2012年12月8日 讯 /生物谷BIOON/ --俗称为运动失调的家族性障碍不仅可以影响个体言语表达、平衡协调性，而且可以使得病情急剧恶化，近日，来自牛津大学和爱丁堡大学的研究者揭示了引发并连接“林肯运动失调”（ 林肯共济失调）综合征的一个新的家族成员，相关研究成果刊登于国际杂志PLoS Genetics上。
林肯共济失调（Lincoln ataxia）可以影响个体的小脑功能，而小脑又是控制个体运动和平衡的关键部位，林肯共济失调是由于小脑中β-III膜收缩蛋白基因的改变所引发的，每一个正常人这个基因都会有两个拷贝，然而在林肯共济失调症患者中，其中一个基因拷贝发生了改变。意外的是，英国的研究者也发现了该基因两个拷贝的改变可以引发一种新的病症，名为“SPARCA1”，其和儿童共济失调以及认知损伤直接相关。
这项研究中，研究者运用全基因组测序的新技术来对个体的全身遗传信息进行测序分析，与此同时研究者使用缺少β-III膜收缩蛋白基因的小鼠进行研究，加上此前的研究工作，此前的研究工作中，研究者发现脑部区域神经细胞中β-III膜收缩蛋白的缺失和协调行为、认知能力直接相关。
本文的研究工作揭示了，在林肯共济失调和SPARCA1中正常β-III膜收缩蛋白功能的缺失，大量的β-III膜收缩蛋白的缺失会引发个体认知能力的下降。
研究结果揭示了膜收缩蛋白在正常大脑功能中所表现的广谱的角色，人类的大脑中存在许多膜收缩蛋白，如今研究小组正在寻找膜收缩蛋白的其它异常情况。该项研究对于我们理解个体的运动失调以及帮助研究者开发新型疗法提供了帮助和希望。（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.
