title: Misregulation of mitotic chromosome segregation in a new type of autosomal recessive primary microcephaly.
abstract: Primary autosomal recessive microcephaly (MCPH) is a congenital disorder characterized by a pronounced reduction of brain size and mental retardation. We present here a consanguineous Turkish family clinically diagnosed with MCPH and without linkage to any of the known loci (MCPH1-MCPH7). Autozygosity mapping identified a homozygous region of 15.8 Mb on chromosome 10q11.23-21.3, most likely representing a new locus for MCPH. Although we were unable to identify the underlying genetic defect after extensive molecular screening, we could delineate a possible molecular function in chromosome segregation by the characterization of mitosis in the patients' cells. Analyses of chromosome nondisjunction in T-lymphocytes and fibroblasts revealed a significantly elevated rate of nondisjunction in the patients' cells as compared to controls. Mitotic progression was further explored by immunofluorescence analyses of several chromosome and spindle associated proteins. We detected a remarkable alteration in the anaphase distribution of Aurora B and INCENP, which are key regulators of chromosome segregation. In particular, a fraction of both proteins remained abnormally loaded on chromosomes during anaphase in MCPH patients' cells while in cells of normal control subjects both proteins are completely transferred to the spindle midzone. We did not observe any other alterations regarding cell cycle progression, chromosome structure, or response to DNA damage. Our observations point towards a molecular role of the underlying gene product in the regulation of anaphase/telophase progression possibly through interaction with chromosomal passenger proteins. In addition, our findings represent further evidence for the proposed role of MCPH genes in the regulation of mitotic progression.
authors.affiliation: Institute of Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany. jamaor@ujaen.es
authors.forename: Juan Alberto
authors.initials: JA
authors.lastname: Marchal
authors.forename: Mahdi
authors.initials: M
authors.lastname: Ghani
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Ioannis
authors.initials: I
authors.lastname: Gavvovidis
authors.forename: Tina
authors.initials: T
authors.lastname: Winkler
authors.forename: Veronique
authors.initials: V
authors.lastname: Esquitino
authors.forename: Nadine
authors.initials: N
authors.lastname: Sternberg
authors.forename: Andreas
authors.initials: A
authors.lastname: Busche
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.forename: Joachim
authors.initials: J
authors.lastname: Hecht
authors.forename: Peter
authors.initials: P
authors.lastname: Robinson
authors.forename: Stephan
authors.initials: S
authors.lastname: Mundlos
authors.forename: Luitgard
authors.initials: L
authors.lastname: Graul-Neumann
authors.forename: Karl
authors.initials: K
authors.lastname: Sperling
authors.forename: Marc
authors.initials: M
authors.lastname: Trimborn
authors.forename: Heidemarie
authors.initials: H
authors.lastname: Neitzel
mesh_terms: D000293:Adolescent; D000705:Anaphase; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001921:Brain / Q000002:abnormalities; D002648:Child; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D002874:Chromosome Mapping; D020090:Chromosome Segregation; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D000013:Congenital Abnormalities / Q000473:pathology; D003241:Consanguinity; D005260:Female; D005455:Fluorescent Antibody Technique; D015894:Genome, Human; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D008938:Mitosis; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014421:Turkey
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases