Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
Neurobiol Aging. 2012 Oct;33(10):2528.e7-14. doi: 10.1016/j.neurobiolaging.2012.06.008. Epub 2012 Jul 4.
A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.
C9ORF72 基因中的六核苷酸重复扩展（RE）最近被报道为肌萎缩侧索硬化症（ALS）和额颞叶痴呆的主要原因。我们在一个由 259 名家族性 ALS、1275 名散发性 ALS 和 862 名意大利裔对照个体组成的大队列中筛选了 C9ORF72。我们发现 23.9%的家族性 ALS、5.1%的散发性 ALS 和 0.2%的对照个体存在 RE。两个病例同时携带 RE 和其他 ALS 相关基因的突变。RE 携带者的表型特征为延髓起病、生存时间更短，并与认知和行为障碍有关。少数患者还出现锥体外系和小脑体征。基因型数据显示，95%的 RE 携带者共享先前报道的 20 个单核苷酸多态性风险单倍型内的一个受限制的 10 个单核苷酸多态性单倍型，仅在 27%的无扩展 ALS 病例和 28%的对照个体中可检测到，提示与北欧人群的共同祖先有关。尽管 C9ORF72 RE 与疾病分离，但在对照个体和携带其他致病性突变的患者中都发现了 RE，这表明 C9ORF72 RE 的外显率和表型表达可能取决于其他遗传风险因素。
