Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture

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Abstract

Genes associated with human microcephaly, a condition characterized by a small brain, include critical regulators of proliferation, cell fate, and DNA repair. We describe a syndrome of congenital microcephaly and diverse defects in cerebral cortical architecture. Genome-wide linkage analysis in two families identified a 7.5 Mb locus on chromosome 19q13.12 containing 148 genes. Targeted high throughput sequence analysis of linked genes in each family yielded > 4000 DNA variants and implicated a single gene, WDR62, as harboring potentially deleterious changes. We subsequently identified additional WDR62 mutations in four other families. MRI and postmortem brain analysis supports important roles for WDR62 in proliferation and migration of neuronal precursors. WDR62 is a WD40 repeat-containing protein expressed in neuronal precursors as well as postmitotic neurons in the developing brain and localizes to the spindle poles of dividing cells. The diverse phenotypes of WDR62 suggest central roles in many aspects of cerebral cortical development.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 15 September 2010

Publication date (Electronic): 3 October 2010

Publication date (Print): November 2010

Publication date PMC-release: 1 May 2011

Volume: 42

Issue: 11

Pages: 1015-1020

Affiliations

[1 ]Division of Genetics, Department of Medicine, Children’s Hospital Boston, Boston, MA 02115

[2 ]Manton Center for Orphan Disease Research, Children’s Hospital Boston, Boston, MA 02115

[3 ]Howard Hughes Medical Institute, Children’s Hospital Boston, Boston, MA 2115

[4 ]Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02215

[5 ]Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02138

[6 ]Division of Child Neurology, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

[7 ]Bill and Melinda Gates Foundation, New Delhi, India

[8 ]Department of Clinical Neurosciences, Division of Paediatric Neurology, Alberta Children’s Hospital, University of Calgary Faculty of Medicine, Calgary, AB T3B 6A8, -Canada

[9 ]Department of Laboratory Medicine & Pathology, University of Alberta Hospital, 5B4.09 Walter Mackenzie Health Sciences Centre, Edmonton, AB T6G 2B7, Canada

[10 ]Institute of Pathology, Medical University of Innsbruck, Muellerstrasse 44, AT-6020 Innsbruck, Austria

[11 ]Department of Pediatrics Section of Pediatric Neurology, Hacettepe University, Medical Faculty, Ihsan Dogramaci Children’s Hospital, Sihhiye 06100, Ankara, Turkey

[12 ]Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27710

[13 ]Division of Genetics, University of Washington at Seattle, WA 98195

[14 ]Division of Neuropathology, Brigham and Women’s Hospital, Boston, MA 02115

[15 ]Department of Radiology, University of California San Francisco, San Francisco, CA 94143

Author notes

Corresponding author: Dr. Christopher A. Walsh, Mailing address: Division of Genetics, Children's Hospital Boston, Center for Life Sciences 15062.2, 3 Blackfan Circle, Boston, MA 02115, Telephone number: 617-919-2923, Fax number: 617-919-2010, Christopher.Walsh@ 123456childrens.harvard.edu

Article

Manuscript ID: nihpa236207

DOI: 10.1038/ng.683

PMC ID: 2969850

PubMed ID: 20890278

SO-VID: e9533f75-5fca-493c-b058-f443296f412b

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