WDR62 is associated with the spindle pole and is mutated in human microcephaly (original) (raw)

Nature Genetics volume 42, pages 1010–1014 (2010)Cite this article

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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.

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Figure 2: Subcellular localization of WDR62 throughout the cell cycle.

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Figure 3: Overexpression of WDR62-GFP wild type and c.1313G>A (p.Arg438His) mutant constructs in HeLa cells.

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Figure 4: Endogenous expression pattern of WDR62 in human and mouse embryonic brain.

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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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Author notes

  1. Adeline K Nicholas, Maryam Khurshid and Julie Désir: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
    Adeline K Nicholas, Maryam Khurshid, Ofélia P Carvalho, James J Cox, Gemma Thornton & C Geoffrey Woods
  2. Department of Medical Genetics, Hôpital Erasme and Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université libre de Bruxelles (IRIBHM), ULB, Brussels, Belgium
    Julie Désir & Marc Abramowicz
  3. Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
    Rizwana Kausar, Muhammad Ansar & Wasim Ahmad
  4. Department of Genetics, Robert Debré University Hospital, Paris, France
    Alain Verloes & Sandrine Passemard
  5. Department of Child Neurology, Assistance publique-Hôpitaux de Paris (AP-HP) Robert Debré University Hospital, Paris, France
    Sandrine Passemard
  6. University of Liège Medical School and Department of Pediatrics, La Citadelle University Hospital, Liège, Belgium
    Jean-Paul Misson
  7. Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK
    Susan Lindsay
  8. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK
    Fanni Gergely
  9. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA
    William B Dobyns
  10. Microcephaly and Neurogenesis research group, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK
    Emma Roberts

Authors

  1. Adeline K Nicholas
  2. Maryam Khurshid
  3. Julie Désir
  4. Ofélia P Carvalho
  5. James J Cox
  6. Gemma Thornton
  7. Rizwana Kausar
  8. Muhammad Ansar
  9. Wasim Ahmad
  10. Alain Verloes
  11. Sandrine Passemard
  12. Jean-Paul Misson
  13. Susan Lindsay
  14. Fanni Gergely
  15. William B Dobyns
  16. Emma Roberts
  17. Marc Abramowicz
  18. C Geoffrey Woods

Contributions

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.

Corresponding authors

Correspondence toMarc Abramowicz or C Geoffrey Woods.

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The authors declare no competing financial interests.

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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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