Mutations in Centrosomal Protein CEP152 in Primary Microcephaly Families Linked to MCPH4

Abstract

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.

Small organelle, big responsibility: the role of centrosomes in development and disease

“…Remarkably, CPAP and CEP152 are mutated in both MCPH and Seckel syndrome, suggesting that the two disorders might represent different ends of a disease continuum [26,100,102,144]. Indeed, recent reports uncovered mutations in the Seckel genes ATR and CtIP that cause primary microcephaly without PD, whereas short stature has been noted in some individuals with mutations in the MCPH gene, CDK5RAP2 [16,89,145].…”

Mechanisms and pathways of growth failure in primordial dwarfism

“…This also suggests a functional link between primary microcephaly and microcephalic dwarfism, and there is increasing evidence of overlap between these conditions (Al-Dosari et al Guernsey et al 2010;Kalay et al 2011). Several other genes encoding centrosomal proteins cause primary microcephaly (Thornton and Woods 2009;Nicholas et al 2010).…”

Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43–q44

“…Mutations in centrosomal proteins cause microcephaly. 17,18 Recently, it has been demonstrated that centrosomal proteins are essential for microtubule organization and centrosome motility that have important roles in axonal formation. 19 ZNF238 is a POZ/zinc finger transcriptional repressor gene.…”