[Pseudohypoparathyroidism and variants: A translational medicine success story]

Pseudohypoparathyroidism (PHP) is an uncommon disorder which is characterized by end-organ PTH resistance. The genetic defect is located at the GNAS locus that encodes the alpha-subunit of the stimulatory G protein (Gα_s) and several splice variants thereof. This complex locus undergoes parental specific methylation changes that result in tissue-specific silencing of the paternal allele. Heterozygous inactivating mutations that disrupt Gα_s function or epigenetics changes that impair Gα_s expression contribute to a wide clinical spectrum of the disease: PHP1A, PHP1B, osseous heteroplasia, osteodystrophy, obesity, intrauterine growth retardation… whose mechanisms at the molecular level remain unresolved.