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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All data described in this paper are present either in the main text or in the Supplementary Information. Source data for Fig. 2 are presented with the paper. The sequence data obtained by WES and WGS are not publicly available because the study participants did not give full consent for releasing data publicly.
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This project was supported by the NINDS (R01NS075764 to S.Z. and M.S.; R01NS105755 to S.Z.), the NIH (R21GM119018 and 1R61AT010408 to R.G.Z.), the NCATS (U54NS065712 to M.S.), the CMT Association, the Hereditary Neuropathy Foundation, The Genesis Project foundation, the Muscular Dystrophy Association, the European Union’s Horizon 2020 research and innovation programme under the ERA-NET Cofund action no. 643578 under the frame of the E-Rare-3 network PREPARE (01GM1607 to M.S.; and unfunded to S.Z.), the grant 779257 ‘Solve-RD’ (to R.S. and M.S., M.M.R. and H.H.) and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to M.L.). The project received further support from the ‘Bundesministerium für Bildung und Forschung’ (BMBF) via funding for the TreatHSP consortium (01GM1905 to R.S.) and the National Institutes of Health (grant 5R01NS072248 to R.S. and S.Z.), the Austrian Science Fund (FWF, P27634FW to M.A.-G.) and the National Natural Science Foundation of China (81771366). A.C. thanks the Medical Research Council (MR/T001712/1), the Wellcome Trust (204841/Z/16/Z), the Fondazione CARIPLO (2019-1836), the Italian Ministry of Health Ricerca Corrente 2018–2019 and the Inherited Neuropathy Consortium (INC) for grant support. H.H. and M.M.R. thank the MRC, the Wellcome Trust, the MDA, MD UK, Ataxia UK, The MSA Trust, the Rosetrees Trust and the NIHR UCLH BRC for grant support. A.M.R. is funded by a Wellcome Trust Postdoctoral Fellowship for Clinicians (110043/Z/15/Z). D.N.H. receives grant support through NIH U54 NS065712-09, the Muscular Dystrophy Association, the Friedreich’s Ataxia Alliance and Voyager Pharmaceuticals. We thank M. Tekin for kindly providing DNA from healthy controls or Turkish ancestry. We also thank Twenty Three Calvin (Marie Stargala and Matthew Rosen) for creating the cover art for the issue.
The authors declare no competing interests.
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The squares indicate males, the circles females, and the diagonal lines deceased individuals. Patients are indicated with filled shapes. Genotypes are provided when tested by Sanger sequencing.
Life span of control flies (yw) and Sodh2MB01265/MB01265 flies. Data are shown in Kaplan-Meier survival plot. n = 100 biologically independent animals. Significance level was established by a two-sided log-rank test.
Extended Data Fig. 3 Double knockdown of Drosophila Sodh1 and Sodh2 causes age-dependent synaptic degeneration.
a,b, Laminae of control (GMR-GAL4 heterozygotes) or Sodh1 and Sodh2 double knockdown homozygous flies at 2 DAE and 10 DAE were stained with HRP (green; marks neuronal membranes) and BRP (magenta; marks synaptic active zones). Yellow arrowheads indicate vacuole-like structures in the lamina that correspond to missing terminals. The areas outlined by yellow boxes are shown at higher magnification. The intensity of BRP is indicated using a red spectrum. Dotted lines indicate the area of lamina vacuole-like structures. Scale bars: 30 μm. c, Quantification of the number and size of vacuole-like structures. n = 8 biologically independent samples. Data are presented as mean ± s.d. (error bars). Statistical analysis was performed using two-way ANOVA followed by post-hoc Tukey’s multiple comparison test.
Extended Data Fig. 4 Treatment with aldose reductase inhibitors Epalrestat and Ranirestat restore locomotor function in Sodh1 and Sodh2 double knockdown flies.
Locomotor activity of control flies (yw) feeding with DMSO, or flies with neuronal-specific knockdown of Sodh1 and Sodh2 feeding with DMSO, 80 μg/ml Epalrestat, or 80 μg/ml Ranirestat. n = 10 in 2, 10, 20, 30, 40 DAE, and n = 8 in 50 DAE. Data are presented as mean ± s.d. (error bars). Statistical analysis was performed using two-way ANOVA followed by post-hoc Tukey’s multiple comparison test.
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Cortese, A., Zhu, Y., Rebelo, A.P. et al. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet 52, 473–481 (2020). https://doi.org/10.1038/s41588-020-0615-4
Nature Genetics (2020)