Albright hereditary osteodystrophy (AHO) is an autosomal dominant disorder characterized by short stature, obesity, subcutaneous ossifications and brachydactyly. Some family members have these features in association with resistance to multiple hormones which activate Gs-coupled receptors (pseudohypoparathyroidism type Ia, PHP Ia) while others present with the somatic features alone (pseudopseudohypoparathyroidism, PPHP). Peripheral tissues from most affected patients have a 50% deficiency in Gs-alpha subunit function and/or expression in peripheral tissues (both PHP Ia and PPHP). We have identified a number of heterozygous inactivating mutations of the Gs- alpha gene in affected patients (both PHP Ia and PPHP). Examination of the biochemical properties of these mutants and others demonstrates that arginine 258 in the switch 3 region interacts with a residue in the helical domain and that this interaction is critical for guanine nucleotide binding. This mutation leads to decreased receptor-mediated activation by increasing the rate of the turn-off mechanism, namely the hydrolysis of bound GTP to GDP. Mutation of glutamate 259 also leads to defective G protein activation, although by different mechanisms. It has been proposed that tissue-specific imprinting of the Gs-alpha gene may explain the observation that maternal transmission of the Gs defect leads to offspring with PHP Ia while paternal transmission leads to PPHP. We demonstrated in Gs-alpha knockout (GsKO) mice that the gene is imprinted in a tissue-specific manner such that in certain tissues the expression of the paternal allele is less than the paternal allele, and this likely explains the variable and tissue-specific hormone resistance in these mice (and likely in AHO). We and others have shown that in fact the Gs-alpha gene (Gnas) produces several products due to the use of alternative promoters and upstream exons, some which are maternally imprinted and others which are paternally imprinted. We have identified a differentially methylated region within the gene which may be important in establishing imprinting of the gene. Maternal GsKO mice have increased lipid accumulation in adipose tissue associated with decreased metabolism while paternal GsKO mice have decreased lipid accumulation with increased metabolism. Both paternal and maternal GsKO mice have increased insulin sensitivity. Studies are underway to define the mechanisms which underlie these abnormalities. Studies are also underway to determine whether the human disorder pseudohypoparathyroidism type Ib, which is characterized by renal resistance to parathyroid hormone, is associated with Gnas imprinting defects - G protein Albright hereditary osteodystrophy pseudohypoparathyroidism pseudopseudohypoparathyroidism signal transduction genomic imprinting DNA methylation - Human Subjects
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