WDR62 is associated with the spindle pole and is mutated in human microcephaly

Adeline K. Nicholas, Maryam Khurshid, Julie Désir, Ofélia P. Carvalho, James J. Cox, Gemma Thornton, Rizwana Kausar, Muhammad Ansar, Wasim Ahmad, Alain Verloes, Sandrine Passemard, Jean Paul Misson, Susan Lindsay, Fanni Gergely, William B. Dobyns, Emma Roberts, Marc Abramowicz, C. Geoffrey Woods

Research output: Contribution to journalArticlepeer-review

238 Scopus citations

Abstract

Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. 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 proteins. 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 brain.

Original languageEnglish (US)
Pages (from-to)1010-1014
Number of pages5
JournalNature Genetics
Volume42
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Bibliographical note

Funding Information:
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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