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

LS Weinstein, T Xie, QH Zhang, M Chen - Pharmacology & therapeutics, 2007 - Elsevier
LS Weinstein, T Xie, QH Zhang, M Chen
Pharmacology & therapeutics, 2007Elsevier
The heterotrimeric G protein α-subunit Gsα 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
Gsα isoform XLαs and the chromogranin-like protein NESP55, which are specifically
expressed from the paternal and maternal alleles, respectively. Gsα itself is imprinted in a
tissue-specific manner, being biallelically expressed in most tissues but paternally silenced …
The heterotrimeric G protein α-subunit Gsα 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 Gsα isoform XLαs and the chromogranin-like protein NESP55, which are specifically expressed from the paternal and maternal alleles, respectively. Gsα 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 Gsα 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 Gsα imprinting. XLαs deficiency leads to a perinatal suckling defect and a lean phenotype with increased insulin sensitivity. The opposite metabolic effects of Gsα 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 Gsα knockout models have identified important roles for Gsα 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.
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