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。
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