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SORD的双等位基因突变会引起常见的遗传性神经病
2020-05-06 14:40

美国迈阿密大学Stephan Zuchner、R. Grace Zhai、Andrea Cortese等研究人员合作发现,SORD的双等位基因突变会引起常见的遗传性神经病,并对糖尿病有影响。这一研究成果于2020年5月4日在线发表在国际学术期刊《自然—遗传学》上。

研究人员发现,山梨糖醇脱氢酶基因(SORD)中的双等位基因突变是遗传性神经病的最常见隐性形式。研究人员鉴定了来自38个家庭的45名个体,这些个体在纯合或复合杂合状态下在SORD中携带无意义的c.757delG(p.Ala253GlnfsTer27)变异。
 
SORD是一种酶,可通过两步多元醇途径将山梨糖醇转化为果糖,这在之前与糖尿病性神经病有关联。在患者来源的成纤维细胞中,研究人员发现SORD蛋白完全丧失,细胞内山梨糖醇增加。此外,患者的血清禁食山梨糖醇水平显著增加。
 
在果蝇中,SORD直系同源物的丢失会引起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能够减少多元醇流入,从而可以使患者来源的成纤维细胞和果蝇中的细胞内山梨糖醇水平正常化,并且还可以显著改善运动和眼部表型。总之,这些发现建立了神经病的新型原因,并且可能有助于更好地了解糖尿病的病理生理。
 
附:英文原文

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

Author: Andrea Cortese, Yi Zhu, Adriana P. Rebelo, Sara Negri, Steve Courel, Lisa Abreu, Chelsea J. Bacon, Yunhong Bai, Dana M. Bis-Brewer, Enrico Bugiardini, Elena Buglo, Matt C. Danzi, Shawna M. E. Feely, Alkyoni Athanasiou-Fragkouli, Nourelhoda A. Haridy, Rosario Isasi, Alaa Khan, Matilde Laur, Stefania Magri, Menelaos Pipis, Chiara Pisciotta, Eric Powell, Alexander M. Rossor, Paola Saveri, Janet E. Sowden, Stefano Tozza, Jana Vandrovcova, Julia Dallman, Elena Grignani, Enrico Marchioni, Steven S. Scherer, Beisha Tang, Zhiqiang Lin, Abdullah Al-Ajmi, Rebecca Schle, Matthis Synofzik, Thierry Maisonobe, Tanya Stojkovic, Michaela Auer-Grumbach, Mohamed A. Abdelhamed, Sherifa A. Hamed, Ruxu Zhang, Fiore Manganelli, Lucio Santoro, Franco Taroni, Davide Pareyson, Henry Houlden, David N. Herrmann, Mary M. Reilly, Michael E. Shy, R. Grace Zhai, Stephan Zuchner

Issue&Volume: 2020-05-04

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.

DOI: 10.1038/s41588-020-0615-4

Source: https://www.nature.com/articles/s41588-020-0615-4

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:41.307
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex


本期文章:《自然—遗传学》:Online/在线发表

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