近日一個由英美等國科學(xué)家組成國際研究小組稱，他們找到了一個與運(yùn)動神經(jīng)元疾?。∕ND）相關(guān)的新基因，有近40%的運(yùn)動神經(jīng)元疾病是由該基因變異引起,。這是迄今為止發(fā)現(xiàn)的該類疾病最常見的致病因素,。相關(guān)成果發(fā)表在最近一期《神經(jīng)元》雜志上。
該研究小組對來自芬蘭的MND患者和英國威爾士的一家庭成員的基因情況進(jìn)行了研究,。該威爾士家庭有著多年的遺傳病史,，家庭中許多人死于早發(fā)性MND和神經(jīng)退行性變疾病——額顳葉癡呆（FTD,，也稱皮克病）,。研究人員通過DNA（脫氧核糖核酸）樣本分析后發(fā)現(xiàn),，兩組人群在9號染色體上存在著一個同樣的基因變異，他們的C9orf72基因中的DNA重復(fù)序列多達(dá)數(shù)百個,，而正常人的C9orf72基因中只有20個DNA重復(fù)序列,。雖然C9orf72基因中這種“重復(fù)擴(kuò)增”的確切作用目前還不清楚，但研究人員認(rèn)為,，有可能是這一活動打亂了運(yùn)動神經(jīng)細(xì)胞的多種機(jī)制,，最終導(dǎo)致其功能衰竭和死亡。
通過進(jìn)一步研究,，研究人員在北美,、德國和意大利有該種遺傳病史的人身上找到了同樣的基因變異。他們發(fā)現(xiàn),，有38%的遺傳MND與此變異有關(guān),。
運(yùn)動神經(jīng)元病是一種慢性進(jìn)行性變性疾病，十分致命,，病患一般在兩至五年內(nèi)即會死亡,。人們熟知的漸凍人癥即是該類疾病中的一種。9號染色體被認(rèn)為是運(yùn)動神經(jīng)元疾病的頭號嫌犯,，但經(jīng)過多年的持續(xù)研究,，科學(xué)家雖已確認(rèn)該區(qū)域與運(yùn)動神經(jīng)元病顯著相關(guān)，卻一直沒有確定與該疾病相關(guān)的基因,。而C9orf72基因的發(fā)現(xiàn)無疑對理解運(yùn)動神經(jīng)元疾病具有重大意義,。(生物谷 Bioon.com）
doi:10.1016/j.neuron.2011.09.011
PMC:
PMID:
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
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 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.
