AJHG：科学家发现智力残疾的新基因

成瘾性和精神健康中心研究人员领导的一项研究发现智力残疾的新基因，以及该基因是如何可能影响认知能力，破坏神经元运作的。

科学家博士约翰·文森特和他的团队发现有智障的三姐妹体内中基因NSUN2存在突变，相关研究结果发表在American Journal of Human Genetics杂志上。三姐妹来自一个巴基斯坦家庭， 7个兄弟姐妹中有三个是智力残疾以及肌肉无力、行走困难。

智力残疾又被称为智力落后、智力障碍、智力低下或弱智等等。它影响百分之三的人口，往往是由基因突变引起的。

文森特领导的研究还确定了伊朗和库尔德人家庭中某些智障成员的NSUN2基因突变。至于巴基斯坦家庭，研究人员发现携带突变的第一个表兄的婚姻增加了子女智力残疾的可能性之间。

文森特博士说：研究结果意味着NSUN2是由隐性基因造成的智力残疾的最常见的原因。

作为一种隐性遗传疾病，孩子必须从父母双方各继承一个缺陷的NSUN2基因。这个基因位于染色体5P上，编码一种称为RNA甲基的蛋白质。

在细胞水平上，研究人员发现抑制达到细胞核内的目标区域可以防止蛋白突变。结果是该蛋白在细胞分裂和/或RNA的甲基化过程中无法执行其正常的功能。
（生物谷：Bioon.com)

doi:10.1016/j.ajhg.2012.03.023
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Mutation in NSUN2, which Encodes an RNA Methyltransferase, Causes Autosomal-Recessive Intellectual Disability

Muzammil Ahmad Khan1, 2, Muhammad Arshad Rafiq1, Abdul Noor1, Shobbir Hussain3, Joana V. Flores3, Verena Rupp4, Akshita K. Vincent1, Roland Malli5, Ghazanfar Ali2, 6, Falak Sher Khan2, Gisele E. Ishak7, Dan Doherty8, Rosanna Weksberg9, Muhammad Ayub10, 11, Christian Windpassinger1, 4, Shahnaz Ibrahim12, Michaela Frye3, Muhammad Ansar2 and John B. Vincent

Causes of autosomal-recessive intellectual disability (ID) have, until very recently, been under researched because of the high degree of genetic heterogeneity. However, now that genome-wide approaches can be applied to single multiplex consanguineous families, the identification of genes harboring disease-causing mutations by autozygosity mapping is expanding rapidly. Here, we have mapped a disease locus in a consanguineous Pakistani family affected by ID and distal myopathy. We genotyped family members on genome-wide SNP microarrays and used the data to determine a single 2.5 Mb homozygosity-by-descent (HBD) locus in region 5p15.32p15.31; we identified the missense change c.2035G>A (p.Gly679Arg) at a conserved residue within NSUN2. This gene encodes a methyltransferase that catalyzes formation of 5-methylcytosine at C34 of tRNA-leu(CAA) and plays a role in spindle assembly during mitosis as well as chromosome segregation. In mouse brains, we show that NSUN2 localizes to the nucleolus of Purkinje cells in the cerebellum. The effects of the mutation were confirmed by the transfection of wild-type and mutant constructs into cells and subsequent immunohistochemistry. We show that mutation to arginine at this residue causes NSUN2 to fail to localize within the nucleolus. The ID combined with a unique profile of comorbid features presented here makes this an important genetic discovery, and the involvement of NSUN2 highlights the role of RNA methyltransferase in human neurocognitive development.