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

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.

SUBMITTER: Cortese A

PROVIDER: S-EPMC8353599 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Cortese Andrea A Zhu Yi Y Rebelo Adriana P AP Negri Sara S Courel Steve S Abreu Lisa L Bacon Chelsea J CJ Bai Yunhong Y Bis-Brewer Dana M DM Bugiardini Enrico E Buglo Elena E Danzi Matt C MC Feely Shawna M E SME Athanasiou-Fragkouli Alkyoni A Haridy Nourelhoda A NA Isasi Rosario R Khan Alaa A Laurà Matilde M Magri Stefania S Pipis Menelaos M Pisciotta Chiara C Powell Eric E Rossor Alexander M AM Saveri Paola P Sowden Janet E JE Tozza Stefano S Vandrovcova Jana J Dallman Julia J Grignani Elena E Marchioni Enrico E Scherer Steven S SS Tang Beisha B Lin Zhiqiang Z Al-Ajmi Abdullah A Schüle Rebecca R Synofzik Matthis M Maisonobe Thierry T Stojkovic Tanya T Auer-Grumbach Michaela M Abdelhamed Mohamed A MA Hamed Sherifa A SA Zhang Ruxu R Manganelli Fiore F Santoro Lucio L Taroni Franco F Pareyson Davide D Houlden Henry H Herrmann David N DN Reilly Mary M MM Shy Michael E ME Zhai R Grace RG Zuchner Stephan S

Nature genetics 20200504 5

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, ...[more]

PMID: 32367058

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Project description:Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G>T (p.1Met?) was identified in the COQ7 gene. This gene encodes a protein required for coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood samples and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G>T (p.1Met?) in the COQ7 gene and the effect of coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient's fibroblasts, resulting in a decrease in coenzyme Q10 production and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient's plasma. Normal coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing the COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair the mitochondrial respiratory chain. Seahorse experiments showed that the patient's cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by coenzyme Q10 supplementation of the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

Dataset Information

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

Publications

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

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