Tissue-specific expression of antisense and sense transcripts at the imprinted Gnas locus

The mouse Gnas gene encodes an important signal transduction protein, the a subunit of the stimulatory G protein, G(s). In humans, partial deficiency of G(s)alpha, the a subunit of G(s), results in the hormone-resistance syndrome pseudohypoparathyroidism type 1a. The mouse Gnas (and the human GNAS1) locus is transcribed from three promoter regions. Transcripts from P1, which encode Nesp55, are derived from the maternal allele only. Transcripts from P2 encode Xl alphas and are derived only from the paternal allele, while transcripts from P3 encode the alpha subunit and are from both parental alleles. The close proximity of reciprocal imprinting suggests the presence of important putative imprinting elements in this region. In this report, we demonstrate that the reciprocal imprinting occurs in normal tissues of interspecific (Mus spretus x C57BL/6) mice. Transcripts from P1 are most abundant in CNS (pons and medulla) in contrast to the more ubiquitous expression from P2 and P3. In the P1-P2 genomic region,we have identified an antisense transcript that starts 2.2 kb upstream of the P2 exon and spans the pi region. While the P1 transcript is derived from the maternal allele, the P1-antisense (Gnas-as) is derived only from the paternal allele in most but not all tissues. Although both the Nesp55 region and the Gnas-as transcripts are present in cerebral cortex, adrenal, and spleen, Gnas-as is abundant in some tissues in which transcription from the Nesp55 region is negligible. Furthermore, the Nesp55 region transcripts remain strictly imprinted in tissues that lack Gnas-as. Our results suggest that multiple imprinting elements, including the unique Gnas-as, regulate the allelic expression of the Nesp55 region sense transcript. (C) 2000 Academic Press.