Studies of the regulation and function of the Gsα gene Gnas using gene targeting technology

Abstract The heterotrimeric G protein α-subunit G s α is ubiquitously expressed and mediates receptor-stimulated intracellular cAMP generation. Its gene Gnas is a complex imprinted gene which uses alternative promoters and first exons to generate other gene products, including the G s α isoform XLαs and the chromogranin-like protein NESP55, which are specifically expressed from the paternal and maternal alleles, respectively. G s α itself is imprinted in a tissue-specific manner, being biallelically expressed in most tissues but paternally silenced in a few tissues. Gene targeting of specific Gnas transcripts demonstrates that heterozygous mutation of G s α on the maternal (but not the paternal) allele leads to early lethality, perinatal subcutaneous edema, severe obesity, and multihormone resistance, while the paternal mutation leads to only mild obesity and insulin resistance. These parent-of-origin differences are the consequence of tissue-specific G s α imprinting. XLαs deficiency leads to a perinatal suckling defect and a lean phenotype with increased insulin sensitivity. The opposite metabolic effects of G s α and XLαs deficiency are associated with decreased and increased sympathetic nervous system activity, respectively. NESP55 deficiency has no metabolic consequences. Other gene targeting experiments have shown Gnas to have 2 independent imprinting domains controlled by 2 different imprinting control regions. Tissue-specific G s α knockout models have identified important roles for G s α signaling pathways in skeletal development, renal function, and glucose and lipid metabolism. Our present knowledge gleaned from various Gnas gene targeting models are discussed in relation to the pathogenesis of human disorders with mutation or abnormal imprinting of the human orthologue GNAS .