Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration
Missense variants in AIMP1 gene are implicated in autosomal recessive intellectual disability without neurodegeneration
复制标题
DOI：
10.1038/ejhg.2015.148
复制
发表时间：
2016-03-01
影响因子：
5.2
通讯作者：
van Bokhoven, Hans
中科院分区：
文献类型：
--
作者：
Iqbal, Zafar;Puettmann, Lucia;van Bokhoven, Hans
AIMP1/p43 是多合成酶复合物的多功能非催化成分。该复合物由九个催化蛋白和三个非催化蛋白组成，它们催化氨基酸与其同源 tRNA 同工受体的连接，用于蛋白质翻译。迄今为止，AIMP1 基因中的两个等位基因变异已被报道为常染色体隐性遗传原发性神经退行性疾病的根本原因。在这里，我们介绍了来自巴基斯坦和伊朗的两个近亲家庭，他们患有中度至重度智力障碍、整体发育迟缓和言语障碍，但没有神经退行性变。通过纯合性作图和下一代测序的结合，我们在 AIMP1 基因中鉴定了两个纯合错义变体 p.(Gly299Arg) 和 p.(Val176Gly)，它们与各自家族中的表型共分离。变体的分子模型揭示了对蛋白质结构的有害影响，预计会导致 AIMP1 功能降低。我们的研究结果表明 AIMP1 缺陷的临床范围比迄今为止所观察到的更广泛。
AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.