Abstract
Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain1,2. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins3,4,5. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain6,7,8,9.
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Acknowledgements
The authors would like to thank the research families for their participation in this project and the Wellcome Trust, Medical Research Council, Action Research and the Higher Education Commission of Pakistan for funding (to A.K.N., M.K., O.P.C., J.J.C., G.T. and E.R.). J.D. was supported by the Belgian Kids' Fund. M.A. was supported by grants from the Fonds Erasme and the Belgian Fonds de la Recherche Scientifique Médicale (FRSM). We thank S. Strollo for expert technical assistance. We thank the Medical Research Council (MRC)-Wellcome Trust Human Developmental Biology Resource (HDBR), Newcastle for providing the human tissue for the expression studies.
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The following authors contributed to the design of the study: A.K.N., M.K., J.J.C., F.G., E.R., M. Abramowicz and C.G.W. The following authors generated experimental data: A.K.N., M.K., J.D., O.P.C., G.T., R.K., M. Ansar, F.G., W.B.D., E.R. and C.G.W. Reagents were contributed by R.K., M. Abramowicz, W.A., A.L., S.P., J.-P.M., S.L., M. Abramowicz and C.G.W. The paper was written by A.K.N., M.K., O.P.C., J.J.C., W.A., S.L., F.G., W.B.D. and C.G.W.
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Nicholas, A., Khurshid, M., Désir, J. et al. WDR62 is associated with the spindle pole and is mutated in human microcephaly. Nat Genet 42, 1010–1014 (2010). https://doi.org/10.1038/ng.682
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DOI: https://doi.org/10.1038/ng.682
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