Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4
Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4
复制标题
DOI：
10.1016/j.ajhg.2010.06.003
复制
发表时间：
2010-07-09
影响因子：
9.8
通讯作者：
Samuels, Mark E.
中科院分区：
文献类型：
--
作者：
Guernsey, Duane L.;Jiang, Haiyan;Samuels, Mark E.
原发性小头畸形是一种罕见的疾病，其大脑尺寸大幅缩小，但没有其他综合征异常。七个常染色体位点已被基因定位，并且已确定 MCPH1、MCPH3、MCPH5、MCPH6 和 MCPH7 的潜在致病基因，但尚未确定 MCPH2 或 MCPH4 的潜在致病基因。已知的基因在有丝分裂和细胞分裂中发挥作用。我们确定了来自加拿大东部亚人群的三个家庭，每个家庭都有一名小头症儿童。使用全基因组密集 SNP 基因分型对两个家族进行纯合性分析，支持与染色体 15q21.1 上已发表的 MCPH4 基因座的连锁。对该区间内候选基因的编码外显子进行测序，发现中心体蛋白 CEP152 的高度保守残基中存在非保守氨基酸变化。这两个家庭中受影响的儿童都是这种错义变异的纯合子。第三个受影响的孩子是错义突变的复合杂合子，加上第二个提前终止突变，截断了三分之一的蛋白质并阻止其定位到转染细胞的中心体。 CEP152 是果蝇 asterless 的假定哺乳动物直系同源物，其突变影响果蝇的有丝分裂。已发表的斑马鱼数据也与 CEP152 在中心体功能中的作用一致。通过 RT-PCR，CEP152 在小鼠胚胎大脑中表达，与其他 MCPH 基因类似。与其他一些 MCPH 基因一样，CEP152 在人类谱系中显示出正选择的特征。 CEP152 是 MCPH4 因果基因的有力候选者，并且可能是人类大脑大小进化的重要基因。
Primary microcephaly is a rare condition in which brain size is substantially diminished without other syndromic abnormalities. Seven autosomal loci have been genetically mapped, and the underlying causal genes have been identified for MCPH1, MCPH3, MCPH5, MCPH6, and MCPH7 but not for MCPH2 or MCPH4. The known genes play roles in mitosis and cell division. We ascertained three families from an Eastern Canadian subpopulation, each with one microcephalic child. Homozygosity analysis in two families using genome-wide dense SNP genotyping supported linkage to the published MCPH4 locus on chromosome 15q21.1. Sequencing of coding exons of candidate genes in the interval identified a nonconservative amino acid change in a highly conserved residue of the centrosomal protein CEP152. The affected children in these two families were both homozygous for this missense variant. The third affected child was compound heterozygous for the missense mutation plus a second, premature-termination mutation truncating a third of the protein and preventing its localization to centrosomes in transfected cells. CEP152 is the putative mammalian ortholog of Drosphila asterless, mutations in which affect mitosis in the fly. Published data from zebrafish are also consistent with a role of CEP152 in centrosome function. By RT-PCR, CEP152 is expressed in the embryonic mouse brain, similar to other MCPH genes. Like some other MCPH genes, CEP152 shows signatures of positive selection in the human lineage. CEP152 is a strong candidate for the causal gene underlying MCPH4 and may be an important gene in the evolution of human brain size.