Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

An Author Correction to this article was published on 26 May 2020

This article has been updated

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Biallelic mutations in SORD cause autosomal recessive dHMN/CMT2.
Fig. 2: Decreased SORD expression and sorbitol accumulation in patients.
Fig. 3: Loss of Drosophila Sodh2 causes age-dependent synaptic degeneration.
Fig. 4: Treatment with aldose reductase inhibitors epalrestat and ranirestat decreases sorbitol levels and prevents functional losses.

Data availability

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.

Change history

References

  1. 1.

    Rossor, A. M., Tomaselli, P. J. & Reilly, M. M. Recent advances in the genetic neuropathies. Curr. Opin. Neurol. 29, 537–548 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Fridman, V. et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J. Neurol. Neurosurg. Psychiatry 86, 873–878 (2015).

    CAS  PubMed  Google Scholar 

  3. 3.

    Cortese, A. et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology 94, e51–e61 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gonzalez, M. et al. Innovative genomic collaboration using the GENESIS (GEM.app) platform. Hum. Mutat. 36, 950–956 (2015).

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Hellgren, M., Kaiser, C., de Haij, S., Norberg, A. & Höög, J.-O. A hydrogen-bonding network in mammalian sorbitol dehydrogenase stabilizes the tetrameric state and is essential for the catalytic power. Cell. Mol. Life Sci. 64, 3129–3138 (2007).

    CAS  PubMed  Google Scholar 

  6. 6.

    Carr, A. S. et al. A study of the neuropathy associated with transthyretin amyloidosis (ATTR) in the UK. J. Neurol. Neurosurg. Psychiatry 87, 620–627 (2016).

    CAS  PubMed  Google Scholar 

  7. 7.

    1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Google Scholar 

  8. 8.

    Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Lazarin, G. A. et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet. Med. 15, 178–186 (2013).

    PubMed  Google Scholar 

  10. 10.

    Antonarakis, S. E. Carrier screening for recessive disorders. Nat. Rev. Genet. 20, 549–561 (2019).

    CAS  PubMed  Google Scholar 

  11. 11.

    Murphy, S. M. et al. Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J. Peripher. Nerv. Syst. 16, 191–198 (2011).

    PubMed  PubMed Central  Google Scholar 

  12. 12.

    Johansson, K. et al. Crystal structure of sorbitol dehydrogenase. Chem. Biol. Interact. 130–132, 351–358 (2001).

    PubMed  Google Scholar 

  13. 13.

    Lindstad, R. I., Teigen, K. & Skjeldal, L. Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides. Biochem. Biophys. Res. Commun. 435, 202–208 (2013).

    CAS  PubMed  Google Scholar 

  14. 14.

    Luque, T. et al. Sorbitol dehydrogenase of Drosophila. Gene, protein, and expression data show a two-gene system. J. Biol. Chem. 273, 34293–34301 (1998).

    CAS  PubMed  Google Scholar 

  15. 15.

    Bellen, H. J. et al. The Drosophila Gene Disruption Project: progress using transposons with distinctive site specificities. Genetics 188, 731–743 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Bausenwein, B., Dittrich, A. P. & Fischbach, K. F. The optic lobe of Drosophila melanogaster. II. Sorting of retinotopic pathways in the medulla. Cell Tissue Res. 267, 17–28 (1992).

    CAS  PubMed  Google Scholar 

  17. 17.

    Kikkawa, R. et al. Effect of a new aldose reductase inhibitor, (E)-3-carboxymethyl-5-[(2E)-methyl-3-phenylpropenylidene]rhodanine (ONO-2235) on peripheral nerve disorders in streptozotocin-diabetic rats. Diabetologia 24, 290–292 (1983).

    CAS  PubMed  Google Scholar 

  18. 18.

    Matsumoto, T. et al. Long-term treatment with ranirestat (AS-3201), a potent aldose reductase inhibitor, suppresses diabetic neuropathy and cataract formation in rats. J. Pharmacol. Sci. 107, 340–348 (2008).

    CAS  PubMed  Google Scholar 

  19. 19.

    Ramirez, M. A. & Borja, N. L. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28, 646–655 (2008).

    CAS  PubMed  Google Scholar 

  20. 20.

    Hao, W. et al. Hyperglycemia promotes Schwann cell de-differentiation and de-myelination via sorbitol accumulation and Igf1 protein down-regulation. J. Biol. Chem. 290, 17106–17115 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Grewal, A. S., Bhardwaj, S., Pandita, D., Lather, V. & Sekhon, B. S. Updates on aldose reductase inhibitors for management of diabetic complications and non-diabetic diseases. Mini Rev. Med. Chem. 16, 120–162 (2016).

    CAS  PubMed  Google Scholar 

  22. 22.

    Chalk, C., Benstead, T. J. & Moore, F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst. Rev. 17, CD004572 (2007).

    Google Scholar 

  23. 23.

    Polydefkis, M. et al. Safety and efficacy of ranirestat in patients with mild-to-moderate diabetic sensorimotor polyneuropathy. J. Peripher. Nerv. Syst. 20, 363–371 (2015).

    PubMed  Google Scholar 

  24. 24.

    Sekiguchi, K. et al. Aldose reductase inhibitor ranirestat significantly improves nerve conduction velocity in diabetic polyneuropathy: a randomized double-blind placebo-controlled study in Japan. J. Diabetes Investig. 10, 466–474 (2019).

    CAS  PubMed  Google Scholar 

  25. 25.

    Züchner, S. et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat. Genet. 36, 449–451 (2004).

    PubMed  Google Scholar 

  26. 26.

    De Vos, M., Hayward, B. E., Picton, S., Sheridan, E. & Bonthron, D. T. Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome. Am. J. Hum. Genet. 74, 954–964 (2004).

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Rumsby, G., Carroll, M. C., Porter, R. R., Grant, D. B. & Hjelm, M. Deletion of the steroid 21-hydroxylase and complement C4 genes in congenital adrenal hyperplasia. J. Med. Genet. 23, 204–209 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Chen, J.-M., Cooper, D. N., Chuzhanova, N., Férec, C. & Patrinos, G. P. Gene conversion: mechanisms, evolution and human disease. Nat. Rev. Genet. 8, 762–775 (2007).

    CAS  PubMed  Google Scholar 

  29. 29.

    Harel, T. et al. Recurrent de novo and biallelic variation of ATAD3A, encoding a mitochondrial membrane protein, results in distinct neurological syndromes. Am. J. Hum. Genet. 99, 831–845 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Lupski, J. R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

    CAS  PubMed  Google Scholar 

  31. 31.

    Schmidt, R. E. et al. Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes. J. Neuropathol. Exp. Neurol. 60, 1153–1169 (2001).

    CAS  PubMed  Google Scholar 

  32. 32.

    Schmidt, R. E. et al. A potent sorbitol dehydrogenase inhibitor exacerbates sympathetic autonomic neuropathy in rats with streptozotocin-induced diabetes. Exp. Neurol. 192, 407–419 (2005).

    CAS  PubMed  Google Scholar 

  33. 33.

    Obrosova, I. G. Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxid. Redox Signal. 7, 1543–1552 (2005).

    CAS  PubMed  Google Scholar 

  34. 34.

    Sango, K. et al. High glucose-induced activation of the polyol pathway and changes of gene expression profiles in immortalized adult mouse Schwann cells IMS32. J. Neurochem. 98, 446–458 (2006).

    CAS  PubMed  Google Scholar 

  35. 35.

    Holmes, R. S., Duley, J. A. & Hilgers, J. Sorbitol dehydrogenase genetics in the mouse: a “null” mutant in a “European” C57BL strain. Anim. Blood Groups Biochem. Genet. 13, 263–272 (1982).

    CAS  PubMed  Google Scholar 

  36. 36.

    Lee, A. Y., Chung, S. K. & Chung, S. S. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc. Natl Acad. Sci. USA 92, 2780–2784 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Ng, T. F. et al. Effects of sorbitol dehydrogenase deficiency on nerve conduction in experimental diabetic mice. Diabetes 47, 961–966 (1998).

    CAS  PubMed  Google Scholar 

  38. 38.

    Ruff, J. S. et al. Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice. Nat. Commun. 4, 2245 (2013).

    PubMed  Google Scholar 

  39. 39.

    Callaghan, B. C., Cheng, H. T., Stables, C. L., Smith, A. L. & Feldman, E. L. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 11, 521–534 (2012).

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Dyck, P. J. et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology 43, 817–824 (1993).

    CAS  PubMed  Google Scholar 

  41. 41.

    Lorenzi, M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp. Diabetes Res. 2007, 61038 (2007).

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Li, L. et al. The induction of trehalose and glycerol in Saccharomyces cerevisiae in response to various stresses. Biochem. Biophys. Res. Commun. 387, 778–783 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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.

Author information

Affiliations

Authors

Consortia

Contributions

Conceptualization: A.C. and S.Z. Funding acquisition: S.Z., M.E.S., M.M.R., H.H., R.S. and M.S., Investigation: A.C., Y.Z., A.P.R., S.N., S.C., M.P., E.Buglo, R.G.Z. and S.Z. Resources: A.C., Y.Z., A.P.R., S.N., S.C., L.A., A.A.-A, M.A.-G., C.J.B., Y.B., D.M.B-.B., E.Bugiardini, J.D., M.C.D., S.M.E.F., A.A.-F., E.G., M.A.A., S.A.H., N.A.H., H.H., R.I., A.K., M.L., Z.L., S.M., T.M., F.M., E.M., D.P., M.P., C.P., E.P., A.M.R., L.S., S.S.S., R.S., J.E.S., T.S., M.S., P.S., B.T., F.T., S.T., J.V., R.Z., D.N.H., M.M.R., M.E.S., R.G.Z. and S.Z. Supervision: S.Z. and R.G.Z. Writing–original draft: A.C., Y.Z., A.P.R., R.G.Z. and S.Z. All authors contributed to revising the manuscript.

Corresponding authors

Correspondence to Andrea Cortese or R. Grace Zhai or Stephan Zuchner.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Pedigrees of families carrying biallelic mutations in SORD.

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.

Extended Data Fig. 2 Loss of Drosophila Sodh does not affect life span.

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.

Supplementary information

Source data

Source Data Fig. 2

Unprocessed western blots for Fig. 2.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing