Pseudohypoparathyroidism -: New insights into an old disease

The complex GNAS1 gene (chromosome 20q13.3) encodes the stimulatory G protein (Gs-alpha) and at least three additional, alternatively spliced transcripts, XLas, NESP55, and AS, which are derived either from the paternal or the maternal allele, or from both. Pseudohypoparathyroidism type Ia (PHP-Ia) and pseudopseudohypoparathyroidism (pPHP) are caused by heterozygous mutations in the coding exons of GNAS1, but the endocrine abnormalities occur only if the genetic defect is inherited from an obligate female carrier. Recent linkage studies have shown that the genetic defect responsible for pseudohypoparathyroidism type Ib (PHP-Ib) maps also to the GNAS1 locus and that this disorder is paternally imprinted just as PHP-Ia/pPHP. It therefore appears likely that mutations in distinct regions of the GNAS1 gene are the cause of at least three different forms of PHP.