The GNAS Locus and Pseudohypoparathyroidism

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Abstract
Pseudohypoparathyroidism (PHP) is a disorder of end-organ resistance primarily affecting the actions of parathyroid hormone (PTH). Genetic defects associated with different forms of PHP involve the α-subunit of the stimulatory G protein (Gsα), a signaling protein essential for the actions of PTH and many other hormones. Heterozygous inactivating mutations within Gsα-encoding GNAS exons are found in patients with PHP-Ia, who also show resistance to other hormones and a constellation of physical features called Albright’s hereditary osteodystrophy (AHO). Patients who exhibit AHO features without evidence for hormone resistance, who are said to have pseudopseudohypoparathyroidism (PPHP), also carry heterozygous inactivating Gsα mutations. Maternal inheritance of such a mutation leads to PHP-Ia, i.e., AHO plus hormone resistance, while paternal inheritance of the same mutation leads to PPHP, i.e., AHO only. This imprinted mode of inheritance for hormone resistance can be explained by the predominantly maternal expression of Gsα in certain tissues, including renal proximal tubules. Patients with PHP-Ib lack coding Gsα mutations but display epigenetic defects of the GNAS locus, with the most consistent defect being a loss of imprinting at the exon A/B differentially methylated region (DMR). This epigenetic defect presumably silences, in cis, Gsα expression in tissues where this protein is derived from the maternal allele only, leading to a marked reduction of Gsα levels. The familial form of PHP-Ib (AD-PHP-Ib) is typically associated with an isolated loss of imprinting at the exon A/B DMR. A unique 3-kb microdeletion that disrupts the neighboring STX16 locus has been identified in this disorder and appears to be the cause of the loss of imprinting. In addition, deletions removing the entire NESP55 DMR, located within GNAS, have been identified in some AD-PHP-Ib kindreds in whom affected individuals show loss of all the maternal GNAS imprints. Mutations identified in different forms of PHP-Ib thus point to different cis-acting elements that are apparently required for the proper imprinting of the GNAS locus. Most sporadic PHP-Ib cases also have imprinting abnormalities of GNAS that involve multiple DMRs, but the genetic lesion(s) responsible for these imprinting abnormalities remain to be discovered.