title: Mutations in microcephalin cause aberrant regulation of chromosome condensation.
abstract: Microcephalin (MCPH1) is a gene mutated in primary microcephaly, an autosomal recessive neurodevelopmental disorder in which there is a marked reduction in brain size. PCC syndrome is a recently described disorder of microcephaly, short stature, and misregulated chromosome condensation. Here, we report the finding that MCPH1 primary microcephaly and PCC syndrome are allelic disorders, both having mutations in the MCPH1 gene. The two conditions share a common cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for individuals with MCPH1 gene mutations. We demonstrate that an siRNA-mediated depletion of MCPH1 is sufficient to reproduce this phenotype and also show that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicate microcephalin as a novel regulator of chromosome condensation and link the apparently disparate fields of neurogenesis and chromosome biology. Further characterization of MCPH1 is thus likely to lead to fundamental insights into both the regulation of chromosome condensation and neurodevelopment.
authors.affiliation: Institute of Human Genetics, Charité Universitary Medicine Berlin, Campus Virchow, Humboldt University, Berlin, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Bell
authors.forename: Clive
authors.initials: C
authors.lastname: Felix
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Rashid
authors.forename: Hussain
authors.initials: H
authors.lastname: Jafri
authors.forename: Paul D
authors.initials: PD
authors.lastname: Griffiths
authors.forename: Luitgard M
authors.initials: LM
authors.lastname: Neumann
authors.forename: Alice
authors.initials: A
authors.lastname: Krebs
authors.forename: André
authors.initials: A
authors.lastname: Reis
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002875:Chromosomes / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D005260:Female; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins