title: A truncating mutation of CEP135 causes primary microcephaly and disturbed centrosomal function.
abstract: 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 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.
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Muhammad Sajid
authors.initials: MS
authors.lastname: Hussain
authors.forename: Shahid Mahmood
authors.initials: SM
authors.lastname: Baig
authors.forename: Sascha
authors.initials: S
authors.lastname: Neumann
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Muhammad
authors.initials: M
authors.lastname: Farooq
authors.forename: Ilyas
authors.initials: I
authors.lastname: Ahmad
authors.forename: Thomas
authors.initials: T
authors.lastname: Alef
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: Martin
authors.initials: M
authors.lastname: Technau
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Peter
authors.initials: P
authors.lastname: Frommolt
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Angelika Anna
authors.initials: AA
authors.lastname: Noegel
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018385:Centrosome; D002648:Child; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005091:Exons; D005260:Female; D055785:Gene Knockdown Techniques; D008040:Genetic Linkage; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000503:physiopathology; D009154:Mutation; D010154:Pakistan / Q000453:epidemiology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference; D017422:Sequence Analysis, DNA
chemical_list: C534330:CEP135 protein, human; D002352:Carrier Proteins