A GNAS1 imprinting defect in pseudohypoparathyroidism type IB

Pseudohypoparathyroidism type IB (PHPIB) is characterized by renal resistan ce to parathyroid hormone (PTH) and the absence of other endocrine or physi cal abnormalities. Familial PHPIB has been mapped to 20q13, near GNAS1, whi ch encodes G(s)alpha, the G protein alpha -subunit required for receptor-st imulated cAMP generation. However, G(s)alpha function is normal in blood ce lls from PHPIB patients, ruling out mutations within the G(s)alpha coding r egion. In mice G(s)alpha is expressed only from the maternal allele in rena l proximal tubules (the site of PTH action) but is biallelically expressed in most other tissues. Studies in patients with Albright hereditary osteody strophy suggest a similar G(s)alpha imprinting pattern in humans. Here we i dentify a region upstream of the G(s)alpha promoter that is normally methyl ated on the maternal allele and unmethylated on the paternal allele, but th at is unmethylated on both alleles in all 13 PHPIB patients studied. Within this region is an alternative promoter and first exon (exon 1A), generatin g transcripts that are normally expressed only from the paternal allele, bu t that are biallelically expressed in PHPIB patients. Therefore, PHPIB is a ssociated with a paternal-specific imprinting pattern of the exon 1A region on both alleles, which may lead to decreased G(s)alpha expression in renal proximal tubules. We propose that loss of exon 1A imprinting is the cause of PHPIB.