CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly

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Item Type:	Article
Title:	CDK6 associates with the centrosome during mitosis and is mutated in a large Pakistani family with primary microcephaly
Creators Name:	Hussain, M.S., Baig, S.M., Neumann, S., Peche, V.S., Szczepanski, S., Nürnberg, G., Tariq, M., Jameel, M., Khan, T.N., Fatima, A., Malik, N.A., Ahmad, I., Altmüller, J., Frommolt, P., Thiele, H., Höhne, W., Yigit, G., Wollnik, B., Neubauer, B.A., Nürnberg, P. and Noegel, A.A.
Abstract:	Autosomal recessive primary microcephaly (MCPH) is characterized by reduced head circumference, reduction in the size of the cerebral cortex with otherwise grossly normal brain structure and variable intellectual disability. MCPH is caused by mutations of 11 different genes which code for proteins implicated in cell division and cell cycle regulation. We studied a consanguineous eight-generation family from Pakistan with ten microcephalic children using homozygosity mapping and found a new MCPH locus at HSA 7q21.11-q21.3. Sanger sequencing of the most relevant candidate genes in this region revealed a homozygous single nucleotide substitution c.589G>A in CDK6, which encodes cyclin-dependent kinase 6. The mutation changes a highly conserved alanine at position 197 into threonine (p.Ala197Thr). Post hoc whole-exome sequencing corroborated this mutation's identification as the causal variant. CDK6 is an important protein for the control of the cell cycle and differentiation of various cell types. We show here for the first time that CDK6 associates with the centrosome during mitosis; however, this was not observed in patient fibroblasts. Moreover, the mutant primary fibroblasts exhibited supernumerary centrosomes, disorganized microtubules and mitotic spindles, an increased centrosome nucleus distance, reduced cell proliferation and impaired cell motility and polarity. Upon ectopic expression of the mutant protein and knockdown of CDK6 through shRNA, we noted similar effects. We propose that the identified CDK6 mutation leads to reduced cell proliferation and impairs the correct functioning of the centrosome in microtubule organization and its positioning near the nucleus which are key determinants during neurogenesis.
Keywords:	Centrosome, Chromosome Mapping, Cyclin-Dependent Kinase 6, Genetic Association Studies, Intellectual Disability, Microcephaly, Microtubules, Mitosis, Mutation, Pair 7 Human Chromosomes, Pedigree, Protein Conformation, Single Nucleotide Polymorphism
Source:	Human Molecular Genetics
ISSN:	0964-6906
Publisher:	Oxford University Press
Volume:	22
Number:	25
Page Range:	5199-5214
Date:	20 December 2013
Official Publication:	https://doi.org/10.1093/hmg/ddt374
PubMed:	View item in PubMed

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