Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat.
Behavioral variant frontotemporal lobar degeneration with amyotrophic lateral sclerosis with a chromosome 9p21 hexanucleotide repeat.
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DOI：
10.3389/fneur.2012.00136
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发表时间：
2012
影响因子：
3.4
通讯作者：
Hardy J
中科院分区：
文献类型：
--
作者：
Friedland RP;Shah JJ;Farrer LA;Vardarajan B;Rebolledo-Mendez JD;Mok K;Hardy J
为了确定家族性额颞叶变性（FTLD）伴肌萎缩侧索硬化（ALS）的遗传基础，我们对一个受累家族进行了临床和遗传分析。一名51岁男性，患有行为变异型FTLD伴ALS，其家族史提示常染色体显性遗传伴不完全显性遗传。该患者的遗传学研究表明，在9号染色体开放阅读框72（C9 ORF72）基因中存在扩增的六核苷酸重复（>30）多态性，该基因先前被确定为FTLD的原因。其他五名不受该家庭影响的人的检测结果为阴性（均少于11次重复）。由于FTLD和AD之间的临床和病理重叠，我们进行了一项更大的全基因组关联研究，并没有发现C9ORF72基因中的单核苷酸多态性（SNP）与阿尔茨海默病（AD）风险的关联。使用基因表达Omnibus数据库对C9ORF72进行的生物信息学分析显示，肌营养不良症、神经管缺陷和精神分裂症患者中存在表达差异。我们还报告了使用艾伦人脑图谱分析大脑区域的基因表达。这种最近报道的基因缺陷现在被认为是遗传性ALS的最常见原因，也是遗传性FTLD的重要原因。我们的工作表明，该基因在其他神经和精神疾病中也可能很重要。
To determine the genetic basis of familial frontotemporal lobar degeneration (FTLD) with amyotrophic lateral sclerosis (ALS) we performed a clinical and genetic analysis of an affected family. A 51-year-old man with behavioral variant FTLD with ALS had a family history of the disease suggestive of autosomal dominant inheritance with incomplete penetrance. Genetic studies in this patient demonstrated the presence of an amplified hexanucleotide repeat (>30) polymorphism in the chromosome 9 open reading frame 72 (C9ORF72) gene which was previously identified as a cause of FTLD. Five others unaffected from the family were negative (all had less than 11 repeats). Because of the clinical and pathological overlap between FTLD and AD we performed a larger genome-wide association study and did not find association of single nucleotide polymorphisms (SNPs) in the C9ORF72 gene with Alzheimer’s disease (AD) risk. Bioinformatic analysis of C9ORF72 using the Gene Expression Omnibus database showed expression differences in patients with muscular dystrophy, neural tube defects, and schizophrenia. We also report analysis of gene expression in brain regions using the Allen Human Brain Atlas. Defects in this recently reported gene are now believed to be the most common cause of inherited ALS and an important cause of inherited FTLD. Our work suggests that the gene may also be important in other neurological and psychiatric conditions.