The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins

The GNAS1 gene encodes the α subunit of the G protein G(s), which couples receptor binding by several hormones to activation of adenylate cyclase. Null mutations of GNAS1 cause pseudohypoparathyroidism (PHP) type Ia, in which hormone resistance occurs in association with a characteristic osteodystrophy. The observation that PHP Ia almost always is inherited maternally has led to the suggestion that GNAS1 may be an imprinted gene. Here, we show that, although G(s)α expression (directed by the promoter upstream of exon 1) is biallelic, GNAS1 is indeed imprinted in a promoter-specific fashion. We used parthenogenetic lymphocyte DNA to screen by restriction landmark genomic scanning for loci showing differential methylation between paternal and maternal alleles. This screen identified a region that was found to be methylated exclusively on a maternal allele and was located ≈35 kb upstream of GNAS1 exon 1. This region contains three novel exons that are spliced into alternative GNAS1 mRNA species, including one exon that encodes the human homologue of the large G protein XLαs. Transcription of these novel mRNAs is exclusively from the paternal allele in all tissues examined. The differential imprinting of separate protein products of GNAS1 therefore may contribute to the anomalous inheritance of PHP Ia.