2012年12月8日 訊 /生物谷BIOON/ --俗稱為運動失調(diào)的家族性障礙不僅可以影響個體言語表達,、平衡協(xié)調(diào)性,，而且可以使得病情急劇惡化，近日,，來自牛津大學和愛丁堡大學的研究者揭示了引發(fā)并連接“林肯運動失調(diào)”（ 林肯共濟失調(diào)）綜合征的一個新的家族成員,，相關研究成果刊登于國際雜志PLoS Genetics上。
林肯共濟失調(diào)（Lincoln ataxia）可以影響個體的小腦功能,，而小腦又是控制個體運動和平衡的關鍵部位,，林肯共濟失調(diào)是由于小腦中β-III膜收縮蛋白基因的改變所引發(fā)的，每一個正常人這個基因都會有兩個拷貝,，然而在林肯共濟失調(diào)癥患者中,，其中一個基因拷貝發(fā)生了改變。意外的是,，英國的研究者也發(fā)現(xiàn)了該基因兩個拷貝的改變可以引發(fā)一種新的病癥,，名為“SPARCA1”，其和兒童共濟失調(diào)以及認知損傷直接相關,。
這項研究中,，研究者運用全基因組測序的新技術來對個體的全身遺傳信息進行測序分析，與此同時研究者使用缺少β-III膜收縮蛋白基因的小鼠進行研究,，加上此前的研究工作,，此前的研究工作中，研究者發(fā)現(xiàn)腦部區(qū)域神經(jīng)細胞中β-III膜收縮蛋白的缺失和協(xié)調(diào)行為,、認知能力直接相關,。
本文的研究工作揭示了，在林肯共濟失調(diào)和SPARCA1中正常β-III膜收縮蛋白功能的缺失,，大量的β-III膜收縮蛋白的缺失會引發(fā)個體認知能力的下降,。
研究結(jié)果揭示了膜收縮蛋白在正常大腦功能中所表現(xiàn)的廣譜的角色，人類的大腦中存在許多膜收縮蛋白,，如今研究小組正在尋找膜收縮蛋白的其它異常情況,。該項研究對于我們理解個體的運動失調(diào)以及幫助研究者開發(fā)新型療法提供了幫助和希望。（生物谷Bioon.com）
doi:10.1371/journal.pgen.1003074
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Recessive Mutations in SPTBN2 Implicate β-III Spectrin in Both Cognitive and Motor Development
Stefano Lise1,2#, Yvonne Clarkson3#, Emma Perkins3#, Alexandra Kwasniewska1,4, Elham Sadighi Akha1,2, Ricardo Parolin Schnekenberg1,5, Daumante Suminaite3, Jilly Hope3, Ian Baker6, Lorna Gregory1, Angie Green1, Chris Allan1, Sarah Lamble1, Sandeep Jayawant7, Gerardine Quaghebeur8, M. Zameel Cader9, Sarah Hughes10, Richard J. E. Armstrong4,10, Alexander Kanapin1, Andrew Rimmer1, Gerton Lunter1, Iain Mathieson1, Jean-Baptiste Cazier1, David Buck1, Jenny C. Taylor1,2, David Bentley11, Gilean McVean1, Peter Donnelly1, Samantha J. L. Knight1,2, Mandy Jackson3*, Jiannis Ragoussis1, Andrea H. Németh1,2,4,12*
β-III spectrin is present in the brain and is known to be important in the function of the cerebellum. Heterozygous mutations in SPTBN2, the gene encoding β-III spectrin, cause Spinocerebellar Ataxia Type 5 (SCA5), an adult-onset, slowly progressive, autosomal-dominant pure cerebellar ataxia. SCA5 is sometimes known as “Lincoln ataxia,” because the largest known family is descended from relatives of the United States President Abraham Lincoln. Using targeted capture and next-generation sequencing, we identified a homozygous stop codon in SPTBN2 in a consanguineous family in which childhood developmental ataxia co-segregates with cognitive impairment. The cognitive impairment could result from mutations in a second gene, but further analysis using whole-genome sequencing combined with SNP array analysis did not reveal any evidence of other mutations. We also examined a mouse knockout of β-III spectrin in which ataxia and progressive degeneration of cerebellar Purkinje cells has been previously reported and found morphological abnormalities in neurons from prefrontal cortex and deficits in object recognition tasks, consistent with the human cognitive phenotype. These data provide the first evidence that β-III spectrin plays an important role in cortical brain development and cognition, in addition to its function in the cerebellum; and we conclude that cognitive impairment is an integral part of this novel recessive ataxic syndrome, Spectrin-associated Autosomal Recessive Cerebellar Ataxia type 1 (SPARCA1). In addition, the identification of SPARCA1 and normal heterozygous carriers of the stop codon in SPTBN2 provides insights into the mechanism of molecular dominance in SCA5 and demonstrates that the cell-specific repertoire of spectrin subunits underlies a novel group of disorders, the neuronal spectrinopathies, which includes SCA5, SPARCA1, and a form of West syndrome.
