Open AccessBiallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes
Author(s) -
Andrea Cortese,
Yi Zhu,
Stephan Züchner,
Sara Negri,
Steve Courel,
Lisa Abreu,
Chelsea Bacon,
Yunhong Bai,
Dana M. Bis-Brewer,
Enrico Bugiardini,
Elena Buglo,
Matt C. Danzi,
Shawna Feely,
Alkyoni Athanasiou-Fragkouli,
Nourelhoda A. Haridy,
Rosario Isasi,
Alaa Khan,
Matilde Laurá,
Stefania Magri,
Menelaos Pipis,
Chiara Pisciotta,
Eric Powell,
Alexander M. Rossor,
Paola Saveri,
Janet E. Sowden,
Stefano Tozza,
Jana Vandrovcová,
Julia E. Dallman,
Elena Grignani,
Enrico Marchioni,
Steven S. Scherer,
Beisha Tang,
Zhi Xiu Lin,
Abdullah Al-Ajmi,
Rebecca Schüle,
Matthis Synofzik,
Thierry Maisonobe,
Tanya Stojkovic,
Michaela AuerGrumbach,
Mohamed A. Abdelhamed,
Sherifa A. Hamed,
Ruxu Zhang,
Fiore Manganelli,
Lucio Santoro,
Franco Taroni,
Davide Pareyson,
Henry Houlden,
David N. Herrmann,
Michael E. Shy,
R. Grace Zhai
Publication year - 2020
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/s41588-020-0615-4
Subject(s) - polyol pathway , aldose reductase , sorbitol dehydrogenase , sorbitol , biology , compound heterozygosity , diabetes mellitus , nonsense mutation , genetics , mutation , medicine , endocrinology , gene , biochemistry , missense mutation
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.