Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, 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 those of classic WBS cases. We propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.

Original publication

DOI

10.1126/science.1116142

Type

Journal article

Journal

Science (New York, N.Y.)

Publication Date

03/11/2005

Volume

310

Pages

1184 - 1187

Addresses

Academic Unit of Medical Genetics, University of Manchester, St. Mary's Hospital, Manchester M13 9PL, UK. m.tassabehji@manchester.ac.uk

Keywords

Face, Skull, Cell Line, Chromosomes, Human, Pair 7, Animals, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Humans, Mice, Craniofacial Abnormalities, Williams Syndrome, Muscle Proteins, Transcription Factors, TFII, Trans-Activators, Nuclear Proteins, Gene Deletion, Homozygote, Adolescent, Adult, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Goosecoid Protein