THE HUMAN GNAS1 GENE IS IMPRINTED AND ENCODES DISTINCT PATERNALLY ANDBIALLELICALLY EXPRESSED G-PROTEINS

The GNAS1 gene encodes the cr subunit of the G protein G(s), which cou ples receptor binding by several hormones to activation of adenylate c yclase. Null mutations of GNAS1 cause pseudohypoparathyroidism (PHP) t ype Ia, in which hormone resistance occurs in association with a chara cteristic osteodystrophy. The observation that PHP Ia almost always is inherited maternally has led to the suggestion that GNAS1 may be an i mprinted gene. Here, we show that, although G(s)alpha expression (dire cted by the promoter upstream of exon 1) is biallelic, GNAS1 is indeed imprinted in a promoter-specific fashion. We used parthenogenetic lym phocyte DNA to screen by restriction landmark genomic scanning for loc i showing differential methylation between paternal and maternal allel es. This screen identified a region that was found to be methylated ex clusively on a maternal allele and was located approximate to 35 kb up stream of GNAS1 exon 1. This region contains three novel exons that ar e spliced into alternative GNAS1 mRNA species, including one exon that encodes the human homologue of the large G protein XL alpha s. Transc ription of these novel mRNAs is exclusively from the paternal allele i n all tissues examined. The differential imprinting of separate protei n products of GNAS1 therefore may contribute to the anomalous inherita nce of PHP Ia.