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Dubot P, Sabourdy F, Levade T. Human genetic defects of sphingolipid synthesis. J Inherit Metab Dis 2025; 48:e12745. [PMID: 38706107 PMCID: PMC11730260 DOI: 10.1002/jimd.12745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 05/07/2024]
Abstract
Sphingolipids are ubiquitous lipids, present in the membranes of all cell types, the stratum corneum and the circulating lipoproteins. Autosomal recessive as well as dominant diseases due to disturbed sphingolipid biosynthesis have been identified, including defects in the synthesis of ceramides, sphingomyelins and glycosphingolipids. In many instances, these gene variants result in the loss of catalytic function of the mutated enzymes. Additional gene defects implicate the subcellular localization of the sphingolipid-synthesizing enzyme, the regulation of its activity, or even the function of a sphingolipid-transporter protein. The resulting metabolic alterations lead to two major, non-exclusive types of clinical manifestations: a neurological disease, more or less rapidly progressive, associated or not with intellectual disability, and an ichthyotic-type skin disorder. These phenotypes highlight the critical importance of sphingolipids in brain and skin development and homeostasis. The present article reviews the clinical symptoms, genetic and biochemical alterations, pathophysiological mechanisms and therapeutic options of this relatively novel group of metabolic diseases.
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Affiliation(s)
- Patricia Dubot
- Unité Mixte de Recherche INSERM 1037, CNRS 5071, Université Toulouse III—Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT)ToulouseFrance
- Laboratoire de BiochimieInstitut Fédératif de Biologie, CHU PurpanToulouseFrance
- Centre de RecherchesCHU Sainte‐Justine, Université de MontréalMontréalCanada
| | - Frédérique Sabourdy
- Unité Mixte de Recherche INSERM 1037, CNRS 5071, Université Toulouse III—Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT)ToulouseFrance
- Laboratoire de BiochimieInstitut Fédératif de Biologie, CHU PurpanToulouseFrance
| | - Thierry Levade
- Unité Mixte de Recherche INSERM 1037, CNRS 5071, Université Toulouse III—Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse (CRCT)ToulouseFrance
- Laboratoire de BiochimieInstitut Fédératif de Biologie, CHU PurpanToulouseFrance
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Pahnke J, Bascuñana P, Brackhan M, Stefan K, Namasivayam V, Koldamova R, Wu J, Möhle L, Stefan SM. Strategies to gain novel Alzheimer's disease diagnostics and therapeutics using modulators of ABCA transporters. FREE NEUROPATHOLOGY 2021; 2:33. [PMID: 34977908 PMCID: PMC8717091 DOI: 10.17879/freeneuropathology-2021-3528] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 11/12/2021] [Indexed: 11/30/2022]
Abstract
Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer's disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.
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Affiliation(s)
- Jens Pahnke
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
- LIED, University of Lübeck, Lübeck, Germany
- Department of Pharmacology, Faculty of Medicine, University of Latvia, Rīga, Latvia
| | - Pablo Bascuñana
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Mirjam Brackhan
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
- LIED, University of Lübeck, Lübeck, Germany
| | - Katja Stefan
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Vigneshwaran Namasivayam
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany
| | - Radosveta Koldamova
- Department of Environmental and Occupational Health, School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Jingyun Wu
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Luisa Möhle
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Sven Marcel Stefan
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab, University of Oslo and Oslo University Hospital, Oslo, Norway
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Yogarajah J, Gouveia C, Iype J, Häfliger S, Schaller A, Nuoffer J, Fux M, Gautschi M. Efficacy and safety of secukinumab for the treatment of severe ABCA12 deficiency-related ichthyosis in a child. SKIN HEALTH AND DISEASE 2021; 1:e25. [PMID: 35664977 PMCID: PMC9060064 DOI: 10.1002/ski2.25] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 02/25/2021] [Accepted: 03/04/2021] [Indexed: 12/16/2022]
Abstract
Background Patients with severe autosomal recessive congenital ichthyosis (ARCI) show a T helper 17/interleukin 17 (Th17/IL17) skewing in their skin and serum, resembling the inflammatory profile of psoriatic patients. Secukinumab, an IL-17A inhibitor, has shown clinical efficacy in patients with moderate-to-severe plaque psoriasis. Aims To test the clinical efficacy and safety of secukinumab in a paediatric patient with ATP-binding cassette subfamily A member 12 deficiency-related severe erythrodermic ARCI. Materials & Methods 6-months therapeutic trial. During the first 4-weeks induction period, the patient received weekly subcutaneous injections of 150 mg secukinumab (five injections in total). During the following 20-weeks maintenance period, the patient was given a subcutaneous injection of 150 mg secukinumab every 4 weeks. Result & Discussion After the 6-months therapy period, there was a 48% reduction from the baseline Ichthyosis-Area-Severity-Index (-Erythema/-Scaling) score. The treatment was well tolerated. Moreover, cytokine analysis revealed a reduction of keratinocyte-derived proinflammatory cytokines and an abrogation of Th17-skewing during therapy. Conclusion Further studies are needed to evaluate the effects of the use of IL-17A inhibition in ARCI patients.
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Affiliation(s)
- J. Yogarajah
- Division of Paediatric Endocrinology, Diabetology and MetabolismDepartment of PaediatricsUniversity Hospital BernInselspitalBernSwitzerland
| | - C. Gouveia
- Division of Paediatric Endocrinology, Diabetology and MetabolismDepartment of PaediatricsUniversity Hospital BernInselspitalBernSwitzerland,Department of DermatologyUniversity Hospital BernInselspitalBernSwitzerland
| | - J. Iype
- University Institute of Clinical ChemistryUniversity Hospital BernInselspitalBernSwitzerland
| | - S. Häfliger
- Division of Paediatric Endocrinology, Diabetology and MetabolismDepartment of PaediatricsUniversity Hospital BernInselspitalBernSwitzerland,Department of DermatologyUniversity Hospital BernInselspitalBernSwitzerland
| | - A. Schaller
- Department of Human GeneticsUniversity Hospital BernInselspitalBernSwitzerland
| | - J.M. Nuoffer
- Division of Paediatric Endocrinology, Diabetology and MetabolismDepartment of PaediatricsUniversity Hospital BernInselspitalBernSwitzerland,University Institute of Clinical ChemistryUniversity Hospital BernInselspitalBernSwitzerland
| | - M. Fux
- University Institute of Clinical ChemistryUniversity Hospital BernInselspitalBernSwitzerland
| | - M. Gautschi
- Division of Paediatric Endocrinology, Diabetology and MetabolismDepartment of PaediatricsUniversity Hospital BernInselspitalBernSwitzerland,University Institute of Clinical ChemistryUniversity Hospital BernInselspitalBernSwitzerland
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Ip SCI, Cottle DL, Jones LK, Weir JM, Kelsell DP, O'Toole EA, Meikle PJ, Smyth IM. A profile of lipid dysregulation in harlequin ichthyosis. Br J Dermatol 2017; 177:e217-e219. [PMID: 28493316 DOI: 10.1111/bjd.15642] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- S C I Ip
- Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, 3800, VIC, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic, Australia
| | - D L Cottle
- Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, 3800, VIC, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - L K Jones
- Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, 3800, VIC, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - J M Weir
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, U.K
| | - D P Kelsell
- Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, 3800, VIC, Australia
| | - E A O'Toole
- Department of Anatomy and Developmental Biology, Monash University, Wellington Road, Clayton, 3800, VIC, Australia
| | - P J Meikle
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, U.K
| | - I M Smyth
- Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, 3800, VIC, Australia.,Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia
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Glick JB, Craiglow BG, Choate KA, Kato H, Fleming RE, Siegfried E, Glick SA. Improved Management of Harlequin Ichthyosis With Advances in Neonatal Intensive Care. Pediatrics 2017; 139:peds.2016-1003. [PMID: 27999114 DOI: 10.1542/peds.2016-1003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/05/2016] [Indexed: 11/24/2022] Open
Abstract
Harlequin ichthyosis (HI) is the most severe phenotype of the autosomal recessive congenital ichthyoses. HI is caused by mutations in the lipid transporter adenosine triphosphate binding cassette A 12 (ABCA12). Neonates are born with a distinct clinical appearance, encased in a dense, platelike keratotic scale separated by deep erythematous fissures. Facial features are distorted by severe ectropion, eclabium, flattened nose, and rudimentary ears. Skin barrier function is markedly impaired, which can lead to hypernatremic dehydration, impaired thermoregulation, increased metabolic demands, and increased risk of respiratory dysfunction and infection. Historically, infants with HI did not survive beyond the neonatal period; however, recent advances in neonatal intensive care and coordinated multidisciplinary management have greatly improved survival. In this review, the authors combine the growing HI literature with their collective experiences to provide a comprehensive review of the management of neonates with HI.
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Affiliation(s)
- Jaimie B Glick
- Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn, New York
| | | | - Keith A Choate
- Departments of Dermatology.,Genetics, and.,Pathology, Yale University School of Medicine, New Haven, Connecticut; and
| | | | | | - Elaine Siegfried
- Departments of Pediatrics and.,Dermatology, Saint Louis University School of Medicine, St Louis, Missouri
| | - Sharon A Glick
- Department of Dermatology, State University of New York Downstate Medical Center, Brooklyn, New York;
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The transcription cofactor CRTC1 protects from aberrant hepatic lipid accumulation. Sci Rep 2016; 6:37280. [PMID: 27869139 PMCID: PMC5116671 DOI: 10.1038/srep37280] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 10/27/2016] [Indexed: 12/28/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a rapidly emerging global health-problem. NAFLD encompasses a range of conditions associated with hepatic steatosis, aberrant accumulation of fat in hepatocytes. Although obesity and metabolic syndrome are considered to have a strong association with NAFLD, genetic factors that predispose liver to NAFLD and molecular mechanisms by which excess hepatic lipid develops remain largely unknown. We report that the transcription cofactor CRTC1 confers broad spectrum protection against hepatic steatosis development. CRTC1 directly interferes with the expression of genes regulated by lipogenic transcription factors, most prominently liver x receptor α (LXRα). Accordingly, Crtc1 deficient mice develop spontaneous hepatic steatosis in young age. As a cyclic AMP effector, CRTC1 mediates anti-steatotic effects of calorie restriction (CR). Notably, CRTC1 also mediates anti-lipogenic effects of bile acid signaling, whereas it is negatively regulated by miR-34a, a pathogenic microRNA upregulated in a broad spectrum of NAFLD. These patterns of gene function and regulation of CRTC1 are distinct from other CR-responsive proteins, highlighting critical protective roles that CRTC1 selectively plays against NAFLD development, which in turn provides novel opportunities for selectively targeting beneficial therapeutic effects of CR.
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Popa I, Portoukalian J, Haftek M. Specificity in the alteration of lesional and non-lesional skin lipids in atopic dogs. World J Dermatol 2015; 4:1-7. [DOI: 10.5314/wjd.v4.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 11/29/2014] [Accepted: 12/17/2014] [Indexed: 02/07/2023] Open
Abstract
The present paper is in the same time an overview of the literature concerning the alterations of lipids in the stratum corneum (SC) of atopic dogs and a review of data based on our publications. Knowing the importance of the SC barrier function for against pathogens in atopic dermatitis, we show for the first time a detailed biochemical analysis of lipids corresponding to the same amount of proteins in the successive layers of canine SC taken using tape stripping and their specificity as compared to humans. Also we show new results concerning the changes in the composition for protein-bound ceramides, and for the other lipids in involved and non-involved skin areas in atopic dogs. We show how a topical or oral treatment can restore the SC lipid composition and reconstruct the barrier integrity by up-regulating the biosynthesis of protein-bound ceramides.
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