Deletion of the noncoding GNAS antisense transcript causes pseudohypoparathyroidism type Ib and biparental defects of GNAS methylation in cis.

Context: GNAS encodes the alpha-subunit of the stimulatory G protein as well as additional imprinted transcripts including the maternally expressed NESP55 and the paternally expressed XLalphas, antisense, and A/B transcripts. Most patients with pseudohypoparathyroidism type Ib (PHP-Ib) exhibit imprinting defects affecting the maternal GNAS allele, which are thought to reduce/abolish Gsalpha expression in renal proximal tubules and thereby cause resistance to PTH.

Objective: Our objective was to define the genetic defect in a previously unreported family with autosomal dominant PHP-Ib.