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Neuron:渐冻人症和痴呆症源于同一变异基因

来源:科技部 2011-10-11 14:32

渐冻人症的学名为肌萎缩性脊髓侧索硬化症(英文缩写:ALS),其症状表现为由于上、下运动神经元退化和死亡并停止传送讯息到肌肉,肌肉逐渐衰弱、萎缩,以致最后大脑完全丧失控制肌肉的能力。著名英国物理学家史提芬.霍金患的即是此症。痴呆症又名额颞叶痴呆症(英文缩写:FTD),美国前总统里根、拳王阿里等皆患此症。ALS和FTD的临床症状很不相同,但在某些人身上又有一些相似的地方。2006年,研究人员确认此两种病症源于9号染色体中的某个变异基因,但没能确定具体是哪个基因的突变导致这些疾病,于是展开了一场寻找特定基因的赛跑。

近日,美国梅奥医院(Mayo Clinic)的Rosa Rademakers医生领导的小组和国家老年病研究所(National Institute on Aging)的Bryan Traynor领导的小组分别独立地发现以上两种病症源于同一个基因的突变,该基因就是C9ORF72。Rademakers说,这个基因很不起眼,医生们过去对它的功能一无所知,但它现在是圈内每个人都等待已久的谜底。

上述发现发表在9月21日的《神经元》(Neuron)杂志网络版上。有专家评论说,这是领域内的一大进步,医生们终于找到了罪魁祸首;下一步他们将着手解答何种突变导致ALS何种突变导致FTD,以及这两种疾病的致病机理方面的问题。(生物谷 Bioon.com)

A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD

Alan E. Renton, Elisa Majounie, Adrian Waite, Javier Simón-Sánchez, Sara Rollinson, J. Raphael Gibbs, Jennifer C. Schymick, Hannu Laaksovirta, John C. van Swieten, Liisa Myllykangas, Hannu Kalimo, Anders Paetau, Yevgeniya Abramzon, Anne M. Remes, Alice Kaganovich, Sonja W. Scholz, Jamie Duckworth, Jinhui Ding, Daniel W. Harmer, Dena G. Hernandez, Janel O. Johnson, Kin Mok, Mina Ryten, Danyah Trabzuni, Rita J. Guerreiro, Richard W. Orrell, James Neal, Alex Murray, Justin Pearson, Iris E. Jansen,

The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.

Expanded GGGGCC Hexanucleotide Repeat in Noncoding Region of C9ORF72 Causes Chromosome 9p-Linked FTD and ALS

Mariely DeJesus-Hernandez, Ian R. Mackenzie, Bradley F. Boeve, Adam L. Boxer, Matt Baker, Nicola J. Rutherford, Alexandra M. Nicholson, NiCole A. Finch, Heather Flynn, Jennifer Adamson, Naomi Kouri, Aleksandra Wojtas, Pheth Sengdy, Ging-Yuek R. Hsiung, Anna Karydas, William W. Seeley, Keith A. Josephs, Giovanni Coppola, Daniel H. Geschwind, Zbigniew K. Wszolek, Howard Feldman, David S. Knopman, Ronald C. Petersen, Bruce L. Miller, Dennis W. Dickson, Kevin B. Boylan, Neill R. Graff-Radford, Rosa

everal 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 noncoding 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 (23.5%). 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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