肌萎缩侧索硬化
失智症
错义突变
C9orf72
遗传学
生物
外显子
发病年龄
疾病
单倍型
医学
痴呆
肿瘤科
等位基因
突变
内科学
基因
作者
Kristel Sleegers,Nathalie Brouwers,Sebastian Maurer‐Stroh,Michael A. van Es,Philip Van Damme,Paul W.J. van Vught,Julie van der Zee,Sally Serneels,Tim De Pooter,Marleen Van den Broeck,Marc Cruts,Joost Schymkowitz,Peter De Jonghe,Frédéric Rousseau,Leonard H. van den Berg,Wim Robberecht,Christine Van Broeckhoven
出处
期刊:Neurology
[Ovid Technologies (Wolters Kluwer)]
日期:2008-01-10
卷期号:71 (4): 253-259
被引量:150
标识
DOI:10.1212/01.wnl.0000289191.54852.75
摘要
Null mutations in progranulin (PGRN) cause ubiquitin-positive frontotemporal dementia (FTD) linked to chromosome 17q21 (FTDU-17). Here we examined PGRN genetic variability in amyotrophic lateral sclerosis (ALS), a neurodegenerative motor neuron disease that overlaps with FTD at a clinical, pathologic, and epidemiologic level.We sequenced all exons, exon-intron boundaries, and 5' and 3' regulatory regions of PGRN in a Belgian sample of 230 patients with ALS. The frequency of observed genetic variants was determined in 436 healthy control individuals. The contribution of eight frequent polymorphisms to ALS risk, onset age, and survival was assessed in an association study in the Belgian sample and a replication series of 308 Dutch patients with ALS and 345 Dutch controls.In patients with ALS we identified 11 mutations, 5 of which were predicted to affect PGRN protein sequence or levels (four missense mutations and one 5' regulatory variant). Moreover, common variants (rs9897526, rs34424835, and rs850713) and haplotypes were significantly associated with a reduction in age at onset and a shorter survival after onset of ALS in both the Belgian and the Dutch studies.PGRN acts as a modifier of the course of disease in patients with amyotrophic lateral sclerosis, through earlier onset and shorter survival.
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