David Monk
Imperial College
Both maternal uniparental disomy (mUPD7) and maternally inherited duplications of 7p11.2-p13 have been reported in Silver-Russell syndrome (SRS), suggesting that SRS is caused by the over-expression of a maternally expressed/paternally imprinted gene on human chromosome 7. We have FISH mapped the breakpoints for 8 patients with SRS or SRS-like phenotypes, which includes 4 unrelated maternally inherited duplications of 7p, and a further 4 cases including inversions and a translocation which all have breakpoints localized to a distinct 1 Mb region at 7p11.2. This interval has previously been proposed as a candidate gene region for SRS because it shares homology with the imprinted domain on proximal mouse chromosome 11. Within this region is the imprinted gene GRB10, which shows a complex isoform and tissue specific reciprocal imprinted expression profile. GRB10 is a known growth suppressor that binds to the insulin-like growth factor I receptor (IGF1R) via its Src homology 2 domain and inhibiting the action of insulin and insulin-like growth factors I and II, and so is an excellent candidate for the intrauterine growth restriction associated with both SRS and Mated (proxy 11) mice. However, it has recently been shown that submicroscopic duplications and coding mutations of GRB10 are not common causes of SRS. This suggests that other imprinted genes maybe localized within a yet to be characterized cluster. Using a variety of techniques, including monochromosomal somatic cell hybrids and expressed SNPs in fetal and maternal paired samples, we have shown that thirteen genes surrounding GRB10 are biallelically expressed, suggesting that GRB10 is the only imprinted gene in this region.