Wakeling, Emma L.; (1999) Genomic imprinting and Silver-Russell syndrome: Candidate genes on chromosome 7. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Silver-Russell syndrome (SRS) is characterised by intrauterine and postnatal growth retardation, triangular facies, fifth finger clinodactyly and lateral asymmetry. Maternal uniparental disomy of chromosome 7 (mUDP7) has been demonstrated in approximately 7% of patients. No consistently isodisomic regions have been found. It is likely, therefore, that one or more imprinted gene(s) on chromosome 7 are involved in SRS. Five candidate genes located on this chromosome have been studied. The human chromosomal region 7p11.2-13 is homologous to an imprinted region on mouse proximal chromosome 11. Maternal UPD for this region leads to mice with prenatal growth failure. Three growth-related genes, IGFBP1 and 3 (insulin-like growth factor binding proteins 1 and 3) and EGFR (epidermal growth factor receptor), lie within this region and have been proposed as candidates for SRS. The imprinting status of these genes was previously unknown. Their parental allele expression was therefore investigated in normal fetal tissues using transcribed polymorphisms. Biallelic expression of all three genes was observed. Expression of IGFBP3 and EGFR was also seen in cell lines from mUPD7 patients. Since no evidence for imprinting of these three genes was found, their involvement in SRS seems unlikely. Recently, MEST (mesoderm specific transcript) became the first imprinted gene to be identified on chromosome 7. Its possible role in SRS was investigated by studying allelic methylation patterns using methylation-specific PCR. Normal differential methylation of MEST was found in 46, non-UPD SRS patients. It is therefore unlikely that this gene plays a major role in SRS. Finally, the growth suppressing gene GRB10 (growth factor receptor binding protein 10) has also recently been proposed as a candidate for SRS. A de novo duplication of 7p11.2-p12, including GRBIO, was observed in one SRS proband, providing further support for a role for this gene in SRS. However, Southern blot hybridisation showed normal GRB10 dosage in 36 other, non-UPD patients. Further investigation into the potential role of GRB10 and/or other genes within the region 7p11.2-p12 is needed.

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