Mouse Models of Williams-Beuren Syndrome

• ¹ University of Toronto, Institute of Medical Science, Canada
• ² University of Toronto, Department of Molecular Genetics, Canada
• ³ University of Toronto, Department of Medicine, Canada

In an attempt to dissect the contribution of individual genes to the complex and varied phenotype associated with Williams-Beuren syndrome (WBS), researchers have turned to mouse models. The mouse genome is easily manipulated to produce animals that are genetic copies of humans with genetic conditions, be it with null mutations, hypomorphic mutations, point mutations or even large deletions encompassing many genes.

Over the past few years, several mouse models knocking out genes from the region commonly deleted in WBS, have been generated. The first gene to be inactivated in the mouse was elastin (Eln), and this proved to be an excellent model for most, if not all, of the cardiovascular symptoms associated with ELN hemizygosity in humans. Subsequently, mouse models were generated for Clip2, Limk1, Fkbp6, Stx1a, Fzd9, and Gtf2ird1 and they have provided valuable information about the potential role of theses genes in WBS.

The phenotypic characterization of these mouse models has been quite different but much of the analyses have concentrated on behavior and cognition, aspects that present unique difficulties for assessment in rodents. Not all genes that are haploinsufficient in humans prove to be so in mice, and the effect of the genetic background on which the mice are maintained can also have a significant effect on the penetrance of many phenotypes. So, although mouse models are powerful tools, the information garnered from their study must be carefully interpreted.

The existing mouse models certainly seem to implicate CLIP2 and GTF2IRD1 in WBS, however, even combined, the different models do not recapitulate the full phenotypic spectrum of WBS. This suggests either that an additional gene or genes are haploinsufficient in WBS, or that WBS is the combinatorial result of the deletion of multiple genes rather than solely the result of an additive effect. New mouse models with multiple gene deletions are now emerging and these will help to provide the answer.