Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.
Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS.
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DOI：
10.1016/j.neuron.2011.09.011
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发表时间：
2011-10-20
期刊：
影响因子：
16.2
通讯作者：
Rademakers R
中科院分区：
文献类型：
--
作者：
DeJesus-Hernandez M;Mackenzie IR;Boeve BF;Boxer AL;Baker M;Rutherford NJ;Nicholson AM;Finch NA;Flynn H;Adamson J;Kouri N;Wojtas A;Sengdy P;Hsiung GY;Karydas A;Seeley WW;Josephs KA;Coppola G;Geschwind DH;Wszolek ZK;Feldman H;Knopman DS;Petersen RC;Miller BL;Dickson DW;Boylan KB;Graff-Radford NR;Rademakers R
据报道，有几个家族患有常染色体显性遗传性额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS），与染色体9 p21遗传相关。在这里，我们报告了一个扩展的非编码GGGGCC六核苷酸重复的基因C9 ORF 72，这是强烈相关的疾病在一个大的FTD/ALS的亲属，以前报道的决定性连锁染色体9 p。在大多数具有FTD/ALS表型和基于TDP-43的病理学的家族中发现了相同的重复扩增。扩展临床系列分析发现C9 ORF 72重复扩增是家族性FTD（11.7%）和家族性ALS（22.5%）中最常见的遗传异常。重复扩增导致一个选择性剪接的C9 ORF 72转录物的丢失和核RNA灶的形成，表明多种疾病机制。我们的研究结果表明，C9 ORF 72的重复扩增是FTD和ALS的主要原因。
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
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