Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly
Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly
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DOI：
10.1016/j.ajhg.2009.01.017
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发表时间：
2009-02-13
影响因子：
9.8
通讯作者：
Blanton, Susan H.
中科院分区：
文献类型：
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作者：
Kumar, Arun;Girimaji, Satish C.;Blanton, Susan H.
原发性小头畸形 (MCPH) 是一种常染色体隐性先天性疾病，其特征是大脑尺寸小于正常且智力低下。 MCPH 具有遗传异质性，有六个已知基因座：MCPH1-MCPH6。我们报告了一个新的基因座 MCPH7 映射到标记 D1S2797 和 D1S417 之间的染色体 1p32.3-p33，对应于 8.39 Mb 的物理距离。对先前排除在与 6 个已知 MCPH 位点连锁之外的 24 个家族的异质性分析表明，有 5 个家族 (20.83%) 与 MCPH7 位点有连锁。此外，4 个家族被排除在与 MCPH7 基因座以及所有 6 个先前已知基因座的连锁之外，而其余 15 个家族无法最终排除或纳入。在标记 D1S386（theta = 0.0）处，连锁家族的组合最大两点 LOD 得分为 5.96。标记 D1S2797 和 D1S417 之间的组合多点 LOD 评分为 6.97。此前，编码中心体蛋白的四个基因（MCPH1、CDK5RAP2、ASPM 和 CENPJ）的突变已被证明会导致这种疾病。在来自与 MCPH7 基因座相关的五个家族中的三个家族的患者中，发现了 STIL 的三种不同纯合突变，STIL 编码中心粒周围和中心体蛋白。预计所有这些都会截短 STIL 蛋白。此外，最近确定的另一个家族与原始家族之一具有相同突变的纯合子。没有证据表明存在共同的单倍型。这些结果表明中心体及其相关结构对于控制人类大脑发育中的神经发生非常重要。
Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1-MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3-p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at theta = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.