title: GTF2IRD1 in craniofacial development of humans and mice.
abstract: 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.
authors.affiliation: Academic Unit of Medical Genetics, University of Manchester, St. Mary's Hospital, Manchester M13 9PL, UK. m.tassabehji@manchester.ac.uk
authors.forename: May
authors.initials: M
authors.lastname: Tassabehji
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Annette
authors.initials: A
authors.lastname: Karmiloff-Smith
authors.forename: Pamela
authors.initials: P
authors.lastname: Thompson
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Marian E
authors.initials: ME
authors.lastname: Durkin
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Popescu
authors.forename: Timothy
authors.initials: T
authors.lastname: Hutton
authors.forename: Kay
authors.initials: K
authors.lastname: Metcalfe
authors.forename: Agnes
authors.initials: A
authors.lastname: Rucka
authors.forename: Helen
authors.initials: H
authors.lastname: Stewart
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Read
authors.forename: Mark
authors.initials: M
authors.lastname: Maconochie
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002897:Chromosomes, Human, Pair 7; D019465:Craniofacial Abnormalities / Q000235:genetics*; D005145:Face / Q000196:embryology*; D005260:Female; D017353:Gene Deletion; D051956:Goosecoid Protein / Q000235:genetics / Q000502:physiology; D006720:Homozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D012886:Skull / Q000196:embryology*; D015534:Trans-Activators / Q000502:physiology*; D019473:Transcription Factors, TFII / Q000502:physiology; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: C104259:GTF2I protein, human; C405493:GTF2IRD1 protein, human; D051956:Goosecoid Protein; C497993:Gsc protein, mouse; C486330:Gtf2i protein, mouse; C486558:Gtf2ird1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D019473:Transcription Factors, TFII