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.
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