A Truncating Mutation of CEP135 Causes Primary Microcephaly and Disturbed Centrosomal Function
- 作者：Muhammad ; Sajid Hussain1 ; 2 ; 3 ; 4 ; Shahid ; Mahmood Baig4 ; Sascha Neumann2 ; Gudrun Nü ; rnberg1 ; 3 ; Muhammad Farooq4 ; Ilyas Ahmad1 ; 4 ; Thomas Alef1 ; Hans ; Christian Hennies1 ; 5 ; Martin Technau2 ; Janine Altmü ; ller1 ; Peter Frommolt1 ; 5 ; Holger Thiele1 ; Angelika ; Anna Noegel1 ; 2 ; 3 ; 5 ; noegel@uni-koeln.de ; Peter Nü ; rnberg1 ; 3 ; 5 ; nuernberg@uni-koeln.de
- 刊名：The American Journal of Human Genetics
- 出版年：2012
- 期刊代码：P22_00029297
- 类别：bio
- 出版时间：4 May, 2012
- 卷：90
- 期：5
- 页码：871-878
- 文件大小：1288 K
摘要
Autosomal-recessive primary microcephaly (MCPH) is a rare congenital disorder characterized by intellectual disability, reduced brain and head size, but usually without defects in cerebral cortical architecture, and other syndromic abnormalities. MCPH is heterogeneous. The underlying genes of the seven known loci code for centrosomal proteins. We studied a family from northern Pakistan with two microcephalic children using homozygosity mapping and found suggestive linkage for regions on chromosomes 2, 4, and 9. We sequenced two positional candidate genes and identified a homozygous frameshift mutation in the gene encoding the 135聽kDa centrosomal protein (CEP135), located in the linkage interval on chromosome 4, in both affected children. Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. Fibroblasts obtained from one of the patients showed multiple and fragmented centrosomes, disorganized microtubules, and reduced growth rate. Similar effects were reported after knockdown of CEP135 through RNA interference; we could provoke them also by ectopic overexpression of the mutant protein. Our findings suggest an additional locus for MCPH at HSA 4q12 (MCPH8), further strengthen the role of centrosomes in the development of MCPH, and place CEP135 among the essential components of this important organelle in particular for a normal neurogenesis.