Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy.

Abstract

Patients who have pseudohypoparathyroidism type I associated with Albright hereditary osteodystrophy commonly have a genetic deficiency of the a subunit of the G protein that stimulates adenylyl cyclase (aG3) (ATP pyrophosphate-lyase, EC 4.6.1.1). To discover the molecular mechanism that causes aG5 deficiency in these patients, we examined eight kindreds with one or more members affected with Albright hereditary osteodystrophy or pseudohypoparathyroidism and aG. deficiency. In these families, aG. deficiency and the Albright hereditary osteodystrophy phenotype were transmitted together in a dominant inheritance pattern.Using a cDNA hybridization probe for aG., restriction analysis with several endonucleases showed no abnormalities of restriction fragments or gene dosage. RNA blot and dot blot analysis of total RNA from cultured fibroblasts obtained from the patients revealed ==50% reduced mRNA levels for aGS in affected members of six of the pedigrees but normal levels in affected members of the two other pedigrees, compared to mRNA levels in fibroblasts from unaffected individuals. By contrast, mRNA levels encoding the a subunit of the G protein that inhibits adenylyl cyclase were not altered. Our findings suggest that several molecular mechanisms produce aG. deficiency in patients with pseudohypoparathyroidism type Ia and that major gene rearrangements or deletions are not a common cause for aG5 deficiency in pseudohypoparathyroidism type I.

Differential expression of guanosine triphosphate binding proteins in men at high and low risk for the future development of alcoholism.

“…The GP antisera recognized a single 36-kD band in erythrocyte membranes (Fig. 1 C) (24)(25)(26). Levels of Gsa were increased in FHP subjects using two independent techniques, immunoblot analysis and cholera toxin-induced ADP-ribosylation.…”

A Patient with Acute-Onset HAM/TSP after Blood Transfusion Complicated with Pseudopseudohypoparathyroidism.

“…However,we have only found 4 patients to date, who showed symptoms within a year after blood transfusion among 53 patients in Kagoshima district; excluding the present patient, the other three showedinsidious onset after gastric cancer operation. The results indicated that this patient had had PPHP (4,5). In patients receiving blood transfusion, preexisting PHP la or PPHPis a risk for contracting HAM/TSP rather than HTLV-I causing PHP la or PPHP, as described previously (1, 2), although the quantity of infecting virus in the blood transfusion, the reason for surgery, and the postoperative condition were also factors.…”

An Inherited Mutation Associated with Functional Deficiency of the α-Subunit of the Guanine Nucleotide-Binding Protein Gs in Pseudo- and Pseudopseudohypoparathyroidism1

“…The findings that urinary cAMP excretion in response to exogenous PTH is reduced or absent and of an excessive TSH response to TRH are consistent with inadequate activation of the PTH-and TRH-responsive adenylyl cyclase and different isotypes thereof, and activation of phosphodiesterase (4,16). To this end, G s activity was shown to be reduced (7)(8)(9)(10)(11). Subsequently, several mutations of the G s ␣-encoding gene have been discovered (12-16).…”