A GENE IMPLICATED IN THE NEUROBEHAVIOURAL ABNORMALITIES OF WILLIAMS-BEUREN SYNDROME, GTF2IRD1, ENCODES A NOVEL EPIGENETIC REGULATOR. P. Carmona-Mora1, J. Widagdo1, F. Tomasetig1, K. M. Taylor1, Y. Cha1, R.T-W Pang1, N. A. Twine2, M. R. Wilkins2, P. W. Gunning3, E. C. Hardeman1, S. J. Palmer1 1) School of Medical Sciences, Neuromuscular and Regenerative Medicine Unit, University of New South Wales, Sydney, NSW 2052, Australia; 2) School of Biotechnology and Biomolecular Sciences, The New South Wales Systems Biology Initiative, University of New South Wales, NSW 2052, Australia; 3) School of Medical Sciences, Oncology Research Unit, University of New South Wales, Sydney, NSW 2052, Australia.

   Williams-Beuren syndrome (WBS) is an autosomal dominant disorder resulting from a hemizygous microdeletion within chromosome 7q11.23. The clinical presentation of this multisystem disorder includes craniofacial abnormalities and a distinctive neurocognitive profile. WBS neurobehavioural abnormalities involve intellectual disability, reduced social anxiety, high incidence of psychopathologies such as ADHD and phobias and a visuospatial construction deficit. Genotype/phenotype correlations in patients with atypical deletions implicate a gene discovered in our laboratory, GTF2IRD1, as responsible for the distinctive neurocognitive profile of WBS. However, the molecular and cellular consequences of GTF2IRD1 haploinsufficiency remain unknown. To reveal the normal function of GTF2IRD1 we have combined protein interaction studies, gene expression and transcript profile analyses in Gtf2ird1 knockout mice. The first approach comprised a yeast two-hybrid screening system to discover the molecular interactions of GTF2IRD1. We identified a panel of interacting partners that fall into functional groups, such as DNA binding proteins, post-translational modification machinery (SUMO and ubiquitin ligation proteins) and chromatin modifying factors involved in histone methylation, deacetylation and ubiquitination. We also found that GTF2IRD1 interacts with multiple members of the same gene family, thus expanding its interactional network and illustrating conserved binding domains. Immunofluorescence and co-immunoprecipitation in mammalian cells support these interactions and show a specific pattern of subnuclear localization for endogenous GTF2IRD1. To assess the effect of GTF2IRD1 on gene expression, we conducted microarray transcript profile analyses in corpus striatum tissue from Gtf2ird1 KO mice followed by qRT-PCR validation. This KO mouse model has been shown to mirror many of the defects of WBS, including ataxia and abnormalities of locomotor drive. We found an increased expression of genes involved in neuronal development and a cluster of immediate-early response genes that have previously been linked with hyperactivity. Our data are consistent with a role for GTF2IRD1 as an epigenetic regulator of gene repression that coordinates interactions with transcription factors, DNA binding proteins and components of the chromatin modification machinery and provide a possible explanation for the underlying molecular cause of locomotor changes in WBS patients.

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