An imprinted antisense transcript at the human GNAS1 locus

Recent studies of the GNAS1 gene have shown a highly complex imprinted expr ession pattern, with paternally, maternally and biallelically derived prote in products, raising questions regarding how such transcriptional complexit y is established and maintained. GNAS1 was originally identified as the gen e encoding an important and widely expressed signal transduction protein, t he alpha subunit of the stimulatory G protein G(s). Partial G(s)alpha defic iency results in the hormone resistance syndrome, pseudohypoparathyroidism type la. G(s)alpha is encoded by exons 1-13 of GNAS1 and, in most tissues a t least, expression of this transcript is biallelic. Two large upstream exo ns, however, have monoallelic expression patterns, and in each case their t ranscripts splice onto GNAS1 exon 2. The most 5' of these is maternally exp ressed, and encodes neuroendocrine secretory protein 55 (NESP55), whose cod ing region does not overlap with that of G(s)alpha. The other exon, 14 kb f urther 3', is paternally expressed, and encodes XL alpha s (extra large alp ha s-like protein), translated in-frame with G(s)alpha exons 2-13. This clo se proximity of two oppositely imprinted promoters suggested the likelihood of important regulatory interactions between them, and to investigate this possibility we have performed a search for other transcripts in the region . Here we show that the maternally methylated region upstream of the XL alp ha s exon gives rise to a spliced polyadenylated antisense transcript, whic h spans the upstream NESP55 region. This antisense transcript is imprinted, and expressed only from the paternal allele, suggesting that it may have a specific role in allele, suggesting that it may nave a specific role In su ppressing in cis the activity of the paternal NESP55 allele.