title: 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.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 1X5, Canada.
authors.forename: Duane L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Julie
authors.initials: J
authors.lastname: Hussin
authors.forename: Marc
authors.initials: M
authors.lastname: Arnold
authors.forename: Khalil
authors.initials: K
authors.lastname: Bouyakdan
authors.forename: Scott
authors.initials: S
authors.lastname: Perry
authors.forename: Tina
authors.initials: T
authors.lastname: Babineau-Sturk
authors.forename: Jill
authors.initials: J
authors.lastname: Beis
authors.forename: Nadine
authors.initials: N
authors.lastname: Dumas
authors.forename: Susan C
authors.initials: SC
authors.lastname: Evans
authors.forename: Meghan
authors.initials: M
authors.lastname: Ferguson
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Christine
authors.initials: C
authors.lastname: Macgillivray
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Rideout
authors.forename: Aidan
authors.initials: A
authors.lastname: Thomas
authors.forename: Andrew
authors.initials: A
authors.lastname: Orr
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hoffmann
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Philip
authors.initials: P
authors.lastname: Awadalla
authors.forename: David C
authors.initials: DC
authors.lastname: Meek
authors.forename: Mark
authors.initials: M
authors.lastname: Ludman
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D019295:Computational Biology; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D006801:Humans; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree
chemical_list: C551028:CEP152 protein, human; D018797:Cell Cycle Proteins