Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.
Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes.
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SORD 的双等位基因突变会导致一种常见且可治疗的遗传性神经病，对糖尿病有影响
DOI：
10.1038/s41588-020-0615-4
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发表时间：
2020-05
期刊：
影响因子：
30.8
通讯作者：
Zuchner S
中科院分区：
文献类型：
--
作者：
Cortese A;Zhu Y;Rebelo AP;Negri S;Courel S;Abreu L;Bacon CJ;Bai Y;Bis-Brewer DM;Bugiardini E;Buglo E;Danzi MC;Feely SME;Athanasiou-Fragkouli A;Haridy NA;Inherited Neuropathy Consortium;Isasi R;Khan A;Laurà M;Magri S;Pipis M;Pisciotta C;Powell E;Rossor AM;Saveri P;Sowden JE;Tozza S;Vandrovcova J;Dallman J;Grignani E;Marchioni E;Scherer SS;Tang B;Lin Z;Al-Ajmi A;Schüle R;Synofzik M;Maisonobe T;Stojkovic T;Auer-Grumbach M;Abdelhamed MA;Hamed SA;Zhang R;Manganelli F;Santoro L;Taroni F;Pareyson D;Houlden H;Herrmann DN;Reilly MM;Shy ME;Zhai RG;Zuchner S
在这里，我们报告山梨醇脱氢酶基因（SORD）的双等位基因突变作为最常见的隐性遗传性神经病。我们确定了来自38个家庭的45个个体，在多个祖先携带无义c.757delG（p.Ala253GlnfsTer27）变异的SORD，在纯合或复合杂合状态。SORD是一种酶，在先前涉及糖尿病神经病变的两步多元醇途径中将山梨糖醇转化为果糖。在患者来源的成纤维细胞中，我们发现SORD蛋白完全丢失，细胞内山梨醇增加。此外，患者的血清空腹山梨醇水平显著升高。在果蝇中，SORD同源基因的丢失导致突触变性和进行性运动障碍。通过用醛糖还原酶抑制剂治疗减少多元醇流入，使患者来源的成纤维细胞和果蝇中的细胞内山梨醇水平正常化，并且还显著改善了运动和眼睛表型。总之，这些发现建立了一个新的和潜在的可治疗的神经病变的原因，并可能有助于更好地了解糖尿病的病理生理。山梨醇脱氢酶基因SORD的双等位基因突变被认为是遗传性神经病的常见病因。功能研究表明，SORD缺乏症可以用醛糖还原酶抑制剂治疗。
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. Biallelic mutations in the sorbitol dehydrogenase gene SORD are identified as a common cause of hereditary neuropathy. Functional studies suggest that SORD deficiency may be treatable with aldose reductase inhibitors.
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DOI：
10.1111/j.1529-8027.2011.00350.x
发表时间：
2011-09
期刊：
Journal of the peripheral nervous system : JPNS
影响因子：
--
作者：
Murphy SM;Herrmann DN;McDermott MP;Scherer SS;Shy ME;Reilly MM;Pareyson D
通讯作者：
Pareyson D
DOI：
10.1016/j.bbrc.2013.04.081
发表时间：
2013-05-31
影响因子：
3.1
作者：
Lindstad, Rune I.;Teigen, Knut;Skjeldal, Lars
通讯作者：
Skjeldal, Lars
影响因子：
3.6
作者：
BAUSENWEIN, B;DITTRICH, APM;FISCHBACH, KF
通讯作者：
FISCHBACH, KF
DOI：
10.1073/pnas.92.7.2780
发表时间：
1995-03-28
影响因子：
11.1
作者：
LEE, AYW;CHUNG, SK;CHUNG, SSM
通讯作者：
CHUNG, SSM
影响因子：
3.9
作者：
Gonzalez M;Falk MJ;Gai X;Postrel R;Schüle R;Zuchner S
通讯作者：
Zuchner S