Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Andrea Cortese; Yi Zhu; Adriana P Rebelo; Sara Negri; Steve Courel; Lisa Abreu; Chelsea J Bacon; Yunhong Bai; Dana M Bis-Brewer; Enrico Bugiardini; Elena Buglo; Matt C Danzi; Shawna M E Feely; Alkyoni Athanasiou-Fragkouli; Nourelhoda A Haridy; Rosario Isasi; Alaa Khan; Matilde Laurà; Stefania Magri; Menelaos Pipis; Chiara Pisciotta; Eric Powell; Alexander M Rossor; Paola Saveri; Janet E Sowden; Stefano Tozza; Jana Vandrovcova; Julia Dallman; Elena Grignani; Enrico Marchioni; Steven S Scherer; Beisha Tang; Zhiqiang Lin; Abdullah Al-Ajmi; Rebecca Schüle; Matthis Synofzik; Thierry Maisonobe; Tanya Stojkovic; Michaela Auer-Grumbach; Mohamed A Abdelhamed; Sherifa A Hamed; Ruxu Zhang; Fiore Manganelli; Lucio Santoro; Franco Taroni; Davide Pareyson; Henry Houlden; David N Herrmann; Mary M Reilly; Michael E Shy; R Grace Zhai; Stephan Zuchner

doi:10.1038/s41588-020-0615-4

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Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Journal article

Peer reviewed

Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

Andrea Cortese, Yi Zhu, Adriana P Rebelo, Sara Negri, Steve Courel, Lisa Abreu, Chelsea J Bacon, Yunhong Bai, Dana M Bis-Brewer, Enrico Bugiardini, …

Nature genetics, Vol.52(5), pp.473-481

2020-05

DOI: https://doi.org/10.1038/s41588-020-0615-4

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.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.253 Nerve Disorders; 1.253.1972 Charcot-Marie-Tooth Disease
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics

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Title: 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.uk
Yi Zhu - Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA
Adriana 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, USA
Sara Negri - Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy
Steve 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, USA
Lisa 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, USA
Chelsea J Bacon - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Yunhong Bai - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Dana 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, USA
Enrico Bugiardini - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Elena 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, USA
Matt 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, USA
Shawna M E Feely - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Alkyoni Athanasiou-Fragkouli - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Nourelhoda A Haridy - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt
Rosario 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, USA
Alaa Khan - Molecular Diagnostic Unit, Clinical Laboratory Department, King Abdullah Medical City in Makkah, Mecca, Saudi Arabia
Matilde Laurà - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Stefania Magri - Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Menelaos Pipis - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Chiara Pisciotta - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Eric 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, USA
Alexander M Rossor - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Paola Saveri - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Janet E Sowden - Department of Neurology, University of Rochester, Rochester, NY, USA
Stefano Tozza - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
Jana Vandrovcova - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Julia Dallman - Department of Biology, University of Miami, Coral Gables, FL, USA
Elena Grignani - Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy
Enrico Marchioni - IRCCS Mondino Foundation, Pavia, Italy
Steven S Scherer - Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Beisha Tang - Department of Neurology, Xiangya Hospital, Central South University, Changsha, China
Zhiqiang Lin - Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
Abdullah Al-Ajmi - Division of Neurology, Department of Medicine, Al-Jahra Hospital, Al-Jahra, Kuwait
Rebecca Schüle - German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
Matthis Synofzik - German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
Thierry Maisonobe - Department of Neurophysiology, AP-HP, Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, France
Tanya Stojkovic - Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France
Michaela Auer-Grumbach - Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria
Mohamed A Abdelhamed - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt
Sherifa A Hamed - Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt
Ruxu Zhang - Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China
Fiore Manganelli - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
Lucio Santoro - Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy
Franco Taroni - Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Davide Pareyson - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
Henry Houlden - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
David N Herrmann - Department of Neurology, University of Rochester, Rochester, NY, USA
Mary M Reilly - Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK
Michael E Shy - Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
R Grace Zhai - Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.edu
Stephan 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
Publication Details: Nature genetics, Vol.52(5), pp.473-481
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
Academic Unit: Leadership Department; Miller School of Medicine; College of A&S; John P. Hussman Institute for Human Genomics; Molecular and Cellular Pharmacology Research; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); A&S - Biology
Language: English
Resource Type: Journal article
PMID: 32367058
Record Identifier: 991031576551702976