Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes
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
Collaborators
- Inherited Neuropathy Consortium:
Aixa Rodriguez, Alexa Bacha, Ashley Kosikowski, Beth Wood, Brett McCray, Brianna Blume, Carly Siskind, Charlotte Sumner, Daniela Calabrese, David Walk, Dragan Vujovic, Eun Park, Francesco Muntoni, Gabrielle Donlevy, Gyula Acsadi, John Day, Joshua Burns, Jun Li, Karen Krajewski, Kate Eichinger, Kayla Cornett, Krista Mullen, Perez Quiros Laura, Laurie Gutmann, Maria Barrett, Mario Saporta, Mariola Skorupinska, Natalie Grant, Paula Bray, Reza Seyedsadjadi, Riccardo Zuccarino, Richard Finkel, Richard Lewis, Rosemary R Shy, Sabrina Yum, Sarah Hilbert, Simone Thomas, Steffen Behrens-Spraggins, Tara Jones, Thomas Lloyd, Tiffany Grider, Tim Estilow, Vera Fridman
Affiliations
- 1Dr. 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.
- 2Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK. andrea.cortese@ucl.ac.uk.
- 3Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. andrea.cortese@ucl.ac.uk.
- 4Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
- 5Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA.
- 6Dr. 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.
- 7Istituiti Clinici Scientifici Maugeri IRCCS, Environmental Research Center, Pavia, Italy.
- 8Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
- 9Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology and The National Hospital for Neurology, London, UK.
- 10Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt.
- 11Molecular Diagnostic Unit, Clinical Laboratory Department, King Abdullah Medical City in Makkah, Mecca, Saudi Arabia.
- 12Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
- 13Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
- 14Department of Neurology, University of Rochester, Rochester, NY, USA.
- 15Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples "Federico II", Naples, Italy.
- 16Department of Biology, University of Miami, Coral Gables, FL, USA.
- 17IRCCS Mondino Foundation, Pavia, Italy.
- 18Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- 19Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
- 20Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
- 21Division of Neurology, Department of Medicine, Al-Jahra Hospital, Al-Jahra, Kuwait.
- 22Department of Neurodegenerative Disease, Hertie-Institute for Clinical Brain Research, and Center for Neurology, University of Tübingen, Tübingen, Germany.
- 23German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany.
- 24Department of Neurophysiology, AP-HP, Sorbonne Université, Hôpital Pitié Salpêtrière, Paris, France.
- 25Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France.
- 26Department of Orthopaedics and Traumatology, Medical University of Vienna, Vienna, Austria.
- 27Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.edu.
- 28Program in Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, FL, USA. gzhai@med.miami.edu.
- 29Dr. 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.
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.
Conflict of interest statement
Competing interests: The authors declare no financial or commercial conflicts of interest.
Similar articles
Zhu Y, Lobato AG, Rebelo AP, Canic T, Ortiz-Vega N, Tao X, Syed S, Yanick C, Saporta M, Shy M, Perfetti R, Shendelman S, Züchner S, Zhai RG.JCI Insight. 2023 May 22;8(10):e164954. doi: 10.1172/jci.insight.164954.PMID: 37014713 Free PMC article.
Long read sequencing overcomes challenges in the diagnosis of SORD neuropathy.
Grosz BR, Stevanovski I, Negri S, Ellis M, Barnes S, Reddel S, Vucic S, Nicholson GA, Cortese A, Kumar KR, Deveson IW, Kennerson ML.J Peripher Nerv Syst. 2022 Jun;27(2):120-126. doi: 10.1111/jns.12485. Epub 2022 Mar 5.PMID: 35224818
Liu X, He J, Yilihamu M, Duan X, Fan D.Front Neurol. 2021 Nov 8;12:733926. doi: 10.3389/fneur.2021.733926. eCollection 2021.PMID: 34819907 Free PMC article.
Polyol pathway and diabetic peripheral neuropathy.
Oates PJ.Int Rev Neurobiol. 2002;50:325-92. doi: 10.1016/s0074-7742(02)50082-9.PMID: 12198816 Review.
Aldose reductase, still a compelling target for diabetic neuropathy.
Oates PJ.Curr Drug Targets. 2008 Jan;9(1):14-36. doi: 10.2174/138945008783431781.PMID: 18220710 Review.
Cited by
Ma Y, Duan X, Liu X, Fan D.Front Genet. 2023 Jul 13;14:1188361. doi: 10.3389/fgene.2023.1188361. eCollection 2023.PMID: 37519884 Free PMC article.
Deep structured learning for variant prioritization in Mendelian diseases.
Danzi MC, Dohrn MF, Fazal S, Beijer D, Rebelo AP, Cintra V, Züchner S.Nat Commun. 2023 Jul 13;14(1):4167. doi: 10.1038/s41467-023-39306-7.PMID: 37443090 Free PMC article.
Clinical Features of a Newly Described Mutation of Myelin Protein Zero in a Family.
Iyer VG, Shields LB, Zhang YP, Shields CB.Cureus. 2023 Jun 2;15(6):e39884. doi: 10.7759/cureus.39884. eCollection 2023 Jun.PMID: 37404437 Free PMC article.
Sharma SN, Hojati A, Gnanasambandam B, Yerrabelli RS, Brozek J.BMC Res Notes. 2023 Jul 3;16(1):129. doi: 10.1186/s13104-023-06367-2.PMID: 37400926 Free PMC article.
Tracer metabolomics reveals the role of aldose reductase in glycosylation.
Radenkovic S, Ligezka AN, Mokashi SS, Driesen K, Dukes-Rimsky L, Preston G, Owuocha LF, Sabbagh L, Mousa J, Lam C, Edmondson A, Larson A, Schultz M, Vermeersch P, Cassiman D, Witters P, Beamer LJ, Kozicz T, Flanagan-Steet H, Ghesquière B, Morava E.Cell Rep Med. 2023 Jun 20;4(6):101056. doi: 10.1016/j.xcrm.2023.101056. Epub 2023 May 30.PMID: 37257447 Free PMC article.