As part of a systematic screen for novel imprinted genes of human chromosome 7 we have investigated GRB10, which belongs to a small family of adapter proteins, known to interact with a number of receptor tyrosine kinases and signalling molecules. Upon allele-specific transcription analysis involving multiple distinct splice variants in various fetal tissues, we found that human GRB10 is imprinted in a highly isoform- and tissue-specific manner. In fetal brains, most variants are transcribed exclusively from the paternal allele. Imprinted expression in this tissue is not accompanied by allele-specific methylation of the most 5' CpG island. In skeletal muscle, one GRB10 isoform, gamma1, is expressed from the maternal allele alone, whereas in numerous other fetal tissues, all GRB10 splice variants are transcribed from both parental alleles. A remarkable finding is paternal-specific expression of GRB10 in the human fetal brain, since, in the mouse, this gene is transcribed exclusively from the maternal allele. To our knowledge, this is the first example of a gene that is oppositely imprinted in mouse and human.

No 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.

No abstract