机构：[1]Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China首都医科大学宣武医院[2]Department of Neurology, Sanming First Hospital Affiliated to Fujian Medical University, Sanming, Fujian China[3]Department of Neurology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China[4]Department of Neurology, The Union Hospital Affiliated to Fujian Medical University, China[5]Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China中山大学附属第一医院[6]Department of Neurology, West China Hospital of Sichuan University, Chengdu, China[7]National Clinical Research Center for Geriatric Diseases, Beijing, China
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Over 90% of cases are sporadic (sALS) and 5%-10% are familial (fALS). So far, more than 20 genes/loci have been linked to ALS. C9orf72, SOD1, TARDBP, and FUS are noted as the most common ALS genes; however, mutations of these genes explain <10% of sALS cases. Recently, Rho guanine nucleotide exchange factor, encoded by ARHGEF28, has been linked to the ALS pathogenesis, possibly by binding low-molecular-weight neurofilament mRNA and affects its stability. However, a systemic screening of ARHGEF28 mutations in ALS is lacking. In this study, we sequenced the entire coding sequence of ARHGEF28 in a Chinese cohort of 399 sporadic ALS and 327 elderly controls. A total of 73 coding variants were identified, including 26 synonymous and 47 nonsynonymous. Among the nonsynonymous variants, 33 were rare (minor allele frequency [MAF] < 0.01), in which 18 were only identified in cases and 12 were only in controls. Three loss-of-function mutations were identified, including 2 truncations (p.Arg231Ter and p.Ser561Ter) and a frameshift deletion (p.Lys1070fs) in 2 cases and 1 control subject. The frequency of total and case-only rare variants was 7.5% (30/399) and 5.0% (20/399), respectively, in the patients. SKAT-O test suggested that the novel coding variants were marginally enriched in the cases (p = 0.049). Single-variant analysis suggested that the p.Asn1046Ser variant had a higher frequency in cases (8/399, 0.02) than in controls (1/327, 0.003) (OR: 6.67, 95% CI: 0.83-53.61; p = 0.046). By contrast, none of the low-frequency (MAF: 0.01-0.05) or common (MAF > 0.05) variants was associated with ALS (p > 0.05). Among all patients, 9 (2.3%) carried rare variants predicted to be deleterious, and the age at onset of these carriers (45.6 +/- 10.9 years) was marginally younger than noncarriers (51.9 +/- 10.7 years) (p = 0.11). Our results supported a possible genetic contribution of rare but not low-frequency and common coding variants to ALS. These data may have implications in the mechanisms and genetic counseling of the disease. (C) 2019 Elsevier Inc. All rights reserved.
基金：
Natural Science Foundation of Fujian Province, ChinaNatural Science Foundation of Fujian Province [2016J01487]; Ministry of Science and Technology [2016YFC1306003]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81771212]; Sichuan Key Project of Science and Technology [2010SZ0086]
第一作者机构：[1]Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China
共同第一作者：
通讯作者：
通讯机构：[*1]Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.[*2]Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.[*3]Department of Neurology, Xuanwu Hospital of Capital Medical University, #45 Changchun Street, 100053 Beijing, China.
推荐引用方式(GB/T 7714)：
Song Yang,Lin Feng,Ye Cheng-hui,et al.Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis[J].NEUROBIOLOGY OF AGING.2020,87:doi:10.1016/j.neurobiolaging.2019.02.021.
APA：
Song, Yang,Lin, Feng,Ye, Cheng-hui,Huang, Huaping,Li, Xuying...&Wang, Chaodong.(2020).Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis.NEUROBIOLOGY OF AGING,87,
MLA：
Song, Yang,et al."Rare, low-frequency and common coding variants of ARHGEF28 gene and their association with sporadic amyotrophic lateral sclerosis".NEUROBIOLOGY OF AGING 87.(2020)
