| Summary: | Genomic rearrangements, particularly deletions and duplications, are known to cause many genetic disorders. The chromosome 7q11.23 region in humans is prone to recurrent chromosomal rearrangement, due to the presence of low copy repeats that promote non-allelic homologous recombination. The most well characterized rearrangement of 7q11.23 is a hemizygous 1.5 million base pair (Mb) deletion spanning more than 25 genes. This deletion causes Williams-Beuren Syndrome (WBS; OMIM 194050), a multisystem developmental disorder with distinctive physical and behavioural features.
Other rearrangements of the region lead to phenotypes distinct from that of WBS. Here we describe the first individual identified with duplication of the same 1.5 Mb region, resulting in severe impairment of expressive language, in striking contrast to people with WBS who have relatively well preserved language skills. We also describe the identification of a new gene for a severe form of childhood epilepsy through the analysis of individuals with deletions on chromosome 7 that extend beyond the boundaries typical for WBS. This gene, MAGI2, is part of the large protein scaffold at the post-synaptic membrane and provides a new avenue of research into both the molecular basis of infantile spasms and the development of effective therapies.
Individuals with smaller than typical deletions of 7q11.23 have delineated a minimal critical region for WBS and have implicated two members of the TFII-I transcription factor family. To better understand the contribution of these genes to WBS, I have generated animal models with these genes deleted singly and in combination. Disruption of the first gene, Gtf2ird1, resulted in phenotypes reminiscent of WBS including alterations in social behaviour, natural fear response and anxiety. An alteration in serotonin function was identified in the frontal cortex and may be linked to these behavioural phenotypes. Together with a model for the second gene, Gtf2i, and the double deletion model that was generated using Cre-loxP technology, these resources will permit the study of the individual and additive effects of hemizygosity for Gtf2i and Gtf2ird1 and will greatly expand our understanding of the role the TFII-I gene family in WBS.
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