2. Academic Validation
  3. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes

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

  • Nat Genet. 2020 May;52(5):473-481. doi: 10.1038/s41588-020-0615-4.
Andrea Cortese # 1 2 3,  Yi Zhu # 4 5,  Adriana P Rebelo # 6,  Sara Negri 7,  Steve Courel 6,  Lisa Abreu 6,  Chelsea J Bacon 8,  Yunhong Bai 8,  Dana M Bis-Brewer 6,  Enrico Bugiardini 9,  Elena Buglo 6,  Matt C Danzi 6,  Shawna M E Feely 8,  Alkyoni Athanasiou-Fragkouli 9,  Nourelhoda A Haridy 9 10,  Inherited Neuropathy Consortium,  Rosario Isasi 6,  Alaa Khan 9 11,  Matilde Laurà 9,  Stefania Magri 12,  Menelaos Pipis 9,  Chiara Pisciotta 13,  Eric Powell 6,  Alexander M Rossor 9,  Paola Saveri 13,  Janet E Sowden 14,  Stefano Tozza 15,  Jana Vandrovcova 9,  Julia Dallman 16,  Elena Grignani 7,  Enrico Marchioni 17,  Steven S Scherer 18,  Beisha Tang 19,  Zhiqiang Lin 20,  Abdullah Al-Ajmi 21,  Rebecca Schüle 22 23,  Matthis Synofzik 22 23,  Thierry Maisonobe 24,  Tanya Stojkovic 25,  Michaela Auer-Grumbach 26,  Mohamed A Abdelhamed 10,  Sherifa A Hamed 10,  Ruxu Zhang 20,  Fiore Manganelli 15,  Lucio Santoro 15,  Franco Taroni 12,  Davide Pareyson 13,  Henry Houlden 9,  David N Herrmann 14,  Mary M Reilly 9,  Michael E Shy 8,  R Grace Zhai 27 28,  Stephan Zuchner 29
Affiliations

Affiliations

  • 1 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. andrea.cortese@ucl.ac.uk.
  • 2 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK. andrea.cortese@ucl.ac.uk.
  • 3 Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. andrea.cortese@ucl.ac.uk.
  • 4 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 5 Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 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.
  • 7 Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy.
  • 8 Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
  • 9 Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
  • 10 Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt.
  • 11 Molecular Diagnostic Unit, Clinical Laboratory Department, King Abdullah Medical City in Makkah, Mecca, Saudi Arabia.
  • 12 Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 13 Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • 14 Department of Neurology, University of Rochester, Rochester, NY, USA.
  • 15 Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy.
  • 16 Department of Biology, University of Miami, Coral Gables, FL, USA.
  • 17 IRCCS Mondino Foundation, Pavia, Italy.
  • 18 Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 19 Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
  • 20 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
  • 21 Division of Neurology, Department of Medicine, Al-Jahra Hospital, Al-Jahra, Kuwait.
  • 22 Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Tübingen, Germany.
  • 23 German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
  • 24 Department of Neurophysiology, AP-HP, Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, France.
  • 25 Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
  • 26 Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria.
  • 27 Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.edu.
  • 28 Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.edu.
  • 29 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.
  • # Contributed equally.
PMID: 32367058 DOI: 10.1038/s41588-020-0615-4
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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