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

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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Figure 1: A summary of the linkage strategy used to define the MCPH2 region and mutations found in WDR62 in MCPH2 families.
Figure 2: Subcellular localization of WDR62 throughout the cell cycle.
Figure 3: Overexpression of WDR62-GFP wild type and c.1313G>A (p.Arg438His) mutant constructs in HeLa cells.
Figure 4: Endogenous expression pattern of WDR62 in human and mouse embryonic brain.
Figure 5: Wdr62 expression in newborn, newly arrived cortical neurons in the developing cerebral cortex and brain imaging from two individuals with WDR62 mutations.

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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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Correspondence to Marc Abramowicz or C Geoffrey Woods.

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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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