Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
04
11
2019
accepted:
20
03
2020
pubmed:
6
5
2020
medline:
6
5
2020
entrez:
6
5
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32367058
doi: 10.1038/s41588-020-0615-4
pii: 10.1038/s41588-020-0615-4
pmc: PMC8353599
mid: NIHMS1700234
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
473-481Subventions
Organisme : Medical Research Council
ID : MR/T001712/1
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/179744
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 110043/Z/15/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 204841/Z/16/Z
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R01 NS105755
Pays : United States
Organisme : NCCIH NIH HHS
ID : R61 AT010408
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS065712
Pays : United States
Organisme : NIGMS NIH HHS
ID : R21 GM119018
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS072248
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS075764
Pays : United States
Investigateurs
Aixa Rodriguez
(A)
Alexa Bacha
(A)
Ashley Kosikowski
(A)
Beth Wood
(B)
Brett McCray
(B)
Brianna Blume
(B)
Carly Siskind
(C)
Charlotte Sumner
(C)
Daniela Calabrese
(D)
David Walk
(D)
Dragan Vujovic
(D)
Eun Park
(E)
Francesco Muntoni
(F)
Gabrielle Donlevy
(G)
Gyula Acsadi
(G)
John Day
(J)
Joshua Burns
(J)
Jun Li
(J)
Karen Krajewski
(K)
Kate Eichinger
(K)
Kayla Cornett
(K)
Krista Mullen
(K)
Perez Quiros Laura
(PQ)
Laurie Gutmann
(L)
Maria Barrett
(M)
Mario Saporta
(M)
Mariola Skorupinska
(M)
Natalie Grant
(N)
Paula Bray
(P)
Reza Seyedsadjadi
(R)
Riccardo Zuccarino
(R)
Richard Finkel
(R)
Richard Lewis
(R)
Rosemary R Shy
(RR)
Sabrina Yum
(S)
Sarah Hilbert
(S)
Simone Thomas
(S)
Steffen Behrens-Spraggins
(S)
Tara Jones
(T)
Thomas Lloyd
(T)
Tiffany Grider
(T)
Tim Estilow
(T)
Vera Fridman
(V)
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Références
Rossor, A. M., Tomaselli, P. J. & Reilly, M. M. Recent advances in the genetic neuropathies. Curr. Opin. Neurol. 29, 537–548 (2016).
pubmed: 27584852
pmcid: 5130159
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).
pubmed: 25430934
Cortese, A. et al. Targeted next-generation sequencing panels in the diagnosis of Charcot-Marie-Tooth disease. Neurology 94, e51–e61 (2020).
pubmed: 31827005
pmcid: 7011687
Gonzalez, M. et al. Innovative genomic collaboration using the GENESIS (GEM.app) platform. Hum. Mutat. 36, 950–956 (2015).
pubmed: 26173844
pmcid: 4682547
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).
pubmed: 17952367
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).
pubmed: 26243339
1000 Genomes Project Consortium et al. A global reference for human genetic variation. Nature 526, 68–74 (2015).
Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).
pubmed: 27535533
pmcid: 27535533
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: 22975760
Antonarakis, S. E. Carrier screening for recessive disorders. Nat. Rev. Genet. 20, 549–561 (2019).
pubmed: 31142809
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: 22003934
pmcid: 3754828
Johansson, K. et al. Crystal structure of sorbitol dehydrogenase. Chem. Biol. Interact. 130–132, 351–358 (2001).
pubmed: 11306057
Lindstad, R. I., Teigen, K. & Skjeldal, L. Inhibition of sorbitol dehydrogenase by nucleosides and nucleotides. Biochem. Biophys. Res. Commun. 435, 202–208 (2013).
pubmed: 23665021
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).
pubmed: 9852094
Bellen, H. J. et al. The Drosophila Gene Disruption Project: progress using transposons with distinctive site specificities. Genetics 188, 731–743 (2011).
pubmed: 21515576
pmcid: 3176542
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).
pubmed: 1735111
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).
pubmed: 6407887
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).
pubmed: 18612195
Ramirez, M. A. & Borja, N. L. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy 28, 646–655 (2008).
pubmed: 18447661
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).
pubmed: 25998127
pmcid: 4498049
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).
pubmed: 26349493
Chalk, C., Benstead, T. J. & Moore, F. Aldose reductase inhibitors for the treatment of diabetic polyneuropathy. Cochrane Database Syst. Rev. 17, CD004572 (2007).
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: 26313450
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).
pubmed: 29975462
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: 15064763
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: 15077197
pmcid: 1181988
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).
pubmed: 3487654
pmcid: 1049628
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).
pubmed: 17846636
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).
pubmed: 27640307
pmcid: 5065660
Lupski, J. R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).
pubmed: 1677316
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).
pubmed: 11764088
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).
pubmed: 15755558
Obrosova, I. G. Increased sorbitol pathway activity generates oxidative stress in tissue sites for diabetic complications. Antioxid. Redox Signal. 7, 1543–1552 (2005).
pubmed: 16356118
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).
pubmed: 16805838
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).
pubmed: 7171128
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).
pubmed: 7708723
pmcid: 42302
Ng, T. F. et al. Effects of sorbitol dehydrogenase deficiency on nerve conduction in experimental diabetic mice. Diabetes 47, 961–966 (1998).
pubmed: 9604875
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: 23941916
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: 22608666
pmcid: 4254767
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).
pubmed: 8469345
Lorenzi, M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp. Diabetes Res. 2007, 61038 (2007).
pubmed: 18224243
pmcid: 1950230
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).
pubmed: 19635452