<i>GNAS</i> Locus and Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia due to resistance to parathyroid hormone (PTH). Patients with PHP-Ia often present with additional hormonal resistance and show characteristic physical features that are collectively termed Albright’s hereditary osteodystrophy (AHO). These features are also present in pseudopseudohypoparathyroidism (PPHP), but patients affected by this disorder do not show hormone resistance. PHP-Ib patients, on the other hand, present predominantly with renal PTH resistance and lack any features of AHO. Most of these PHP forms are caused by defects in <i>GNAS</i> (20q13.3), an imprinted gene locus with multiple transcriptional units. PHP-Ia and PPHP are caused by heterozygous inactivating mutations in those exons of <i>GNAS </i>encoding the α subunit of the stimulatory guanine nucleotide-binding protein (Gsα), and the autosomal dominant form of PHP-Ib (AD-PHP-Ib) is caused by heterozygous mutations disrupting a long-range imprinting control element of <i>GNAS</i>. Expressed nearly in all cells, Gsα plays essential roles in a multitude of physiological processes. Its expression in renal proximal tubules occurs predominantly from the maternal allele, and this tissue- and parent-specific imprinting of Gsα is an important determinant of hormone resistance in kindreds with PHP-Ia/PPHP and AD-PHP-Ib.