Journal article
Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes
Nature genetics, Vol.52(5), pp.473-481
05/2020
DOI: 10.1038/s41588-020-0615-4
PMCID: PMC8353599
PMID: 32367058
Abstract
Here we report biallelic mutations in the sorbitol dehydrogenase gene (SORD) as the most frequent recessive form of hereditary neuropathy. We identified 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG (p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state. SORD is an enzyme that converts sorbitol into fructose in the two-step polyol pathway previously implicated in diabetic neuropathy. In patient-derived fibroblasts, we found a complete loss of SORD protein and increased intracellular sorbitol. Furthermore, the serum fasting sorbitol levels in patients were dramatically increased. In Drosophila, loss of SORD orthologs caused synaptic degeneration and progressive motor impairment. Reducing the polyol influx by treatment with aldose reductase inhibitors normalized intracellular sorbitol levels in patient-derived fibroblasts and in Drosophila, and also dramatically ameliorated motor and eye phenotypes. Together, these findings establish a novel and potentially treatable cause of neuropathy and may contribute to a better understanding of the pathophysiology of diabetes.
Details
- Title: Subtitle
- Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes
- Creators
- Andrea Cortese - Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. andrea.cortese@ucl.ac.ukYi Zhu - Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USAAdriana P Rebelo - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USASara Negri - Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, ItalySteve Courel - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USALisa Abreu - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAChelsea J Bacon - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USAYunhong Bai - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USADana M Bis-Brewer - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAEnrico Bugiardini - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKElena Buglo - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAMatt C Danzi - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAShawna M E Feely - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USAAlkyoni Athanasiou-Fragkouli - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKNourelhoda A Haridy - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, EgyptRosario Isasi - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAAlaa Khan - Molecular Diagnostic Unit, Clinical Laboratory Department, King Abdullah Medical City in Makkah, Mecca, Saudi ArabiaMatilde Laurà - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKStefania Magri - Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyMenelaos Pipis - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKChiara Pisciotta - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyEric Powell - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USAAlexander M Rossor - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKPaola Saveri - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyJanet E Sowden - Department of Neurology, University of Rochester, Rochester, NY, USAStefano Tozza - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, ItalyJana Vandrovcova - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKJulia Dallman - Department of Biology, University of Miami, Coral Gables, FL, USAElena Grignani - Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, ItalyEnrico Marchioni - IRCCS Mondino Foundation, Pavia, ItalySteven S Scherer - Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USABeisha Tang - Department of Neurology, Xiangya Hospital, Central South University, Changsha, ChinaZhiqiang Lin - Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, ChinaAbdullah Al-Ajmi - Division of Neurology, Department of Medicine, Al-Jahra Hospital, Al-Jahra, KuwaitRebecca Schüle - German Center of Neurodegenerative Diseases (DZNE), Tübingen, GermanyMatthis Synofzik - German Center of Neurodegenerative Diseases (DZNE), Tübingen, GermanyThierry Maisonobe - Department of Neurophysiology, AP-HP, Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, FranceTanya Stojkovic - Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, FranceMichaela Auer-Grumbach - Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, AustriaMohamed A Abdelhamed - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, EgyptSherifa A Hamed - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, EgyptRuxu Zhang - Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, ChinaFiore Manganelli - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, ItalyLucio Santoro - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, ItalyFranco Taroni - Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDavide Pareyson - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyHenry Houlden - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKDavid N Herrmann - Department of Neurology, University of Rochester, Rochester, NY, USAMary M Reilly - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UKMichael E Shy - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USAR Grace Zhai - Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.eduStephan Zuchner - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA. szuchner@med.miami.edu
- Resource Type
- Journal article
- Publication Details
- Nature genetics, Vol.52(5), pp.473-481
- DOI
- 10.1038/s41588-020-0615-4
- PMID
- 32367058
- PMCID
- PMC8353599
- NLM abbreviation
- Nat Genet
- ISSN
- 1061-4036
- eISSN
- 1546-1718
- Publisher
- United States
- Grant note
- Department of Health R21 GM119018 / NIGMS NIH HHS R61 AT010408 / NCCIH NIH HHS R01 NS105755 / NINDS NIH HHS 110043/Z/15/Z / Wellcome Trust 204841/Z/16/Z / Wellcome Trust MR/T001712/1 / Medical Research Council MR/179744 / Medical Research Council U54 NS065712 / NINDS NIH HHS R01 NS075764 / NINDS NIH HHS R01 NS072248 / NINDS NIH HHS
- Language
- English
- Date published
- 05/2020
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070216902771
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