The Stimulatory G Protein α-Subunit Gene: Mutations and Imprinting Lead to Complex Phenotypes

Abstract XLαs, the large variant of the stimulatory G protein α subunit (Gsα), is derived from GNAS1 through the use of an alternative first exon and promoter. Gsα and XLαs have distinct amino-terminal domains, but are identical over the carboxyl-terminal portion encoded by exons 2–13. XLαs can mimic some functions of Gsα, including βγ interaction and adenylyl cyclase stimulation. However, previous attempts to demonstrate coupling of XLαs to typically Gs-coupled receptors have not been successful. We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XLαs and Gsα (GnasE2−/E2−). GnasE2−/E2− cells transfected with plasmids encoding XLαs and different heptahelical receptors, including the β2-adrenergic receptor and receptors for PTH, TSH, and CRF, showed agonist-mediated cAMP accumulation that was indistinguishable from that observed with cells transiently coexpressing Gsα and these receptors. Our findings thus indicate that XLαs is capable of functionally coupling to receptors that normally act via Gsα.

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The Stimulatory G Protein α-Subunit Gsα Is Imprinted in Human Thyroid Glands: Implications for Thyroid Function in Pseudohypoparathyroidism Types 1A and 1B

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-030393 ◽

2003 ◽

Vol 88 (9) ◽

pp. 4336-4341 ◽

Cited By ~ 122

Author(s):

Jie Liu ◽

Beth Erlichman ◽

Lee S. Weinstein

Keyword(s):

G Protein ◽

Human Thyroid ◽

Pcr Analysis ◽

Specific Expression ◽

Α Subunit ◽

Albright Hereditary Osteodystrophy ◽

Camp Generation ◽

Gsα Gene ◽

Stimulatory G Protein ◽

G Protein Α Subunit

The stimulatory G protein α-subunit Gsα couples receptors to adenylyl cyclase and is required for hormone-stimulated cAMP generation. In Albright hereditary osteodystrophy, heterozygous Gsα null mutations only lead to PTH, TSH, and gonadotropin resistance when inherited maternally [pseudohypoparathyroidism type 1A; (PHP1A)]. Maternal-specific expression of Gsα in specific hormone targets could explain this observation. Using hot-stop PCR analysis on total RNA from six normal human thyroid specimens, we showed that the majority of the Gsα mRNA (72 ± 3%) was derived from the maternal allele. This is consistent with the presence of TSH resistance in patients with maternal Gsα null mutations (PHP1A) and the absence of TSH resistance in patients with paternal Gsα mutations (pseudopseudohypoparathyroidism). Patients with PTH resistance in the absence of Albright hereditary osteodystrophy (PHP1B) have an imprinting defect of the Gsα gene resulting in both alleles having a paternal epigenotype, which would lead to a more moderate level of thyroid-specific Gsα deficiency. We found evidence of borderline TSH resistance in 10 of 22 PHP1B patients. This study provides further evidence for tissue-specific imprinting of Gsα in humans and provides a potential mechanism for mild to moderate TSH resistance in PHP1A and borderline resistance in some patients with PHP1B.

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