PARENTAL ORIGIN OF GS-ALPHA GENE-MUTATIONS IN ALBRIGHTS HEREDITARY OSTEODYSTROPHY

Heterozygous mutations of the Gs alpha gene leading to reduced Gs alph a activity have been identified in patients with Albright's hereditary osteodystrophy (AHO). However, AHO may be associated with hormone res istance (pseudohypoparathyroidism type Ia, PHPIa) or a normal response (pseudopseudohypoparathyroidism, PPHP). As both disorders may occur w ithin 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 thro ugh a gene imprinting mechanism. We have used an intragenic Gs alpha F okI polymorphism to determine the parental origin of Gs alpha gene mut ations 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 alp ha abnormality was shown to be of paternal origin, while subsequent ma ternal processing and transmission resulted in PHPIa in two offspring. As transmission of PPHP has rarely been reported, determining parenta l origin of the disease allele in sporadic cases may provide insight i nto the mechanism of hormone resistance in AHO.