Purpose of review: To provide the reader with a review of contemporary literature describing the evolving understanding of the molecular pathobiology of pseudohypoparathyroidism (PHP).
Recent findings: The features of PHP type 1 reflect imprinting of the GNAS gene, which encodes the α subunit of the heterotrimeric G protein (Gα(s)) that couples heptahelical receptors to activation of adenylyl cyclase. Transcription of Gα(s) is biallelic in most cells, but is primarily from the maternal allele in some tissues (e.g. proximal renal tubules, thyroid, pituitary somatotropes, gonads). Patients with PHP 1a have heterozygous mutations within the exons of the maternal GNAS allele that encode Gα(s), whereas patients with PHP 1b have methylation defects in the GNAS locus that reduce transcription of Gα(s) from the maternal allele. In both PHP 1a and PHP 1b, paternal imprinting of Gα(s) leads to resistance to parathyroid hormone and TSH. Although brachydactyly is characteristic of PHP 1a, it is sometimes present in patients with PHP 1b.
Summary: Molecular studies enable a distinction between PHP 1a and PHP 1b, with different mechanisms accounting for Gα(s) deficiency. Clinical overlap between these two forms of PHP type 1 is likely due to the variable levels of Gα(s) activity expressed in specific cell types.