Evidence against a major role of PEG1/MEST in Silver–Russell syndrome

Abstract

Silver-Russell syndrome (SRS) is a heterogeneous disorder characterised by interauterine and postnatal growth retardation, with or without additional dysmorphic features. Most cases are sporadic but a few familial cases have been described. A subset of patients exhibit maternal uniparental disomy for chromosome 7 (mUPD7) strongly suggesting that genomic imprinting plays a role in the aetiology of the disease. We and others have recently characterised the human PEG1/MEST gene, the first imprinted gene known to be located on chromosome 7. Although the function of PEG1/MEST is unknown, the paternal-specific expression of this gene and its location at 7q32, render it a promising candidate for SRS. As a prerequisite for mutation screening in 49 patients with SRS and 9 with primordial growth retardation (PGR), we determined the complete genomic structure of the PEG1/MEST gene which consists of 12 exons. Apart from one silent mutation and two novel polymorphisms, nucleotide changes were not detected in any of these patients. Moreover, methylation patterns of the 5' region of PEG1/MEST were found to be normal in 35 SRS and 9 PGR patients and different from the pattern seen in patients with mUPD7. These findings strongly argue against a role of PEG1/MEST in the majority of Silver-Russell syndrome cases.

Zac1 (Lot1), a Potential Tumor Suppressor Gene, and the Gene for ɛ-Sarcoglycan Are Maternally Imprinted Genes: Identification by a Subtractive Screen of Novel Uniparental Fibroblast Lines

“…In mice, mutation of the paternal allele of Peg1 (Mest) resulted in fetal growth retardation and was considered a candidate for SRS (24). However, a recent analysis has suggested that PEG1 has no role in SRS (33). Therefore, Sgce is another candidate for this condition.…”

The Role of Imprinted Genes in Fetal Growth

“…However, mutational screening of SRS patients for PEG1/MEST [48] and GRB10 [49] has not clearly proved their involvement in the etiology of the syndrome.…”

Silver-Russell syndrome and cystic fibrosis associated with maternal uniparental disomy 7

“…Two potential candidate genes for SRS on chromosome 7 (MEST and EGFR) were characterized and tested, but so far none of these have been shown to harbor mutations in SRS patients [Riesewijk et al, 1998;Wakeling et al, 1998b]. The identification and functional characterization of the growth-related gene(s) on chromosome 7 and other human chromosomes known to undergo differential imprinting might ultimately dissect the distinct contribution of maternal and paternal transcripts to the control of intrauterine and postnatal growth.…”