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Published Online November 3, 2005
Science DOI: 10.1126/science.1116142

Reports

Submitted on June 15, 2005
Accepted on October 5, 2005

GTF2IRD1 in Craniofacial Development of Humans and Mice

May Tassabehji 1*, Peter Hammond 2, Annette Karmiloff-Smith 3, Pamela Thompson 1, Snorri S. Thorgeirsson 4, Marian E. Durkin 4, Nicholas C. Popescu 4, Timothy Hutton 2, Kay Metcalfe 1, Agnes Rucka 1, Helen Stewart 5, Andrew P. Read 1, Mark Maconochie 6, Dian Donnai 1

1 Academic Unit of Medical Genetics, University of Manchester, St. Mary's Hospital, Manchester M13 9PL, UK.
2 Eastman Dental Institute
3 Institute of Child Health, University College London, London WC1E 6BT, UK.
4 National Cancer Institute, Bethesda, MD 20814, USA.
5 Churchill Hospital, Oxford OX3 7LJ, UK.
6 School of Life Sciences, University of Sussex, Brighton BN1 9RH, UK.

* To whom correspondence should be addressed.
May Tassabehji , E-mail: m.tassabehji{at}man.ac.uk

Craniofacial abnormalities account for about one third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. Here we demonstrate that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development and implicate another family member, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren Syndrome (WBS). Craniofacial imaging reveals abnormalities in both skull and jaws that may arise through misregulation of goosecoid, a downstream target of Gtf2ird1. In humans, a rare WBS individual with an atypical deletion, including GTF2IRD1, shows facial dysmorphism and cognitive deficits that differ from classic WBS cases. From our findings, we propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.


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