International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Oral Presentation

Tuesday 19 November

10:45 - 11:00 HRS


S Heaney
MRC Human Genetics Unit

Co-Authors: Hill R, Lettice L, Purdie L, Taylor M
Institutions: MRC

The sasquatch (Ssq) mouse is a member of the hemimelia-luxate group of mutations, which display preaxial polydactyly (extra digits). Ssq was generated serendipitously via a transgenic insertion of a reporter construct approximately 1Mb downstream of the gene Sonic hedgehog (Shh). Associated with the Ssq limb defects is the mis-regulation of Shh in the limb bud, resulting in an anterior area of ectopic expression as well as the normal patch of posterior expression. This process of Shh mis-regulation is poorly understood for most of the hemimelia-luxate mutants. But recently using a mouse genetic assay† we have determined that in the case of the Ssq mouse, disruption of a long range Shh limb enhancer is responsible for ectopic Shh expression. Comparative sequence analysis using mouse, human and fugu genomic sequences identified candidate regulatory regions near the Ssq insertion. Transgenic assays have confirmed that one of these conserved regions is capable of driving gene expression in a Shh like pattern in the developing limb.The human genetic disease Preaxial Polydactyly (PPD) maps to a 450kb region syntenic to the Ssq locus. Ssq is most likely the model for PPD confirming the likelihood that enhancer elements responsible for human genetic disease or variation could be acting over 100ís of kb within the human genome. Obviously this has important consequences for the mapping of human genetic disease and reaffirms the importance of mouse models in revealing underlying disease mechanisms.

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