The common defect in nearly all PHP-Ib cases is the loss of GNAS exon A/B imprinting. In fact, this epigenetic defect is necessary for the development of PTH resistance, as documented in a PHP-Ib kindred in whom some individuals lacked both loss of A/B imprinting and PTH resistance despite maternally inheriting the disease-associated haplotype on 20q [166]. The loss of A/B imprinting on the maternal allele is predicted to silence, in cis, Gsα transcription in the proximal tubule. Therefore, methylation of exon A/B DMR and/or the repression of A/B transcription appear to be required for maternal Gsα expression in this and, probably, other tissues, such as the thyroid gland. Supporting this notion, ablation of the paternal exon A/B region derepresses Gsα in cis in tissues where this signaling protein is paternally silenced [81, 88] and, furthermore, rescues the PTH resistance phenotype observed in mice with a point mutation in maternal Gnas exon 6 [80, 81].
