G protein mutations in endocrine diseases

Abstract

This review summarizes the pathogenetic role of naturally occurring mutations of G protein genes in endocrine diseases. Although in vitro mutagenesis and transfection assays indicate that several G proteins have mitogenic potential, to date only two G proteins have been identi®ed which harbor naturally occurring mutations, Gsa, the activator of adenylyl cyclase and Gi2a, which is involved in several functions, including adenylyl cyclase inhibition and ion channel modulation. The gene encoding Gsa (GNAS1) may be altered by loss or gain of function mutations. Indeed, heterozygous inactivating germ line mutations in this gene cause pseudohypoparathyroidism type Ia, in which physical features of Albright hereditary osteodystrophy (AHO) are associated with resistance to several hormones, i.e. PTH, TSH and gonadotropins, that activate Gs-coupled receptors or pseudopseudohypoparathyroidism in which AHO is the only clinical manifestation. Evidence suggests that the variable and tissue-speci®c hormone resistance observed in PHP Ia may result from tissuespeci®c imprinting of the GNAS1 gene, although the Gsa knockout model only in part reproduces the human AHO phenotype. Activating somatic Gsa mutations leading to cell proliferation have been identi®ed in endocrine tumors constituted by cells in which cAMP is a mitogenic signal, i.e. GH-secreting pituitary adenomas, hyperfunctioning thyroid adenomas and Leydig cell tumors. When the same mutations occur very early in embryogenesis they cause McCune±Albright syndrome. Although these mutations would in principle confer growth advantage, studies failed to detect differences in the clinical and hormonal phenotypes, suggesting the existence of mechanisms able to counteract the activation of the cAMP pathway. Activating mutations of Gi2a have been identi®ed in a subset of ovarian, adrenal and pituitary tumors, but their prevalence and signi®cance are still controversial. Finally, although Ga subunits are the only components of the heterotrimeric GTP binding proteins which harbor known mutations, b/g subunits should be considered possible targets of genetic alterations as suggested by the frequent presence of b3 subunit variants in patients with essential hypertension.

High expression of PKA regulatory subunit 1A protein is related to proliferation of human melanoma cells

“…In addition to the control of differentiated functions, cAMP inhibits or stimulates cell proliferation depending on the cell type. Recently, mutations of genes involved in cAMP signaling and resulting in the constitutive activation of cAMP formation have been identified as cause of endocrine neoplasia (Landis et al, 1989;Weinstein et al, 1991;Kirschner et al, 2000;Lania et al, 2001). In particular, germ-line mutations of the gene encoding the PKA type 1A regulatory subunit (R1A) have been demonstrated to be involved in the pathogenesis of Carney complex (Kirschner et al, 2000), while activating mutations of the Gs-a gene lead to the McCune-Albright syndrome (Weinstein et al, 1991).…”

Hypoparathyroidism and pseudohypoparathyroidism

“…In this situation, patients are not only resistant to PTH, but to other peptide hormones like TSH, gonadotrophins, and glucagon. Transmission is autosomic dominant (29). Hypocalcaemia and hyperphosphatemia are not typically present until five years of age, but PTH elevations may be documented much earlier and sometimes are associated with light hypercalcemia.…”

“…Molecular studies do not show an intrinsic defect in the PTH receptor, and present normal G s function in the erythrocytes (25). The majority of cases appear to be sporadic, but some familial cases were described as having autosomic dominant transmission (29,33). As in PHP1a, a defective nephrogenic answer to AMPc occurs in relation to PTH.…”

“…In the majority of tissues, exon 1A is methylated but the repressor is not expressed, and as a result the G s α is expressed biallelically. In PHP1b, the methylation of this exon is absent in the maternal allele, allowing the repressor to link to both alleles and suppress the G s α expression in the renal proximal tubules, raising the G s α deficiency and PTH resistance (26,29,34), which normally only express the maternal allele. These individuals do not present AHO, because the defective imprinting does not have an effect in the G s α expression of the majority of the tissues where it is expressed biallelically.…”

“…Studies show reduced activity of the membrane's adenyl cyclase catalytic subunit. It has yet to be clarified which molecular defect is responsible (29).…”