Gs_α Mutations and Imprinting Defects in Human Disease

Abstract

Gs is the ubiquitously expressed heterotrimeric G protein that couples receptors to the effector enzyme adenylyl cyclase and is required for receptor-stimulated intracellular cAMP generation. Activated receptors promote the exchange of GTP for GDP on the Gs alpha-subunit (Gs(alpha)), resulting in Gs activation; an intrinsic GTPase activity of Gs(alpha) deactivates Gs by hydrolyzing bound GTP to GDP. Mutations of Gs(alpha) residues involved in the GTPase reaction that lead to constitutive activation are present in endocrine tumors, fibrous dysplasia of bone, and McCune-Albright syndrome. Heterozygous loss-of-function mutations lead to Albright hereditary osteodystrophy (AHO), a disease characterized by short stature, obesity, and skeletal defects, and are sometimes associated with progressive osseous heteroplasia. Maternal transmission of Gs(alpha) mutations leads to AHO plus resistance to several hormones (e.g., parathyroid hormone) that activate Gs in their target tissues (pseudohypoparathyroidism type IA), while paternal transmission leads only to the AHO phenotype (pseudopseudohypoparathyroidism). Studies in both mice and humans demonstrate that Gs(alpha) is imprinted in a tissue-specific manner, being expressed primarily from the maternal allele in some tissues and biallelically expressed in most other tissues. This likely explains why multihormone resistance occurs only when Gs(alpha) mutations are inherited maternally. The Gs(alpha) gene GNAS1 has at least four alternative promoters and first exons, leading to the production of alternative gene products including Gs(alpha), XL alphas (a novel Gs(alpha) isoform expressed only from the paternal allele), and NESP55 (a chromogranin-like protein expressed only from the maternal allele). The fourth alternative promoter and first exon (exon 1A) located just upstream of the Gs(alpha) promoter is normally methylated on the maternal allele and is transcriptionally active on the paternal allele. In patients with parathyroid hormone resistance but without AHO (pseudohypoparathyroidism type IB), the exon 1A promoter region is unmethylated and transcriptionally active on both alleles. This GNAS1 imprinting defect is predicted to decrease Gs(alpha) expression in tissues where Gs(alpha) is normally imprinted and therefore to lead to renal parathyroid hormone resistance.

Fibrous dysplasia of bone: a clinicopathologic review

“…The Gsα mutation was first identified in patients with McCune-Albright syndrome, and the Gsα gene has also been linked to other endocrine tumors and human diseases. 21 The strongest evidence to support a genetic link to the etiology of fibrous dysplasia was found in an experimental study by Bianco et al 22 who isolated Gsα genes from patients with McCune-Albright syndrome, transplanted them into immunocompromised mice, and induced dysplastic bone production.…”

“…The clinical presentation varies, depending on the location of the mutation in the cell mass and the size of the cell mass during embryogenesis when the mutation occurs. 21 Severe disease may be associated with an earlier mutational event that leads to a larger number or a more widespread distribution of mutant cells. The sporadic occurrence of these diseases and the characteristic lateralized pattern of skin and bone involvement in the polyostotic forms of fibrous dysplasia suggest this mosaic distribution of abnormal cells.…”

GNAS1 mutation analysis in gastrointestinal tumors

“…It has 13 exons and can undergo alternative splicing [3,4]. GNAS1 codes for the a-stimulatory subunit (Gsa) of heterotrimeric G proteins.…”

Monostotic Fibrous Dysplasia and Ichthyosis Vulgaris ------ A Rare Association

“…The skeletal, skin and endocrine lesion result from a somatic (non hereditary) mutation occurring during embryogenesis that involves the gene that codes for a G-protein. 2 Monostotic fibrous dysplasia accounts for 70% of all cases. It occurs equally in boys and girls usually in early adolescents and often stops growing at the time of growth plate closure.…”

“…Monostotic disease does not evolve into polyostotic form. 2 The initial classic sign is usually painless enlargement of affected bones. Other signs and symptoms include bone pain and bone deformities.…”