Abstract

Heterozygous mutations of the Gs alpha gene leading to reduced Gs alpha activity have been identified in patients with Albright's hereditary osteodystrophy (AHO). However, AHO may be associated with hormone resistance (pseudohypoparathyroidism type Ia, PHPIa) or a normal response (pseudo-pseudohypoparathyroidism, PPHP). As both disorders may occur within the same family, the relationship between Gs alpha genotype and phenotype remains unresolved. The AHO phenotype may be dependent upon the sex of the parent transmitting the Gs alpha mutation, perhaps through a gene imprinting mechanism. We have used an intragenic Gs alpha FokI polymorphism to determine the parental origin of Gs alpha gene mutations in sporadic and familial AHO. We now show that a de novo G-->A substitution at the exon 5 donor splice junction in a child with PPHP was paternally derived. Furthermore, in a female with PPHP, the Gs alpha abnormality was shown to be of paternal origin, while subsequent maternal processing and transmission resulted in PHPIa in two offspring. As transmission of PPHP has rarely been reported, determining parental origin of the disease allele in sporadic cases may provide insight into the mechanism of hormone resistance in AHO.