Abstract for presentation at 11th International Congress of Human Genetics

Gtf2ird1 mutant mice exhibit social phenotypes of Williams-Beuren syndrome and show altered expression of genes important for neuronal migration

  • Jennifer O'Leary, University of Toronto, Canada
  • Edwin Young, University of Toronto, Canada
  • Dr Tatiana Lipina, Samuel Lunenfeld Research Institute, Canada
  • Ariane Mandel, University of Toronto, Canada
  • Allison Bechard, Samuel Lunenfeld Research Institute, Canada
  • Elaine Tam, University of Toronto, Canada
  • Dr John Roder, Samuel Lunenfeld Research Institute, Canada
  • Lucy Osborne, University of Toronto, Canada

    • Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by the hemizygous deletion of genes on chromosome 7q11.23. It presents with a characteristic behavioural profile consisting of both hypersociability and anxiety. The GTF2IRD1 transcription factor is a candidate for aspects of the neurological phenotype, and to learn more about the role of this gene in the mammalian brain, we generated a Gtf2ird1 gene targeted mouse. Analysis of this mouse revealed features seen in patients with WBS, such as growth retardation and mild craniofacial abnormalities. In addition, the mice showed impaired cued fear conditioned learning, reduced innate fear and impaired latent inhibition, and were significantly less aggressive to unknown mice during the resident-intruder test. They also exhibited reduced anxiety in the elevated plus maze, unlike people with WBS who show high anxiety, however, this test may not be a physiological measure of the phobic anxiety found in WBS, but rather may reflect the general reduction in innate fear. This decrease in natural and learned fear, and increased sociability are similar to behaviours seen in people with WBS. To attempt to unravel the molecular basis for the intriguing phenotype seen in these mice, we performed microarray analysis of brain tissue from newborn mice. Microarray was performed using pooled RNA from 9 different pups on Affymetix Mouse Expression 430 arrays (3 null and 3 normal pools). Signals were normalized using RMA and then subject to SAM analysis. Results showed alteration in gene expression for 61 transcripts with a false discovery rate of 3.3%, around half of which were uncharacterized ESTs. Known genes with altered expression in the brains of newborn Gtf2ird1 null mice included several with roles in neuronal migration, such as Dcx, Mapk8, Ndel1 and Nogo. Further experiments will be required to determine whether these genes represent direct or indirect targets of Gtf2ird1.

    Conference Organiser - ICMS Pty Ltd