SORD的雙等位基因突變會引起常見的遺傳性神經病
作者：
小柯機器人發布時間：2020/5/6 14:40:08
美國邁阿密大學Stephan Zuchner、R. Grace Zhai、Andrea Cortese等研究人員合作發現，SORD的雙等位基因突變會引起常見的遺傳性神經病，並對糖尿病有影響。這一研究成果於2020年5月4日在線發表在國際學術期刊《自然—遺傳學》上。
研究人員發現，山梨糖醇脫氫酶基因（SORD）中的雙等位基因突變是遺傳性神經病的最常見隱性形式。研究人員鑑定了來自38個家庭的45名個體，這些個體在純合或複合雜合狀態下在SORD中攜帶無意義的c.757delG（p.Ala253GlnfsTer27）變異。
SORD是一種酶，可通過兩步多元醇途徑將山梨糖醇轉化為果糖，這在之前與糖尿病性神經病有關聯。在患者來源的成纖維細胞中，研究人員發現SORD蛋白完全喪失，細胞內山梨糖醇增加。此外，患者的血清禁食山梨糖醇水平顯著增加。
在果蠅中，SORD直系同源物的丟失會引起突觸變性和進行性運動障礙。通過用醛糖還原酶抑制劑治療能夠減少多元醇流入，從而可以使患者來源的成纖維細胞和果蠅中的細胞內山梨糖醇水平正常化，並且還可以顯著改善運動和眼部表型。總之，這些發現建立了神經病的新型原因，並且可能有助於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