Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 87, Issue 1, Pages 40-51Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2010.06.003
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Funding
- Genome Canada
- Genome Atlantic
- Nova Scotia Health Research Foundation
- Nova Scotia Research and Innovation Trust
- IWK Health Centre Foundation
- Dalhousie Medical Research Fund
- Capital Health Research Fund
- Centre de Recherche du CHU Ste-Justine
- Canadian Institutes of Health Research
- Ministry of Economic Development, Innovation and Export Trade [PSR-SIIRI-195]
- Genome Quebec Chair of Population and Medical Genomics
- Deutsche Jose Carreras-Leukamie Stiftung [DJCLC R07/21v]
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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.
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