Mutation of Gtf2ird1 from the Williams-Beuren syndrome critical region results in facial dysplasia, motor dysfunction, and altered vocalisations

Neurobiol Dis. 2012 Mar;45(3):913-22. doi: 10.1016/j.nbd.2011.12.010. Epub 2011 Dec 11.


Insufficiency of the transcriptional regulator GTF2IRD1 has become a strong potential explanation for some of the major characteristic features of the neurodevelopmental disorder Williams-Beuren syndrome (WBS). Genotype/phenotype correlations in humans indicate that the hemizygous loss of the GTF2IRD1 gene and an adjacent paralogue, GTF2I, play crucial roles in the neurocognitive and craniofacial aspects of the disease. In order to explore this genetic relationship in greater detail, we have generated a targeted Gtf2ird1 mutation in mice that blocks normal GTF2IRD1 protein production. Detailed analyses of homozygous null Gtf2ird1 mice have revealed a series of phenotypes that share some intriguing parallels with WBS. These include reduced body weight, a facial deformity resulting from localised epidermal hyperplasia, a motor coordination deficit, alterations in exploratory activity and, in response to specific stress-inducing stimuli; a novel audible vocalisation and increased serum corticosterone. Analysis of Gtf2ird1 expression patterns in the brain using a knock-in LacZ reporter and c-fos activity mapping illustrates the regions where these neurological abnormalities may originate. These data provide new mechanistic insight into the clinical genetic findings in WBS patients and indicate that insufficiency of GTF2IRD1 protein contributes to abnormalities of facial development, motor function and specific behavioural disorders that accompany this disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Animals, Newborn / blood
  • Body Temperature / genetics
  • Body Weight / genetics
  • Brain / metabolism
  • Circadian Rhythm / genetics
  • Corticosterone / blood
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Fats
  • Female
  • Focal Epithelial Hyperplasia / etiology*
  • Focal Epithelial Hyperplasia / genetics
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Skills Disorders / etiology*
  • Motor Skills Disorders / genetics
  • Muscle Proteins / genetics*
  • Muscle Strength
  • Muscle, Skeletal / pathology
  • Mutation / genetics*
  • Nuclear Proteins / genetics*
  • Phenotype
  • Sex Factors
  • Sleep / genetics
  • Sound Spectrography
  • Stress, Psychological / genetics
  • Swimming / psychology
  • Trans-Activators / genetics*
  • Vocalization, Animal / physiology*
  • Williams Syndrome / complications*
  • Williams Syndrome / genetics
  • Williams Syndrome / pathology


  • Fats
  • GTF2IRD1 protein, human
  • Muscle Proteins
  • Nuclear Proteins
  • Trans-Activators
  • Corticosterone