The GNAS locus and pseudohypoparathyroidism

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 alpha-subunit of the stimulatory G protein (Gsalpha), a signaling protein essential for the actions of PTH and many other hormones. Heterozygous inactivating mutations within Gsalpha-encoding GNAS exons are found in patients with PHP-Ia, who also show resistance to other hormones and a constellation ofphysical 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 Gsalpha 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 Gsalpha in certain tissues, including renal proximal tubules. Patients with PHP-Ib lack coding Gsalpha 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, Gsalpha expression in tissues where this protein is derived from the maternal allele only, leading to a marked reductio…