Molecular Biology Laboratory, Department of Maternal and Fetal Medicine; Queen Charlotte's and Chelsea Hospital
Silver-Russell syndrome (SRS) is characterized primarily by intrauterine and postnatal growth restriction, triangular facies, and facial, limb or truncal asymmetry. Maternal uniparental disomy for chromosome 7 (mUPD7) has been identified in about 7% of SRS patients in our cohort (1). The recent demonstration of consistent heterodisomy for the entire chromosome 7 in a group of five mUPD7 cases indicates that altered expression of an imprinted gene (or genes) is the most likely cause of SRS is this category of patients (2). The region on human 7pl1.2-12 contains the epidermal growth factor receptor (EGFR), growth factor bound protein 10 (GRB10) and insulin-like growth factor binding proteins 1 (IGFBP1) and insulin-like growth factor binding proteins 3 (IGFBP3) genes. This region is syntenic to proximal mouse chromosome 11, which demonstrates a growth-related imprinting phenotype. Any involvement of the EGFR, IGFBP1 and IGFBP3 genes in the SRS phenotype seems unlikely, as each of these genes is biallelically expressed in relevant tissues (3,4). Murine Grb10 was identified as a maternally expressed gene by subtractive hybridization experiments using normal and androgenetic mouse embryos (5). Grb10 binds to the insulin and insulin-like growth factor receptors, and may act as an inhibitor of the respective post-receptor cascades. GRB10 is thus a prime candidate for a causal role in the SRS phenotype. We have analyzed the imprinting status of human GRB10 in multiple fetal tissues by tracing the allelic origin of expression of intragenic polymorphisms. The results will be discussed with respect to any role GRB10 might play in SRS, and to the reported imprinting status of the murine homologue.
Preece ,M.A. et al. Maternal uniparental disomy 7 in the Silver-Russell syndrome. J. Med. Genet. 7: 34: 6-9, 1997.
Preece, M.A. et al. An analysis of the distribution of hetero- and isodisomic regions of chromosome 7 in five mUPD7 Silver-Russell syndrome probands. J. Med. Genet. 33: 457-460, 1999.
Wakeling, E.L. et al. Human EGFR, a candidate gene for the Silver-Russell syndrome, is biallelically expressed in a wide range of fetal tissues. Eur. J. Hum. Genet. 6: 158-164, 1998.
Wakeling, E.L. et al. Biallelic expression of IGFBP1 and IGFBP3, two candidate genes for the Silver-Russell syndrome. J Med. Genet. (in press).
Miyoshi, N. et al. Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver-Russell syndrome gene. Proc. Nad. Acad Sci. USA 95: 1102-1107, 1998.