title: Kinetochore KMN network gene CASC5 mutated in primary microcephaly.
abstract: Several genes expressed at the centrosome or spindle pole have been reported to underlie autosomal recessive primary microcephaly (MCPH), a neurodevelopmental disorder consisting of an important brain size reduction present since birth, associated with mild-to-moderate mental handicap and no other neurological feature nor associated malformation. Here, we report a mutation of CASC5 (aka Blinkin, or KNL1, or hSPC105) in MCPH patients from three consanguineous families, in one of which we initially reported the MCPH4 locus. The combined logarithm of odds score of the three families was >6. All patients shared a very rare homozygous mutation of CASC5. The mutation induced skipping of exon 18 with subsequent frameshift and truncation of the predicted protein. CASC5 is part of the KMN network of the kinetochore and is required for proper microtubule attachment to the chromosome centromere and for spindle-assembly checkpoint (SAC) activation during mitosis. Like MCPH gene ASPM, CASC5 is upregulated in the ventricular zone (VZ) of the human fetal brain. CASC5 binds BUB1, BUBR1, ZWINT-1 and interestingly it binds to MIS12 through a protein domain which is truncated by the mutation. CASC5 localized at the equatorial plate like ZWINT-1 and BUBR1, while ASPM, CEP152 and PCTN localized at the spindle poles in our patients and in controls. Comparison of primate and rodent lineages indicates accelerated evolution of CASC5 in the human lineage. Our data provide strong evidence for CASC5 as a novel MCPH gene, and underscore the role of kinetochore integrity in proper volumetric development of the human brain.
authors.affiliation: Institute of Interdisciplinary Research IRIBHM , Université Libre de Bruxelles, Anderlecht, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Genin
authors.forename: Julie
authors.initials: J
authors.lastname: Desir
authors.forename: Nelle
authors.initials: N
authors.lastname: Lambert
authors.forename: Martine
authors.initials: M
authors.lastname: Biervliet
authors.forename: Nathalie
authors.initials: N
authors.lastname: Van Der Aa
authors.forename: Genevieve
authors.initials: G
authors.lastname: Pierquin
authors.forename: Audrey
authors.initials: A
authors.lastname: Killian
authors.forename: Mario
authors.initials: M
authors.lastname: Tosi
authors.forename: Montse
authors.initials: M
authors.lastname: Urbina
authors.forename: Anne
authors.initials: A
authors.lastname: Lefort
authors.forename: Frederick
authors.initials: F
authors.lastname: Libert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Pirson
authors.forename: Marc
authors.initials: M
authors.lastname: Abramowicz
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D018386:Kinetochores / Q000378:metabolism*; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C467202:ASPM protein, human; C551028:CEP152 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C472643:Knl1 protein, human; C492664:MIS12 protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C413695:ZWINT protein, human; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases