nail malformation, patella dysplasia, restricted elbow movement, and pes planus. Both his mother and sister exhibited symptoms related to the skeletal system. WES identified a novel c.812G>C (p.R271T) variant in the affected family members. Bioinformatic analyses revealed structural modification in the protein and predicted functional impairment. Western blotting showed no significant difference in the expression level between wild-type and mutant protein. However, immunofluorescence demonstrated distinct changes in the subcellular localization of c.812G>C mutant. Conclusion NPS is a rare multisystem disorder with variable clinical presentations. In this family, the skeletal system was mainly involved with variations among different members. Our study identified a novel c.812G > c variant in the LMX1B gene, changing the nuclear localization of the protein.
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Affiliation(s)
- Qian Sun
- Department of Orthopedics, Children’s Hospital of Soochow University, Suzhou, China
| | - Yaqiong Ren
- Laboratory of Pediatric Research, Children’s Hospital of Wujiang District, Suzhou, China
| | - Yue Cao
- Laboratory of Pediatric Research, Children’s Hospital of Wujiang District, Suzhou, China
| | - Wen Zheng
- Department of Orthopedics, Children’s Hospital of Soochow University, Suzhou, China
| | - Guanghao Su
- Department of Orthopedics, Children’s Hospital of Soochow University, Suzhou, China
| | - Xiaodong Wang
- Department of Orthopedics, Children’s Hospital of Soochow University, Suzhou, China
| | - Hongying Wang
- Department of Clinical Laboratory, Children’s Hospital of Soochow University, Suzhou, China
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2
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Shiraz ZK, Faizullah F, Khan QA, Ullah I, Khan M, Semakieh B, Islam ZU, Verma R. Triangular Lunulae in Papillon-Lefèvre Syndrome: A Case Report. Clin Case Rep 2025; 13:e70339. [PMID: 40236306 PMCID: PMC11997255 DOI: 10.1002/ccr3.70339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 01/09/2025] [Accepted: 02/14/2025] [Indexed: 04/17/2025] Open
Abstract
Triangular lunulae, typically associated with Nail-Patella Syndrome, may also present in other syndromes, as seen in this case. Papillon-Lefèvre syndrome is a rare genodermatosis linked to significant morbidity. Consanguinity is a recognized high-risk factor. Early diagnosis and treatment can reduce morbidity in affected individuals, and raising societal awareness about consanguinity can help alleviate the disease's burden in populations where this practice is prevalent.
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Affiliation(s)
| | | | | | - Irfan Ullah
- Khyber Teaching HospitalMTI KTHPeshawarPakistan
| | - Mehran Khan
- Khyber Teaching HospitalMTI KTHPeshawarPakistan
| | - Bader Semakieh
- Arkansas College of Osteopathic MedicineFort SmithArkansasUSA
| | | | - Ravina Verma
- St. George's University School of MedicineTrue BlueGrenada
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3
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Cappato S, Divizia MT, Menta L, Rosti G, Puliti A, Martinheira Da Silva JS, Santamaria G, Di Duca M, Ronchetto P, Faravelli F, Zara F, Bocciardi R. LMX1B haploinsufficiency due to variants in the 5'UTR as a cause of Nail-Patella syndrome. NPJ Genom Med 2025; 10:10. [PMID: 39939609 PMCID: PMC11822002 DOI: 10.1038/s41525-024-00460-6] [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: 07/23/2024] [Accepted: 12/20/2024] [Indexed: 02/14/2025] Open
Abstract
Nail-Patella syndrome (NPS) is a rare autosomal dominant condition due to haploinsufficiency of LMX1B, caused by loss-of-function variants affecting the coding sequence, or partial/whole deletions of the gene. In here, we describe two familial cases of NPS, carrying novel variants of the LMX1B 5'UTR region (-174C>T and -226G>A). To verify their pathogenic role, we carried out a functional characterization, both by reporter gene assays in heterologous systems and in patient's derived cells. We demonstrated that both variants impair LMX1B expression at post-transcriptional level. They introduce two upstream open reading frames (uORFs), out-of-frame with the main LMX1B coding sequence, generating transcripts detected by the non-sense mediated decay (NMD). We also demonstrated that the escape of the altered mRNA from NMD, if any, may lead to the synthesis of an aberrant LMX1B protein.
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Affiliation(s)
- Serena Cappato
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Maria Teresa Divizia
- Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Ludovica Menta
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy
| | - Giulia Rosti
- Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy
| | - Aldamaria Puliti
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy
| | - Joana Soraia Martinheira Da Silva
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy
| | - Giuseppe Santamaria
- Laboratory of Genetics and Genomics of Rare Diseases, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marco Di Duca
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | | | - Francesca Faravelli
- Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Federico Zara
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy
| | - Renata Bocciardi
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Sciences (DINOGMI), University of Genoa, Genoa, Italy.
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Castilla‐Ibeas A, Zdral S, Oberg KC, Ros MA. The limb dorsoventral axis: Lmx1b's role in development, pathology, evolution, and regeneration. Dev Dyn 2024; 253:798-814. [PMID: 38288855 PMCID: PMC11656695 DOI: 10.1002/dvdy.695] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 01/14/2024] [Accepted: 01/14/2024] [Indexed: 12/20/2024] Open
Abstract
The limb anatomy displays well-defined dorsal and ventral compartments, housing extensor, and flexor muscles, which play a crucial role in facilitating limb locomotion and manipulation. Despite its importance, the study of limb dorsoventral patterning has been relatively neglected compared to the other two axes leaving many crucial questions about the genes and developmental processes implicated unanswered. This review offers a thorough overview of the current understanding of limb dorsoventral patterning, synthesizing classical literature with recent research. It covers the specification of dorsal fate in the limb mesoderm and its subsequent translation into dorsal morphologies-a process directed by the transcription factor Lmx1b. We also discuss the potential role of dorsoventral patterning in the evolution of paired appendages and delve into the involvement of LMX1B in Nail-Patella syndrome, discussing the molecular and genetic aspects underlying this condition. Finally, the potential role of dorsoventral polarity in digit tip regeneration, a prominent instance of multi-tissue regeneration in mammals is also considered. We anticipate that this review will renew interest in a process that is critical to limb function and evolutionary adaptations but has nonetheless been overlooked.
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Affiliation(s)
- Alejandro Castilla‐Ibeas
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
| | - Sofía Zdral
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
| | - Kerby C. Oberg
- Department of Pathology and Human AnatomyLoma Linda University, School of MedicineLoma LindaCaliforniaUSA
| | - Marian A. Ros
- Department of Cellular and Molecular SignallingInstituto de Biotecnología y Biomedicina de Cantabria (IBBTEC), CSIC‐SODERCAN‐University of Cantabria)SantanderSpain
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5
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Matsumoto K, Matsumoto Y, Nawachi S, Asano Y, Katayama Y, Miyawaki Y, Katsuyama T, Katsuyama E, Nasu Y, Sada KE, Wada J. The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report. BMC Musculoskelet Disord 2024; 25:139. [PMID: 38355529 PMCID: PMC10865650 DOI: 10.1186/s12891-024-07242-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 01/29/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.
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Affiliation(s)
- Kazuya Matsumoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yoshinori Matsumoto
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan.
- Department of Rheumatology, Chugoku Central Hospital, 148-13 Kamiiwanari, Miyuki-Cho, Fukuyama, 720-0001, Japan.
| | - Shoichi Nawachi
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yosuke Asano
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yu Katayama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yoshia Miyawaki
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Takayuki Katsuyama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Eri Katsuyama
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Department of Medical Laboratory Science, Okayama University Graduate School of Health Sciences, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Yoshihisa Nasu
- Department of Orthopaedic Surgery, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
| | - Ken-Ei Sada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
- Department of Clinical Epidemiology, Kochi Medical School, Kochi University, Kohasu, Oko-Cho, Nankoku, 783-8505, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-Cho, Kita-Ku, Okayama, 700-8558, Japan
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6
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Francis D, Lall P, Ayres S, Van Bergen NJ, Christodoulou J, Brown NJ, Kalitsis P. De novo enhancer deletion of LMX1B produces a mild nail-patella clinical phenotype. Clin Genet 2024; 105:214-219. [PMID: 37899549 DOI: 10.1111/cge.14447] [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: 08/23/2023] [Revised: 10/13/2023] [Accepted: 10/14/2023] [Indexed: 10/31/2023]
Abstract
Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss-of-function sequence variants and deletions cause Nail-Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%-10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B-binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail-Patella phenotype that includes ophthalmological and renal manifestations.
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Affiliation(s)
- David Francis
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
| | - Paula Lall
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
| | - Samantha Ayres
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
- Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Australia
| | - Nicole J Van Bergen
- Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Australia
- Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Parkville, Australia
| | - John Christodoulou
- Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Australia
- Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Parkville, Australia
| | - Natasha J Brown
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
- Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Australia
| | - Paul Kalitsis
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Australia
- Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Parkville, Australia
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7
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Ng SY. Anonychia. J Pediatr 2023; 263:113664. [PMID: 37562741 DOI: 10.1016/j.jpeds.2023.113664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/12/2023]
Affiliation(s)
- Su Yuen Ng
- Paediatrics Department, Hospital Raja Permaisuri Bainun, Ipoh, Malaysia
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8
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Dharmshaktu GS, Dharmshaktu IS. Nail-Patella Syndrome: A Case Series From Northern India. Cureus 2023; 15:e47792. [PMID: 38022029 PMCID: PMC10676625 DOI: 10.7759/cureus.47792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/26/2023] [Indexed: 12/01/2023] Open
Abstract
The nail-patella syndrome (NPS) is an uncommon entity with a characteristic set of anomalies. The presence of classical tetrad of hypoplastic or absent fingernails, hypoplastic or absent patellae, bilateral iliac horns and varying grades of elbow deformities are well elucidated in the literature. The spectrum of clinical manifestation varies, resulting in very few cases presenting to the healthcare facility or being diagnosed appropriately. We, hereby, describe our experience of three separate cases of the NPS, diagnosed on clinical and radiological basis. All cases were diagnosed incidentally and none presented to us for consultation regarding the anomalies due to this disorder. In one of the cases, a young girl was managed medically for an associated abdominal complaint. Her father was also found with the clinical features of the disorder thus making the father-daughter duo, part of our series. One case presenting with a femur fracture was managed with fracture fixation surgery leading to an uneventful healing of fracture. There was neither a history of any other family member having similar anomalies nor other systemic disorders in all three cases. Knowledge of the condition may help in improving the diagnosis of NPS and enrich the medical literature.
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9
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Morito N, Usui T, Ishibashi S, Yamagata K. Podocyte-specific Transcription Factors: Could MafB Become a Therapeutic Target for Kidney Disease? Intern Med 2023; 62:11-19. [PMID: 35249929 PMCID: PMC9876710 DOI: 10.2169/internalmedicine.9336-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
The increasing number of patients with chronic kidney disease (CKD) is being recognized as an emerging global health problem. Recently, it has become clear that injury and loss of glomerular visceral epithelial cells, known as podocytes, is a common early event in many forms of CKD. Podocytes are highly specialized epithelial cells that cover the outer layer of the glomerular basement membrane. They serve as the final barrier to urinary protein loss through the formation and maintenance of specialized foot-processes and an interposed slit-diaphragm. We previously reported that the transcription factor MafB regulates the podocyte slit diaphragm protein production and transcription factor Tcf21. We showed that the forced expression of MafB was able to prevent CKD. In this review, we discuss recent advances and offer an updated overview of the functions of podocyte-specific transcription factors in kidney biology, aiming to present new perspectives on the progression of CKD and respective therapeutic strategies.
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Affiliation(s)
- Naoki Morito
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Toshiaki Usui
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Shun Ishibashi
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Japan
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10
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Pallozzi Lavorante N, Iester M, Bonzano C, Bagnis A, Traverso CE, Cutolo CA. Nail-Patella Syndrome and Glaucoma: A Case Report and Review of the Literature. Case Rep Ophthalmol 2022; 13:984-990. [PMID: 36605036 PMCID: PMC9808124 DOI: 10.1159/000527234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 08/11/2022] [Indexed: 11/26/2022] Open
Abstract
Nail-patella syndrome (NPS) is a rare autosomal dominant disease characterized by nail dysplasia, aplastic or hypoplastic patellae, elbow dysplasia, and presence of iliac horns. Renal or ocular abnormalities are also associated with the disease. We report the case of a 57-year-old woman affected by NPS and having haploinsufficiency of the LMX1B gene who experienced severe bilateral chronic angle-closure glaucoma in both eyes and that was successfully managed with a flap-express procedure in the right eye. The left eye had no light perception, and medical treatment was considered. Glaucoma is the most frequent ocular abnormalities observed in association with NPS and usually presents with an open angle. Glaucoma associated with NPS typically has an early onset open-angle phenotype. In fewer cases, it may present with an angle-closure phenotype. Therefore, we emphasize the need for glaucoma case-finding protocols comprehensive of gonioscopy in NPS patients and their relatives.
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Affiliation(s)
- Nicola Pallozzi Lavorante
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Michele Iester
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Chiara Bonzano
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Alessandro Bagnis
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Carlo Enrico Traverso
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Carlo Alberto Cutolo
- Clinica Oculistica, DINOGMI, University of Genoa, Genova, Italy,IRCCS Ospedale Policlinico San Martino, Genova, Italy
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11
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Adeva-Andany MM, Carneiro-Freire N. Biochemical composition of the glomerular extracellular matrix in patients with diabetic kidney disease. World J Diabetes 2022; 13:498-520. [PMID: 36051430 PMCID: PMC9329837 DOI: 10.4239/wjd.v13.i7.498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/19/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
In the glomeruli, mesangial cells produce mesangial matrix while podocytes wrap glomerular capillaries with cellular extensions named foot processes and tether the glomerular basement membrane (GBM). The turnover of the mature GBM and the ability of adult podocytes to repair injured GBM are unclear. The actin cytoskeleton is a major cytoplasmic component of podocyte foot processes and links the cell to the GBM. Predominant components of the normal glomerular extracellular matrix (ECM) include glycosaminoglycans, proteoglycans, laminins, fibronectin-1, and several types of collagen. In patients with diabetes, multiorgan composition of extracellular tissues is anomalous, including the kidney, so that the constitution and arrangement of glomerular ECM is profoundly altered. In patients with diabetic kidney disease (DKD), the global quantity of glomerular ECM is increased. The level of sulfated proteoglycans is reduced while hyaluronic acid is augmented, compared to control subjects. The concentration of mesangial fibronectin-1 varies depending on the stage of DKD. Mesangial type III collagen is abundant in patients with DKD, unlike normal kidneys. The amount of type V and type VI collagens is higher in DKD and increases with the progression of the disease. The GBM contains lower amount of type IV collagen in DKD compared to normal tissue. Further, genetic variants in the α3 chain of type IV collagen may modulate susceptibility to DKD and end-stage kidney disease. Human cellular models of glomerular cells, analyses of human glomerular proteome, and improved microscopy procedures have been developed to investigate the molecular composition and organization of the human glomerular ECM.
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12
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Lindelöf H, Horemuzova E, Voss U, Nordgren A, Grigelioniene G, Hammarsjö A. Case Report: Inversion of LMX1B - A Novel Cause of Nail-Patella Syndrome in a Swedish Family and a Longtime Follow-Up. Front Endocrinol (Lausanne) 2022; 13:862908. [PMID: 35769074 PMCID: PMC9235307 DOI: 10.3389/fendo.2022.862908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/28/2022] [Indexed: 11/16/2022] Open
Abstract
Nail-patella syndrome (NPS, OMIM #161200) is a rare autosomal dominant disorder with symptoms from many different parts of the body, including nails, knees, elbows, pelvis, kidneys and eyes. It is caused by truncating variants in the LMX1B gene, which encodes a transcription factor with important roles during embryonic development, including dorsoventral patterning of the limbs. To our knowledge, inversions disrupting the LMX1B gene have not been reported. Here, we report a family with an inversion disrupting the LMX1B gene in five affected family members with mild but variable clinical features of NPS. Our finding demonstrates that genomic rearrangements must be considered a possible cause of NPS.
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Affiliation(s)
- Hillevi Lindelöf
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Hillevi Lindelöf,
| | - Eva Horemuzova
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ulrika Voss
- Department of Pediatric Radiology, Karolinska University Hospital, Stockholm, Sweden
| | - Ann Nordgren
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Giedre Grigelioniene
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Hammarsjö
- Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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13
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Identification of limb-specific Lmx1b auto-regulatory modules with Nail-patella syndrome pathogenicity. Nat Commun 2021; 12:5533. [PMID: 34545091 PMCID: PMC8452625 DOI: 10.1038/s41467-021-25844-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 08/31/2021] [Indexed: 01/18/2023] Open
Abstract
LMX1B haploinsufficiency causes Nail-patella syndrome (NPS; MIM 161200), characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma. Accordingly in mice, Lmx1b has been shown to play crucial roles in the development of the limb, kidney and eye. Although one functional allele of Lmx1b appears adequate for development, Lmx1b null mice display ventral-ventral distal limbs with abnormal kidney, eye and cerebellar development, more disruptive, but fully concordant with NPS. In Lmx1b functional knockouts (KOs), Lmx1b transcription in the limb is decreased nearly 6-fold, indicating autoregulation. Herein, we report on two conserved Lmx1b-associated cis-regulatory modules (LARM1 and LARM2) that are bound by Lmx1b, amplify Lmx1b expression with unique spatial modularity in the limb, and are necessary for Lmx1b-mediated limb dorsalization. These enhancers, being conserved across vertebrates (including coelacanth, but not other fish species), and required for normal locomotion, provide a unique opportunity to study the role of dorsalization in the fin to limb transition. We also report on two NPS patient families with normal LMX1B coding sequence, but with loss-of-function variations in the LARM1/2 region, stressing the role of regulatory modules in disease pathogenesis. Nail-patella syndrome (NPS) is characterized by nail dysplasia, absent/hypoplastic patellae, chronic kidney disease, and glaucoma and can be caused by haploinsufficiency of LMX1B; however, not all patients harbor pathogenic LMX1B mutations. Here the authors show that loss-of-function variations in upstream enhancer sequences are responsible for a limb specific form of human NPS.
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14
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Oe Y, Mishima E, Mori T, Okamoto K, Honkura Y, Nagasawa T, Yoshida M, Sato H, Suzuki J, Ikeda R, Sohara E, Uchida S, Katori Y, Miyazaki M. A Novel Mutation in LMX1B (p.Pro219Ala) Causes Focal Segmental Glomerulosclerosis with Alport Syndrome-like Phenotype. Intern Med 2021; 60:2991-2996. [PMID: 33814499 PMCID: PMC8502659 DOI: 10.2169/internalmedicine.6987-20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A 69-year-old woman presented with mild renal dysfunction, proteinuria, and sensorineural hearing loss. A renal biopsy showed focal segmental glomerulosclerosis with thinning of the glomerular basement membrane. There was a positive family history of end-stage kidney disease and hearing loss. Although Alport syndrome was suspected from these features, a genetic test using next-generation sequencer identified a novel missense mutation in LMX1B, c.655C>G: p. (Pro219Ala). In silico analyses predicted the pathogenicity of the mutation. Thus, the present case was diagnosed as LMX1B-associated nephropathy presenting with Alport syndrome-like phenotype, expanding the disease spectrum of LMX1B nephropathy.
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Affiliation(s)
- Yuji Oe
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
- Department of Community Medical Support, Tohoku Medical Megabank Organization, Tohoku University, Japan
| | - Eikan Mishima
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Takayasu Mori
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Japan
| | - Koji Okamoto
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
- Department of Community Medical Support, Tohoku Medical Megabank Organization, Tohoku University, Japan
| | - Yohei Honkura
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Japan
| | - Tasuku Nagasawa
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | - Mai Yoshida
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
| | | | - Jun Suzuki
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Japan
| | - Ryoukichi Ikeda
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Japan
| | - Eisei Sohara
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan
| | - Shinichi Uchida
- Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan
| | - Yukio Katori
- Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Japan
| | - Mariko Miyazaki
- Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, Japan
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15
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Kondkar AA, Azad TA, Alobaidan AS, Sultan T, Osman EA, Almobarak FA, Lobo GP, Al-Obeidan SA. Lack of Association Between Polymorphisms in TXNRD2 and LMX1B and Primary Open-Angle Glaucoma in a Saudi Cohort. Front Genet 2021; 12:690780. [PMID: 34408771 PMCID: PMC8365832 DOI: 10.3389/fgene.2021.690780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/08/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: Recent studies have demonstrated an association of single nucleotide polymorphisms (SNPs) rs35934224 in TXNRD2 and rs6478746 near LMX1B genes in primary open-angle glaucoma (POAG) among Europeans. We performed a retrospective, case-control study to investigate the association between the rs35934224 (TXNRD2) and rs6478746 (LMX1B) and POAG in a middle-eastern population from Saudi Arabia. Methods: DNA from 399 participants consisting of 150 POAG cases (83 males and 67 females) and 249 controls (135 males and 114 females) were genotyped using TaqMan® real-time PCR. Statistical tests were performed to evaluate genetic association with POAG and related clinical indices. Results: The minor allele frequency (MAF) of rs35934224[T] was 0.19 and 0.20 in POAG and controls, respectively. The difference was non-significant (odds ratio [OR] = 1.08, 95% confidence interval [CI] = 0.75-1.55, p = 0.663). Likewise, rs6478746[G] MAF was 0.12 in both cases and controls with no statistical significance (OR = 1.02, 95% CI = 0.67-1.56, p = 0.910). Genotype analysis showed no association with POAG for both the SNPs in combined and gender-stratified groups. Regression analysis showed no significant effect of risk factors such as age, sex, rs35934224, and rs6478746 genotypes on POAG outcome. Furthermore, both the SNPs showed no significant genotype effect on clinical indices such as intraocular pressure (IOP) and cup/disc ratio in POAG patients. Conclusions: Rs35934224 in TXNRD2 and rs6478746 near LMX1B genes are not associated with POAG or related clinical indices such as IOP and cup/disc ratio in a Saudi cohort. Since the study is limited by sample size further investigations are needed to confirm these results in a larger cohort.
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Affiliation(s)
- Altaf A Kondkar
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Glaucoma Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia
| | - Taif A Azad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | | | - Tahira Sultan
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Essam A Osman
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Faisal A Almobarak
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Glaucoma Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Glenn P Lobo
- Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, United States
| | - Saleh A Al-Obeidan
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Glaucoma Research Chair in Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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16
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Arthrogryposis as a presenting feature of nail-patella syndrome: a lesser-known feature and the perils of negative whole-genome sequencing. Clin Dysmorphol 2021; 29:177-181. [PMID: 32639239 DOI: 10.1097/mcd.0000000000000334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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17
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Vakharia RM, Meneses ZA, Ardeljan AD, Roche MW. Robotic-Assisted Lateral Unicompartmental Knee Arthroplasty in a Patient With Nail-Patella Syndrome. Arthroplast Today 2021; 8:171-175. [PMID: 33889699 PMCID: PMC8049876 DOI: 10.1016/j.artd.2021.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/20/2021] [Accepted: 02/24/2021] [Indexed: 11/18/2022] Open
Abstract
A 59-year-old woman with nail patella syndrome (NPS) presented with progressive and severe right knee pain for the past 3 years. Imaging demonstrated laterally dislocated patella, with asymmetric femoral trochlea, and advanced lateral compartment arthritis. The patient underwent robotic-assisted lateral unicompartmental knee arthroplasty (RAUKA). The patient saw marked improvements in patient-reported outcome measurements from her initial visit to the last follow-up visit. While treatment of knee osteoarthritis in patients with NPS can be difficult, especially with attempts of patellar realignment, we present a case of a patient who underwent RAUKA, with sustained improvements in patient outcomes and range of motion, at the 2-year follow-up visit. This study is the first of its kind to demonstrate the use of a novel technology in a rare condition.
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Affiliation(s)
- Rushabh M. Vakharia
- Department of Orthopaedic Surgery, Maimonides Medical Center, Brooklyn, NY
- Corresponding author. 927 49th Street, Brooklyn, NY 11219. Tel.: (678) 232 7451.
| | | | - Andrew D. Ardeljan
- Nova Southeastern University, Osteopathic School of Medicine, Ft. Lauderdale, FL
| | - Martin W. Roche
- Department of Orthopaedic Surgery, Hospital for Special Surgery, West Palm Beach, FL
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18
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Gardin MA, Khor CC, Silva L, Krefting EA, Ritch R. Plateau iris syndrome and angle-closure glaucoma in a patient with nail-patella syndrome. Am J Ophthalmol Case Rep 2020; 20:100886. [PMID: 32954044 PMCID: PMC7486444 DOI: 10.1016/j.ajoc.2020.100886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 07/17/2020] [Accepted: 08/16/2020] [Indexed: 01/18/2023] Open
Abstract
PURPOSE To describe a case of plateau iris syndrome (PIS) and angle-closure glaucoma (ACG) in a patient with nail-patella syndrome (NPS). OBSERVATION A 33 year-old woman of Slovakian ancestry from Norway with a history of NPS presented with angle-closure secondary to plateau iris. At the time of her NPS diagnosis, she had no ocular pathology. Genetic testing revealed a rare de novo mutation in LMX1B [c.668G>C (p.Arg223Pro)]. Two years later, she experienced acute bilateral ocular pain and blurred vision in the setting of one year of reported visual loss. Subsequent ophthalmic examinations revealed closed angles and plateau iris OU with ACG OD and angle-closure OS. Perimetry showed superonasal visual field defects OD and no defects OS. Ocular coherence tomography (OCT) revealed thinning of the inferior pole of the optic nerve OD. Medical management proved ineffective. A laser peripheral iridotomy (LPI) OD was performed, without resolution of the angle-closure, and a diagnosis of plateau iris syndrome (PIS) was made. She was then treated with an argon laser peripheral iridoplasty (ALPI) and clear lens extraction with a posterior chamber intraocular lens (PCIOL) and goniosynechialysis OD, but her IOP remained elevated OU. She was referred to New York Eye and Ear Infirmary of Mount Sinai, where an LPI OS was performed, but angle-closure persisted, consistent with PIS. An ALPI OS with touch-up was performed, and her IOP normalized with dark-room gonioscopy revealing open angles OU. CONCLUSIONS AND IMPORTANCE NPS has been associated with ocular hypertension (OHTN) and open-angle glaucoma (OAG); however, to our knowledge, no association between NPS and angle-closure has previously been reported. The case described here, of a patient with a rare de novo mutation and ocular findings of PIS with associated ACG, represents a novel genetic and clinical presentation of NPS.
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Affiliation(s)
- Margot A. Gardin
- Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, 310 E 14th St, New York, NY, 10003, USA
| | - Chiea Chuen Khor
- Division of Human Genetics, Genome Institute of Singapore, 60 Biopolis St, Singapore, 138672, Singapore
| | - Luis Silva
- Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, 310 E 14th St, New York, NY, 10003, USA
| | - Einar A. Krefting
- Eye Department, University Hospital of North Norway, Sykehusvegen 38, 9019, Tromsø, Norway
| | - Robert Ritch
- Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, 310 E 14th St, New York, NY, 10003, USA
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19
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Carinelli S, Blanco OA, Perdomo-Ramirez A, Claverie-Martin F. Nail-Patella syndrome with early onset end-stage renal disease in a child with a novel heterozygous missense mutation in the LMX1B homeodomain: A case report. Biomed Rep 2020; 13:49. [PMID: 32963778 PMCID: PMC7490783 DOI: 10.3892/br.2020.1356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/20/2020] [Indexed: 01/18/2023] Open
Abstract
Nail-Patella syndrome (NPS) is an inherited disease characterized by nail and skeletal anomalies, nephropathy and glaucoma. The diagnosis of NPS is based on clinical findings, including hypoplastic or absent patella, dystrophic nails, dysplasia of the elbows and iliac horns. However, the main determinant of NPS prognosis is nephropathy, which may range from asymptomatic proteinuria to end-stage renal disease. NPS is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes the LIM homeodomain transcription factor LMX1B. LMX1B serves an essential role in the physiological development of dorsal-ventral limb structures, morphogenesis and function of podocytes, as well as in development of the anterior segments of the eyes, and in certain types of neurons. The present study aimed to identify the disease-causing mutation in a 2-year old girl with nephrotic syndrome that evolved rapidly to end-stage renal disease. The patient showed classical symptoms of NPS including dystrophic nails and an absence of the patellae. DNA sequence analysis identified a novel missense variant in exon 4 of LMX1B (c.709T>C, p.S237P); this substitution affected a conserved serine residue in the homeodomain of LMX1B and was predicted to be pathogenic. In silico modeling of the homeodomain revealed that the p.S237P mutation converted the A236-S237-F238 segment of α-helix 1 into a strand. It was hypothesized that this mutation affected binding of the transcription factor to its target DNA, thus abrogating transcription activation, which would explain the phenotype that manifested in the patient.
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Affiliation(s)
- Soledad Carinelli
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Olalla Alvarez Blanco
- Nefrologia Infantil, Hospital General Univesitario Gregorio Marañón, 28007 Madrid, Spain
| | - Ana Perdomo-Ramirez
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
| | - Felix Claverie-Martin
- Unidad de Investigación, Hospital Universitario Nuestra Señora de Candelaria, 38010 Santa Cruz de Tenerife, Spain
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20
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Lei L, Oh G, Sutherland S, Abra G, Higgins J, Sibley R, Troxell M, Kambham N. Myelin bodies in LMX1B-associated nephropathy: potential for misdiagnosis. Pediatr Nephrol 2020; 35:1647-1657. [PMID: 32356190 DOI: 10.1007/s00467-020-04564-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 03/20/2020] [Accepted: 03/30/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Myelin figures, or zebra bodies, seen on electron microscopy were historically considered pathognomonic of Fabry disease, a rare lysosomal storage disorder caused by alpha-galactosidase A deficiency and associated with X-linked recessive mode of inheritance. More recently, iatrogenic phospholipidosis has emerged as an important alternate cause of myelin figures in the kidney. METHODS We report two families with autosomal dominant nephropathy presenting with proteinuria and microscopic hematuria, and the kidney biopsies were notable for the presence of myelin figures and zebra bodies. RESULTS Laboratory and genetic work-up for Fabry disease was negative. Genetic testing in both families revealed the same heterozygous missense mutation in LMX1B (C.737G>A, p.Arg246Gln). LMX1B mutations are known to cause nail-patella syndrome, featuring dysplastic nails and patella with or without nephropathy, as well as isolated LMX1B-associated nephropathy in the absence of extrarenal manifestations. CONCLUSIONS LMX1B mutation-associated nephropathy should be considered in hereditary cases of proteinuria and/or hematuria, even in the absence of unique glomerular basement membrane changes indicative of nail-patella syndrome. In addition, LMX1B mutation should be included in the differential diagnosis of myelin figures and zebra bodies on kidney biopsy, so as to avoid a misdiagnosis.
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Affiliation(s)
- Li Lei
- Department of Pathology, Stanford University, H2110, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Gia Oh
- Randall Children's Hospital, Portland, OR, USA
| | - Scott Sutherland
- Department of Pediatrics & Division of Nephrology, Stanford University, Stanford, CA, USA
| | | | - John Higgins
- Department of Pathology, Stanford University, H2110, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Richard Sibley
- Department of Pathology, Stanford University, H2110, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Megan Troxell
- Department of Pathology, Stanford University, H2110, 300 Pasteur Drive, Stanford, CA, 94305, USA
| | - Neeraja Kambham
- Department of Pathology, Stanford University, H2110, 300 Pasteur Drive, Stanford, CA, 94305, USA.
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21
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Hosseinipour M, Inkumsah G. Visual Diagnosis: Dysplastic Nails and Elbows in a 15-year-old Boy. Pediatr Rev 2020; 41:e26-e30. [PMID: 32611806 DOI: 10.1542/pir.2018-0100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Affiliation(s)
| | - Gretchen Inkumsah
- Department of Pediatrics, Campbell University School of Osteopathic Medicine, Lillington, NC
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22
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Harita Y, Urae S, Akashio R, Isojima T, Miura K, Yamada T, Yamamoto K, Miyasaka Y, Furuyama M, Takemura T, Gotoh Y, Takizawa H, Tamagaki K, Ozawa A, Ashida A, Hattori M, Oka A, Kitanaka S. Clinical and genetic characterization of nephropathy in patients with nail-patella syndrome. Eur J Hum Genet 2020; 28:1414-1421. [PMID: 32457516 PMCID: PMC7608088 DOI: 10.1038/s41431-020-0655-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 03/30/2020] [Accepted: 05/12/2020] [Indexed: 01/18/2023] Open
Abstract
Nail-patella syndrome (NPS) is a multi-system disorder characterized by hypoplastic nails, hypoplastic patella, skeletal deformities, and iliac horns, which is caused by heterozygous variants of LMX1B. Nephropathy ranging from mild urinary abnormality to end-stage renal disease occurs in some individuals with NPS. Because of the low prevalence of NPS and the lack of longitudinal studies of its kidney involvement, the clinical, pathological, and genetic features characterizing severe nephropathy remain unclear. We conducted a Japanese survey of NPS with nephropathy, and analyzed their clinical course, pathological features, and factors associated with severe renal phenotype. LMX1B gene analysis and luciferase reporter assay were also performed. Among 13 NPS nephropathy cases with genetic validation, 5 patients who had moderate-to-massive proteinuria progressed to advanced chronic kidney disease or end-stage renal disease. Pathological findings in the early phase did not necessarily correlate with renal prognosis. Variants associated with deteriorated renal function including a novel variants were confined to the N-terminal region of the LIM domain and a short sequence in the LMX1B homeodomain, which were distinct from reported variants found in isolated nephropathy without extrarenal manifestation (LMX1B-associated nephropathy). Luciferase reporter analysis demonstrated that variants in patients with severe renal phenotype caused haploinsufficiency, but no dominant-negative effects on promoter activation. A distinct proportion of NPS nephropathy patients progressed to end-stage renal disease in adolescence or young adulthood. Patients with moderate or severe proteinuria, especially those with variants in specific regions of LMX1B, should be monitored for potential deterioration of renal function.
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Affiliation(s)
- Yutaka Harita
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Seiya Urae
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Riki Akashio
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Isojima
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kenichiro Miura
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Takeshi Yamada
- Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Katsusuke Yamamoto
- Department of Pediatric Nephrology and Metabolism, Osaka Women's and Children's Hospital, Osaka, Japan
| | - Yasunori Miyasaka
- Department of Nephrology, Japan Community Healthcare Organization Sendai Hospital, Miyagi, Japan
| | - Masayuki Furuyama
- Department of Pediatrics, Okitama Public General Hospital, Yamagata, Japan
| | - Tsukasa Takemura
- Department of Pediatrics, Kushimoto Town Hospital, Wakayama, Japan
| | - Yoshimitsu Gotoh
- Department of Pediatric Nephrology, Japanese Red Cross Nagoya Daini Hospital, Aichi, Japan
| | - Hideki Takizawa
- Department of Nephrology, Teine Keijinkai Hospital, Hokkaido, Japan
| | - Keiichi Tamagaki
- Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Ozawa
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Gunma University Graduate School of Medicine, Gunma, Japan
| | - Akira Ashida
- Department of Pediatrics, Osaka Medical College, Osaka, Japan
| | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Akira Oka
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Sachiko Kitanaka
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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23
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Jourdain A, Petit F, Odou M, Balduyck M, Brunelle P, Dufour W, Boussion S, Brischoux‐Boucher E, Colson C, Dieux A, Gérard M, Ghoumid J, Giuliano F, Goldenberg A, Khau Van Kien P, Lehalle D, Morin G, Moutton S, Smol T, Vanlerberghe C, Manouvrier‐Hanu S, Escande F. Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations. Hum Mutat 2019; 41:222-239. [DOI: 10.1002/humu.23912] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/31/2019] [Accepted: 09/05/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Anne‐Sophie Jourdain
- Service de Biochimie et Biologie MoléculaireCHU LilleLille France
- EA7364 RADEMEUniv. LilleLille France
| | - Florence Petit
- EA7364 RADEMEUniv. LilleLille France
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | - Marie‐Françoise Odou
- Service de Biochimie et Biologie MoléculaireCHU LilleLille France
- Faculty of Pharmacy, UMR995, LIRIC (Lille Inflammation Research International Center)University of LilleLille France
| | - Malika Balduyck
- Service de Biochimie et Biologie MoléculaireCHU LilleLille France
- EA7364 RADEMEUniv. LilleLille France
| | - Perrine Brunelle
- Service de Biochimie et Biologie MoléculaireCHU LilleLille France
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | | | | | | | | | - Anne Dieux
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | | | - Jamal Ghoumid
- EA7364 RADEMEUniv. LilleLille France
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | | | | | | | - Daphné Lehalle
- Reference Center for Developmental Anomalies, Department of Medical GeneticsDijon University HospitalDijon France
| | - Gilles Morin
- Centre d'activité de Génétique et d'OncogénétiqueCHU Amiens PicardieAmiens France
| | - Sébastien Moutton
- Reference Center for Developmental Anomalies, Department of Medical GeneticsDijon University HospitalDijon France
| | - Thomas Smol
- EA7364 RADEMEUniv. LilleLille France
- Institut de Génétique MédicaleCHU LilleLille France
| | - Clémence Vanlerberghe
- EA7364 RADEMEUniv. LilleLille France
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | - Sylvie Manouvrier‐Hanu
- EA7364 RADEMEUniv. LilleLille France
- Clinique de Génétique Guy FontaineCHU LilleLille France
| | - Fabienne Escande
- Service de Biochimie et Biologie MoléculaireCHU LilleLille France
- EA7364 RADEMEUniv. LilleLille France
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Geerts-Crabbé L, Antoine P, Brugallé E, Ghoumid J, Bellengier L, Edery P, Heron D, Manouvrier-Hanu S, Fantini-Hauwel C. Difficulties adapting to Nail-Patella syndrome: A qualitative study of patients' perspectives. J Genet Couns 2019; 28:1011-1020. [PMID: 31313463 DOI: 10.1002/jgc4.1153] [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: 11/19/2018] [Revised: 06/21/2019] [Accepted: 06/21/2019] [Indexed: 11/08/2022]
Abstract
Nail-Patella syndrome (NPS) is a genetic disorder generating physical malformations and, in approximately one in three cases, ocular and renal damage. The present research aimed to deeply understand patients' subjective experience with NPS, particularly the aspects of the syndrome that affect patients' adaptation and to propose interventions that can improve genetic and psychological counseling and help patients cope with their condition. Semi-structured interviews of nine people diagnosed with NPS were analyzed using interpretative phenomenological analysis. Results highlighted attempts to look like a person without disabilities by hiding malformations and not telling the truth about symptoms' genetic origin because of patients' poor self-esteem, negative self-cognition, and social isolation experienced from childhood to adulthood. Difficulties of adaptation to physical limits and pain were also identified. The majority of participants who were not diagnosed at birth tended to consider physical symptoms as "birth malformations" without imagining other potential implications until receiving a diagnosis. Despite the diagnosis, the majority continued to minimize the potential complications by considering NPS as a "physical difference" and not adhering to medical surveillance.
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Affiliation(s)
- Laura Geerts-Crabbé
- National Fund for Scientific Research (FRS-FNRS) - Télévie, Brussels, Belgium.,Center of Clinical Psychology, Psychopathology and Psychosomatic Research, Free University of Brussels, Brussels, Belgium.,SCALab - Cognitives and Affectives Sciences, National Center of Scientific Research (CNRS UMR 9193), University of Lille, Lille, France
| | - Pascal Antoine
- SCALab - Cognitives and Affectives Sciences, National Center of Scientific Research (CNRS UMR 9193), University of Lille, Lille, France
| | - Elodie Brugallé
- SCALab - Cognitives and Affectives Sciences, National Center of Scientific Research (CNRS UMR 9193), University of Lille, Lille, France
| | - Jamal Ghoumid
- RADEME - Maladies Rares du Développement embryonnaire et du Métabolisme: du phénotype au génotype et à la Fonction, CHU Lille, University of Lille, Lille, France
| | - Laurence Bellengier
- RADEME - Maladies Rares du Développement embryonnaire et du Métabolisme: du phénotype au génotype et à la Fonction, CHU Lille, University of Lille, Lille, France
| | - Patrick Edery
- Lyon Neuroscience Research Center (CRNL), National Center of Scientific Research (CNRS UMR 5292), Lyon, France
| | - Delphine Heron
- Département de Génétique et Centre de Référence Déficiences Intellectuelles de Causes Rares et GRC UPMC "Déficiences Intellectuelles et Autisme", Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Sylvie Manouvrier-Hanu
- RADEME - Maladies Rares du Développement embryonnaire et du Métabolisme: du phénotype au génotype et à la Fonction, CHU Lille, University of Lille, Lille, France
| | - Carole Fantini-Hauwel
- Center of Clinical Psychology, Psychopathology and Psychosomatic Research, Free University of Brussels, Brussels, Belgium
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25
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A novel small deletion of LMX1B in a large Chinese family with nail-patella syndrome. BMC MEDICAL GENETICS 2019; 20:71. [PMID: 31053111 PMCID: PMC6499979 DOI: 10.1186/s12881-019-0801-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 04/03/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Nail-patella syndrome (NPS) is an autosomal dominant developmental disorder most commonly characterized by dyplasia of nail or patella, the radial head or the humeral head hypoplasia, and, frequently ocular abnormalities and renal disease. It is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes LIM homeodomain transcription factor and is essential for regulating the dorsal limb fate. METHODS A five generation pedigree was recruited. Genomic DNA was extracted from the peripheral blood samples. Mutation detection was performed by Sanger sequencing the LMX1B gene. In silico functional annotation of the variant was performed using the in silico predictors SIFT, PolyPhen-2 and Mutation Taster. RESULTS A novel heterozygous small deletion within exon 4 of LMX1B, c.712_714delTTC, was identified in a rare five-generation NPS pedigree. The mutation resulted in a deletion of the conserved amino acid phenylalanine at codon 238 (p.Phe238del), which located in the homeodomain of LMX1B may abolish DNA binding with the molecule. Conformational prediction showed that the variation could transform the helical structure comprising p.Phe234, p.Lys235, p.Ala236, and p.Ser237. CONCLUSION We identified a novel NPS-causing LMX1B mutation and expanded the spectrum of mutations in the LMX1B gene. The c.712_714delTTC mutation may affect the quaternary structure of LMX1B, which is essential for the specification of dorsal limb fate at both zeugopodal and autopodal levels, leading to typical NPS.
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Claverie-Martin F, Trindade A, Garcia-Gonzalez NC, Callejon AC. Novel missense mutation affecting the LIM-A domain of LMX1B in a family with Nail-Patella syndrome. Intractable Rare Dis Res 2019; 8:14-19. [PMID: 30881852 PMCID: PMC6409120 DOI: 10.5582/irdr.2018.01131] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Nail-patella syndrome (NPS) is a rare autosomal dominant disease characterized by developmental defects of dorsal limb structures, the kidney, and the eye, that manifest as dysplastic nails, hypoplastic or absent patella, elbow dysplasia, iliac horns, glomerulopathy, and adult-onset glaucoma, respectively. This disorder is inherited in an autosomal dominant mode and is caused by heterozygous loss-of-function mutations in the LMX1B gene, which encodes the LIM homeodomain transcription factor LMX1B. In this study, we report the clinical findings of a Spanish family, from the Canary Islands, with three affected members who displayed varying phenotypes. DNA sequence analysis identified a novel heterozygous missense mutation in LMX1B, c.305A>G, p.(Y102C), that segregated with the disease. The tyrosine residue affected by the mutation is highly conserved in evolution, and is located in the LIM-A domain, next to one of the cysteine residues involved in zinc binding, suggesting that p.(Y102C) affects LMX1B function by disturbing its interactions with other proteins. Our results expand the mutation spectrum of LMX1B and provide insight into the molecular mechanisms of NPS pathology.
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Affiliation(s)
- Felix Claverie-Martin
- Unidad de Investigacion, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Address correspondence to:Dr. Félix Claverie-Martín, Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010 Santa Cruz de Tenerife, Spain. E-mail:
| | - Amelia Trindade
- Unidad de Investigacion, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
- Present address:Departamento de Medicina, Centro de Ciências Biológicas e da Saude (CCBS), Universidade Federal de São Carlos, São Carlos, Brasil
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27
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Total knee arthroplasty in a patient with nail-patella syndrome (NPS). Knee 2019; 26:273-278. [PMID: 30503662 DOI: 10.1016/j.knee.2018.11.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 11/08/2018] [Accepted: 11/10/2018] [Indexed: 02/02/2023]
Abstract
Nail-patella syndrome (NPS) or hereditary onycho-osteodyaplasia is a rare genetic condition involving a mutation in the LMX1B gene affecting nails, elbows, knees, and pelvis. Due to the regulatory functions of the gene in many developmental processes through the body, patients with NPS experience wide-ranging musculoskeletal problems including patellar instability, fingernail anomalies, iliac exostoses/horns, and elbow abnormalities. The patellar changes often involve aplasia, hypoplasia, and chronic dislocation. Due to these musculoskeletal involvement, arthritis of joints can occur in patients with NPS causing severe pain and disability. This is a case report of a patient with NPS who underwent a total knee arthroplasty for symptomatic knee arthritis.
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Fadiloglu E, Unal C, Orgul G, Tanacan A, Beksac MS. Consecutive successful pregnancies of a patient with nail-patella syndrome. CASE REPORTS IN PERINATAL MEDICINE 2018. [DOI: 10.1515/crpm-2018-0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Abstract
Nail-patella syndrome is a genetic disorder with some characteristic features (nail dysplasia, patellar hypoplasia, elbow dysplasia, iliac horns and renal symptoms). Renal involvement of these patients requires close follow-up in pregnancy to avoid complications like preeclampsia. In this report, we have presented two consecutive successful pregnancies of a patient with nail-patella syndrome. The first pregnancy resulted with a newborn with nail-patella syndrome and the second pregnancy resulted in a healthy newborn without any obstetric complications. Renal functions were closely followed-up during both pregnancies, and basal renal functions were normal in the pregestational period, which seems to be the most important predictor of obstetric hypertensive complications. Prenatal diagnosis of nail-patella disease is also challenging due to several possible mutations and a wide range of phenotypes of the disease. Ultrasonographic examination findings may be suspicious for the disease in the fetus like patellar hypoplasia or joint contractures.
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Affiliation(s)
- Erdem Fadiloglu
- Hacettepe University , Division of Perinatalogy , Department of Women’s Health , Ankara , Turkey , Tel.: +90 5464750175
- Division of Perinatology , Department of Obstetrics and Gynecology , Hacettepe University , Ankara , Turkey
| | - Canan Unal
- Division of Perinatology , Department of Obstetrics and Gynecology , Hacettepe University , Ankara , Turkey
| | - Gokcen Orgul
- Division of Perinatology , Department of Obstetrics and Gynecology , Hacettepe University , Ankara , Turkey
| | - Atakan Tanacan
- Division of Perinatology , Department of Obstetrics and Gynecology , Hacettepe University , Ankara , Turkey
| | - Mehmet Sinan Beksac
- Division of Perinatology , Department of Obstetrics and Gynecology , Hacettepe University , Ankara , Turkey
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29
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Negrisolo S, Carraro A, Fregonese G, Benetti E, Schaefer F, Alberti M, Melchionda S, Fischetto R, Giordano M, Murer L. Could the interaction between LMX1B and PAX2 influence the severity of renal symptoms? Eur J Hum Genet 2018; 26:1708-1712. [PMID: 29973660 DOI: 10.1038/s41431-018-0213-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 05/25/2018] [Accepted: 06/19/2018] [Indexed: 01/18/2023] Open
Abstract
Nail Patella syndrome (NPS) is a rare autosomal dominant disease characterized by varying degrees of patella, nail, and elbows dysplasia and also ocular and renal congenital abnormalities. The renal involvement, ranging from hematuria and proteinuria to end-stage renal disease, is present in 22-60% of NPS cases. Heterozygous variants in LMX1B are known to be responsible of NPS and it has been hypothesized that the variable expressivity is due to the interaction of LMX1B with other developmental genes. We reported a case of co-presence of LMX1B and PAX2 variants in a child with extrarenal manifestation of NPS and end-stage renal disease but congenital bilateral renal hypodysplasia and vesicoureteral reflux. The LMX1B variant was de novo, whereas the PAX2 variant was inherited from the mother that had bilateral renal hypoplasia although in presence of only a mild chronic kidney disease. The molecular interaction between LMX1B and PAX2 has been already reported in vitro and this finding suggest that the worst renal NPS phenotype of our patient could be due to the defective expression of these two genes during nephrogenesis. In conclusion, our finding suggests that PAX2 may act as modifier gene in Nail Patella phenotype.
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Affiliation(s)
- Susanna Negrisolo
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, University of Padova, Padua, Italy.
| | - Andrea Carraro
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, University of Padova, Padua, Italy
| | - Giulia Fregonese
- Pediatric Nephrology, Dialysis and Transplant Unit, Department of Women's and Children's Health, Hospital-University of Padova, Padua, Italy
| | - Elisa Benetti
- Pediatric Nephrology, Dialysis and Transplant Unit, Department of Women's and Children's Health, Hospital-University of Padova, Padua, Italy
| | - Franz Schaefer
- Division of Pediatric Nephrology and KFH Children's Kidney Center, Center for Pediatrics and Adolescent Medicine, Heidelberg University Medical Center, Heidelberg, Germany
| | - Marta Alberti
- RCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Clinical Research Center for Rare Diseases "Aldo e Cele Daccò", Bergamo, Italy.,"Centro Anna Maria Astori", Science Technology Park Kilometro Rosso, Bergamo, Italy
| | - Salvatore Melchionda
- Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Rita Fischetto
- Unit of Metabolic Disease and Medical Genetics, University Hospital, P.O. Giovanni XXIII, Bari, Italy
| | - Mario Giordano
- Unit of Pediatric Nephrology, University Hospital, P.O. Giovanni XXIII, Bari, Italy
| | - Luisa Murer
- Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women's and Children's Health, University of Padova, Padua, Italy.,Pediatric Nephrology, Dialysis and Transplant Unit, Department of Women's and Children's Health, Hospital-University of Padova, Padua, Italy
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30
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A multiethnic genome-wide association study of primary open-angle glaucoma identifies novel risk loci. Nat Commun 2018; 9:2278. [PMID: 29891935 PMCID: PMC5995837 DOI: 10.1038/s41467-018-04555-4] [Citation(s) in RCA: 122] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/23/2018] [Indexed: 01/18/2023] Open
Abstract
Primary open-angle glaucoma (POAG) is a leading cause of irreversible vision loss, yet much of the genetic risk remains unaccounted for, especially in African-Americans who have a higher risk for developing POAG. We conduct a multiethnic genome-wide association study (GWAS) of POAG in the GERA cohort, with replication in the UK Biobank (UKB), and vice versa, GWAS in UKB with replication in GERA. We identify 24 loci (P < 5.0 × 10-8), including 14 novel, of which 9 replicate (near FMNL2, PDE7B, TMTC2, IKZF2, CADM2, DGKG, ANKH, EXOC2, and LMX1B). Functional studies support intraocular pressure-related influences of FMNL2 and LMX1B, with certain Lmx1b mutations causing high IOP and glaucoma resembling POAG in mice. The newly identified loci increase the proportion of variance explained in each GERA race/ethnicity group, with the largest gain in African-Americans (0.5-3.1%). A meta-analysis combining GERA and UKB identifies 24 additional loci. Our study provides important insights into glaucoma pathogenesis.
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31
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Wesdorp M, de Koning Gans PAM, Schraders M, Oostrik J, Huynen MA, Venselaar H, Beynon AJ, van Gaalen J, Piai V, Voermans N, van Rossum MM, Hartel BP, Lelieveld SH, Wiel L, Verbist B, Rotteveel LJ, van Dooren MF, Lichtner P, Kunst HPM, Feenstra I, Admiraal RJC, Yntema HG, Hoefsloot LH, Pennings RJE, Kremer H. Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction. Hum Genet 2018; 137:389-400. [PMID: 29754270 PMCID: PMC5973959 DOI: 10.1007/s00439-018-1880-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Accepted: 03/31/2018] [Indexed: 12/20/2022]
Abstract
Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.
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Affiliation(s)
- Mieke Wesdorp
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Pia A M de Koning Gans
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - Margit Schraders
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jaap Oostrik
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Martijn A Huynen
- Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hanka Venselaar
- Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Andy J Beynon
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Judith van Gaalen
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Vitória Piai
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Medical Psychology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Nicol Voermans
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michelle M van Rossum
- Department of Dermatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Bas P Hartel
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Stefan H Lelieveld
- The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Laurens Wiel
- The Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Berit Verbist
- Department of Radiology, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Marieke F van Dooren
- Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Peter Lichtner
- Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
| | - Henricus P M Kunst
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Ilse Feenstra
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ronald J C Admiraal
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Helger G Yntema
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lies H Hoefsloot
- Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Ronald J E Pennings
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Hannie Kremer
- Department of Otorhinolaryngology, Hearing and Genes, Radboud University Medical Center, Internal Postal Code 377, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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32
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Vanlerberghe C, Boutry N, Petit F. Genetics of patella hypoplasia/agenesis. Clin Genet 2018; 94:43-53. [PMID: 29322497 DOI: 10.1111/cge.13209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/02/2018] [Accepted: 01/08/2018] [Indexed: 12/31/2022]
Abstract
The patella is a sesamoid bone, crucial for knee stability. When absent or hypoplastic, recurrent knee subluxations, patellofemoral dysfunction and early gonarthrosis may occur. Patella hypoplasia/agenesis may be isolated or observed in syndromic conditions, either as the main clinical feature (Nail-patella syndrome, small patella syndrome), as a clue feature which can help diagnosis assessment, or as a background feature that may be disregarded. Even in the latter, the identification of patella anomalies is important for an appropriate patient management. We review the clinical characteristics of these rare diseases, provide guidance to facilitate the diagnosis and discuss how the genes involved could affect patella development.
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Affiliation(s)
- C Vanlerberghe
- Univ. Lille, EA7364 RADEME, Lille, France.,CHU Lille, Clinique de Génétique Médicale, Lille, France
| | - N Boutry
- Univ. Lille, EA7364 RADEME, Lille, France.,CHU Lille, Service de Radiopédiatrie, Lille, France
| | - F Petit
- Univ. Lille, EA7364 RADEME, Lille, France.,CHU Lille, Clinique de Génétique Médicale, Lille, France
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33
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Harita Y, Kitanaka S, Isojima T, Ashida A, Hattori M. Spectrum of LMX1B mutations: from nail-patella syndrome to isolated nephropathy. Pediatr Nephrol 2017; 32:1845-1850. [PMID: 27450397 DOI: 10.1007/s00467-016-3462-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 07/04/2016] [Accepted: 07/06/2016] [Indexed: 01/18/2023]
Abstract
Nail-patella syndrome (NPS) is an autosomal-dominant disease caused by LMX1B mutations and is characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Renal involvement is the major determinant of the prognosis for NPS. Patients often present with varying degrees of proteinuria or hematuria, and can occasionally progress to chronic renal failure. Recent genetic analysis has found that some mutations in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). The classic term "nail-patella syndrome" would not represent disease conditions in these cases. This review provides an overview of NPS, and highlights the molecular genetics of NPS nephropathy and LMX1B-associated nephropathy. Our current understanding of LMX1B function in the pathogenesis of NPS and LMX1B-associated nephropathy is also presented, and its downstream regulatory networks discussed. This recent progress provides insights that help to define potential targeted therapeutic strategies for LMX1B-associated diseases.
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Affiliation(s)
- Yutaka Harita
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Sachiko Kitanaka
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Tsuyoshi Isojima
- Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Akira Ashida
- Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan
| | - Motoshi Hattori
- Department of Pediatric Nephrology, Tokyo Women's Medical University, Sinjuku-ku, Tokyo, Japan
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Haro E, Watson BA, Feenstra JM, Tegeler L, Pira CU, Mohan S, Oberg KC. Lmx1b-targeted cis-regulatory modules involved in limb dorsalization. Development 2017; 144:2009-2020. [DOI: 10.1242/dev.146332] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 04/17/2017] [Indexed: 12/28/2022]
Abstract
Lmx1b is a homeodomain transcription factor responsible for limb dorsalization. Despite striking double-ventral (loss-of-function) and double-dorsal (gain-of-function) limb phenotypes, no direct gene targets in the limb have been confirmed. To determine direct targets, we performed a chromatin immunoprecipitation against Lmx1b at E12.5 followed by next generation sequencing (ChIP-seq). Nearly 84% (n=617) of the Lmx1b-bound genomic intervals (LBIs) identified overlap with chromatin regulatory marks indicative of potential cis-regulatory modules (PCRMs). In addition, 73 LBIs mapped to known CRMs active during limb development. We compared Lmx1b-bound PCRMs to genes differentially expressed by Lmx1b and found 292 PCRMs within 1 Mb of 254 Lmx1b-regulated genes. Gene ontologic analysis suggests that Lmx1b targets extracellular matrix production, bone/joint formation, axonal guidance, vascular development, cell proliferation and cell movement. We validated the functional activity of a PCRM associated with joint-related Gdf5 that provides a mechanism for Lmx1b-mediated joint modification and a PCRM associated with Lmx1b that suggests a role in autoregulation. This is the first report to describe genome-wide Lmx1b binding during limb development, directly linking Lmx1b to targets that accomplish limb dorsalization.
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Affiliation(s)
- Endika Haro
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
| | - Billy A. Watson
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
| | - Jennifer M. Feenstra
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
| | - Luke Tegeler
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
| | - Charmaine U. Pira
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
| | - Subburaman Mohan
- Musculoskeletal Disease Center, Loma Linda VA HealthCare System, Loma Linda, CA, USA
| | - Kerby C. Oberg
- Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, CA, USA
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Bergqvist C, Ramia P, Abbas O, Kurban M. Genetics of syndromic and non-syndromic hereditary nail disorders. Clin Genet 2016; 91:813-823. [PMID: 27613389 DOI: 10.1111/cge.12852] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 08/22/2016] [Accepted: 08/22/2016] [Indexed: 01/18/2023]
Abstract
The nail is a unique epithelial skin appendage made up of a fully keratinized nail plate. The nail can be affected in several systemic illnesses, dermatological diseases, and inherited nail disorders. Nail dystrophies can present as isolated disorders or as a part of syndromes. Substantial progress has been achieved in the management and diagnosis of nail diseases; however, not much is known about the underlying molecular controls of nail growth. The homeostasis and development of the nail appendage depend on the intricate interactions between the epidermis and underlying mesenchyme, and comprise different signaling pathways such as the WNT signaling pathway. Digit-tip regeneration in mice and humans has been a known fact for the past six decades; however, only recently the underlying biological mechanisms by which the nail organ achieves digit regeneration have been elucidated. Moreover, significant progress has been made in identifying nail stem cells and localizing stem cell niches in the nail unit. More fascinating, however, is the role they play in orchestrating the processes that lead to the regeneration of the digit. Further elucidating the role of nail stem cells and the signaling pathways driving epithelial-mesenchymal interactions in the nail unit might contribute to the development of novel therapeutic tools for amputees.
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Affiliation(s)
- C Bergqvist
- Department of Dermatology, American University of Beirut, Beirut, Lebanon
| | - P Ramia
- Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - O Abbas
- Department of Dermatology, American University of Beirut, Beirut, Lebanon
| | - M Kurban
- Department of Dermatology, American University of Beirut, Beirut, Lebanon.,Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.,Department of Dermatology, Columbia University Medical Center, New York, NY, USA
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Figueroa-Silva O, Vicente A, Agudo A, Baliu-Piqué C, Gómez-Armayones S, Aldunce-Soto M, Inarejos Clemente E, Navallas Irujo M, Gutiérrez de la Iglesia D, González-Enseñat M. Nail-patella syndrome: report of 11 pediatric cases. J Eur Acad Dermatol Venereol 2016; 30:1614-7. [DOI: 10.1111/jdv.13683] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Accepted: 02/23/2016] [Indexed: 01/18/2023]
Affiliation(s)
- O. Figueroa-Silva
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - A. Vicente
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - A. Agudo
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - C. Baliu-Piqué
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - S. Gómez-Armayones
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - M.J. Aldunce-Soto
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - E.J. Inarejos Clemente
- Department of Diagnostic Imaging; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | - M. Navallas Irujo
- Department of Diagnostic Imaging; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
| | | | - M.A. González-Enseñat
- Department of Dermatology; Hospital Sant Joan de Déu; University of Barcelona; Barcelona Spain
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