title: Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark.
abstract: Grb10/GRB10 encodes a cytoplasmic adapter protein which modulates coupling of a number of cell surface receptor tyrosine kinases with specific signalling pathways. Mouse Grb10 is an imprinted gene with maternal-specific expression. In contrast, human GRB10 is expressed biallelically in most tissues, except for maternal-specific expression of one isoform in muscle and paternal expression in fetal brain. Owing to its location in 7p11.2-p12, GRB10 has been considered a candidate gene for the imprinted growth disorder, the Silver-Russell syndrome (SRS), but its predominantly biallelic expression argues against involvement in the syndrome. To investigate the discrepant imprinting between mouse and human, we compared the sequence organization of their upstream regions, and examined their allelic methylation patterns and the splice variant organization of the mouse locus. Contrary to expectation, we detected both maternal and paternal expression of mouse Grb10. Expression of the paternal allele arises from a different promoter region than the maternal and, as in human, is restricted to the brain. The upstream regions are well conserved, especially the presence of two CpG islands. Surprisingly, both genes have a similar imprinted methylation pattern, the second CpG island is a differentially methylated region (DMR) with maternal methylation in both species. Analysis of 24 SRS patients did not reveal methylation anomalies in the DMR. In the mouse this DMR is a gametic methylation mark. Our results suggest that the difference in imprinted expression in mouse and human is not due to acquisition of an imprint mark but in differences in the reading of this mark.
authors.affiliation: Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Arnaud
authors.forename: David
authors.initials: D
authors.lastname: Monk
authors.forename: Megan
authors.initials: M
authors.lastname: Hitchins
authors.forename: Emma
authors.initials: E
authors.lastname: Gordon
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.forename: Colin V
authors.initials: CV
authors.lastname: Beechey
authors.forename: Jo
authors.initials: J
authors.lastname: Peters
authors.forename: William
authors.initials: W
authors.lastname: Craigen
authors.forename: Michael
authors.initials: M
authors.lastname: Preece
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.forename: Gudrun E
authors.initials: GE
authors.lastname: Moore
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D019175:DNA Methylation; D051383:GRB10 Adaptor Protein; D005786:Gene Expression Regulation; D018392:Genomic Imprinting; D006801:Humans; D051379:Mice; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C495959:Grb10 protein, mouse; D011506:Proteins; D051383:GRB10 Adaptor Protein