Pseudohypoparathyroidism. New Insights into an Old Disease

The GNAS1 gene (chromosome 20q13.3) encodes the alpha subunit of the stimulatory G protein (Gs alpha) and at least three additional, alternatively spliced transcripts, XL alpha s, NESP55, and the antisense transcript AS. Gs alpha transcripts seem to be derived exclusively, at least in the renal cortex, from the maternal allele. XL alpha s and AS are transcribed only from the paternal allele, and NESP55 is transcribed only from the maternal allele. Numerous GNAS1 mutations have been identified in PHP-Ia and pPHP. Patients with either disorder show skeletal and developmental defects now referred to as AHO. Owing to paternal imprinting, that is, inactivation of the paternal allele, which may be tissue- or cell-specific, resistance toward PTH and, often, other hormones is only observed in patients with PHP-Ia. Patients with PHP-Ib show PTH-resistant hypocalcemia and hyperphosphatemia but no AHO. The abnormal regulation of mineral ion homeostasis is paternally imprinted, such as in PHP-Ia/pPHP kindreds, Gs alpha activity/protein is normal in fibroblasts and blood cells, and no GNAS1 mutations have been identified. Recent linkage studies have mapped the genetic defect responsible for PHP-Ib to chromosome 20q13.3, making it likely that mutations in distinct regions of the GNAS1 gene are the cause of at least three different forms of PHP.