Perrone Federica, Nguyen Hung Phuoc, Van Mossevelde Sara, Moisse Matthieu, Sieben Anne, Santens Patrick, De Bleecker Jan, Vandenbulcke Mathieu, Engelborghs Sebastiaan, Baets Jonathan, Cras Patrick, Vandenberghe Rik, De Jonghe Peter, De Deyn Peter P, Martin Jean-Jacques, Van Damme Philip, Van Broeckhoven Christine, van der Zee Julie
Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium.
Neurobiol Aging. 2017 Mar;51:177.e9-177.e16. doi: 10.1016/j.neurobiolaging.2016.12.008. Epub 2016 Dec 21.
Mutation screening and phenotypic profiling of 2 amyotrophic lateral sclerosis-(ALS) and frontotemporal dementia-(FTD) associated genes, CHCHD10 and TUBA4A, were performed in a Belgian cohort of 459 FTD, 28 FTD-ALS, and 429 ALS patients. In CHCHD10, we identified a novel nonsense mutation (p.Gln108*) in a patient with atypical clinical FTD and pathology-confirmed Parkinson's disease (1/459, 0.22%) leading to loss of transcript. We further observed 3 previously described missense variants (p.Pro34Ser, p.Pro80Leu, and p.Pro96Thr) that were also present in the matched control series. In TUBA4A, we detected a novel frameshift mutation (p.Arg64Glyfs*90) leading to a truncated protein in 1 FTD patient (1/459 of 0.22%) with family history of Parkinson's disease and cognitive impairment, and a novel missense mutation (p.Thr381Met) in 2 sibs with familial ALS and memory problems (1 index patient/429, 0.23%) in whom we previously identified a pathogenic Chromosome 9 open reading frame 72 repeat expansion mutation. The present study confirms the role of CHCHD10 and TUBA4A in the FTD-ALS spectrum, although genetic variations in these 2 genes are extremely rare in the Belgian population and often associated with symptomatology of related neurodegenerative diseases including Parkinson's disease and Alzheimer's disease.
在一个由459例额颞叶痴呆（FTD）患者、28例FTD合并肌萎缩侧索硬化（ALS）患者和429例ALS患者组成的比利时队列中，对2个与肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）相关的基因CHCHD10和TUBA4A进行了突变筛查和表型分析。在CHCHD10基因中，我们在1例具有非典型临床FTD且经病理证实患有帕金森病的患者中鉴定出一种新的无义突变（p.Gln108*）（1/459，0.22%），该突变导致转录本缺失。我们还进一步观察到3个先前描述的错义变体（p.Pro34Ser、p.Pro80Leu和p.Pro96Thr），这些变体在匹配的对照系列中也存在。在TUBA4A基因中，我们在1例有帕金森病家族史和认知障碍的FTD患者中检测到一种新的移码突变（p.Arg64Glyfs*90），该突变导致蛋白质截短（459例中的1例，0.22%）；在2例患有家族性ALS且有记忆问题的同胞中检测到一种新的错义突变（p.Thr381Met）（429例中的1例索引患者，0.23%），我们之前在他们身上鉴定出一种致病性的9号染色体开放阅读框72重复扩增突变。本研究证实了CHCHD10和TUBA4A在FTD-ALS谱系中的作用，尽管这两个基因的遗传变异在比利时人群中极为罕见，且常与包括帕金森病和阿尔茨海默病在内的相关神经退行性疾病的症状相关。
