An Imprinted Antisense Transcript at the Human GNAS1 Locus

Recent studies of the GNAS1 gene have shown a highly complex imprinted expression pattern, with paternally, maternally and biallelically derived protein products, raising questions regarding how such transcriptional complexity is established and maintained. GNAS1 was originally identified as the gene encoding an important and widely expressed signal transduction protein, the alpha subunit of the stimulatory G protein G(s). Partial G(s)alpha deficiency results in the hormone resistance syndrome, pseudohypoparathyroidism type 1a. G(s)alpha is encoded by exons 1-13 of GNAS1 and, in most tissues at least, expression of this transcript is biallelic. Two large upstream exons, however, have monoallelic expression patterns, and in each case their transcripts splice onto GNAS1 exon 2. The most 5' of these is maternally expressed, and encodes neuroendocrine secretory protein 55 (NESP55), whose coding region does not overlap with that of G(s)alpha. The other exon, 14 kb further 3', is paternally expressed, and encodes XL(alpha)s (extra large alphas-like protein), translated in-frame with G(s)alpha exons 2-13. This close 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(alpha)s exon gives rise to a spliced polyadenylated antisense transcript, which 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 suppressing in cis the activity of the paternal NESP55 allele.