Human Molecular Genetics, 2003, Vol. 12, No. 9 1005-1019
DOI: 10.1093/hmg/ddg110
© 2003 Oxford University Press
Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark
1Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK, 2Department of Fetal and Maternal Medicine, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College, Du Cane Road, London W12 0NN, UK, 3MRC Mammalian Genetics Unit, Harwell, Didcot, Oxfordshire OX11 0RD, UK and 4Departments of Molecular and Human Genetics, and Pediatrics, Baylor College of Medicine, Houston, TX, USA
Received December 17, 2002; Accepted February 21, 2003
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.
* To whom correspondence should be addressed. Tel: +44 1223496332; Fax: +44 1223496022; Email: gavin.kelsey{at}bbsrc.ac.uk
Present address: Molecular Embryology Unit, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
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