Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families:: novel sequence variants in ASPM gene
Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families:: novel sequence variants in ASPM gene
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DOI：
10.1007/s10048-006-0042-4
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发表时间：
2006-05-01
期刊：
影响因子：
2.2
通讯作者：
Ahmad, W
中科院分区：
文献类型：
--
作者：
Gul, A;Hassan, MJ;Ahmad, W
人类常染色体隐性遗传性原发性小头症(MCPH)是一种罕见的遗传性疾病，患者出生时大脑体积变小。MCPH具有遗传异质性，迄今已报道有6个基因座和4个基因。MCPH5基因座的ASPM基因突变似乎是MCPH最常见的原因。在这项研究中，33个患有原发小头畸形症的巴基斯坦家庭被纳入研究。利用与6个已知的MCPH基因座连锁的微卫星标记进行基因分型，发现有18个家系与MCPH5基因座连锁，2个家系与MCPH2基因座连锁，2个家系与MCPH4基因座连锁，1个家系与MCPH6基因座连锁。剩下的10个家系与任何已知的基因座都没有关联。与MCPH5基因座连锁的家系进一步接受ASPM基因的直接DNA测序筛选。在5个巴基斯坦家系中发现了两个先前报道的变异，3978G>；A(W1326X)和9557C>；G(S3186X)。9118insCATT、9238A>；T(L3080X)、9539A>；C(Q3180P)和1260delTCAAGTC这4个新的非同义序列变异在4个家系内分离，但在200条巴基斯坦对照染色体中未观察到。其中一个变异体9539A>；C(Q3180P)存在于IQ 79结构域，但其功能意义尚待定义。
Human autosomal recessive primary microcephaly (MCPH) is a rare genetic disorder in which affected individuals are born with reduced brain size. MCPH is genetically heterogeneous, with six loci and four genes reported to date. Mutations in the ASPM gene at the MCPH5 locus appear to be the most common cause of MCPH. For this study, 33 Pakistani families with primary microcephaly were enrolled. Genotyping using microsatellite markers linked to the six known MCPH loci showed the linkage of 18 families to the MCPH5 locus, two to the MCPH2 locus, two to the MCPH4 locus, and one to the MCPH6 locus. The remaining ten families were not linked to any of the known loci. Families linked to the MCPH5 locus were further subjected to screening of the ASPM gene with direct DNA sequencing. Two previously reported variants, 3978G > A (W1326X) and 9557C > G (S3186X), were observed in five Pakistani families. Four novel nonsynonymous sequence variants, 9118insCATT, 9238A > T (L3080X), 9539A > C (Q3180P), and 1260delTCAAGTC, were found to segregate within four families, but were not observed in 200 Pakistani control chromosomes. One of the variants, 9539A > C (Q3180P), occurred in the IQ 79 domain, but its functional significance awaits definition.