While loss-of-function mutations in G s โฃ are invariably associated with the short stature and brachydactyly of Albright hereditary osteodystrophy (AHO), the association with hormone resistance (to parathyroid hormone and thyrotropin) typical of pseudohypoparathyroidism type Ia (PHP-Ia) is much more variable. Observational studies and DNA polymorphism analysis suggest that maternal transmission of the G s โฃ mutation may be required for full expression of clinical hormone resistance. To test this hypothesis, we studied transmission of a frameshift mutation in G s โฃ through three generations of a pedigree affected by AHO and PHP-Ia. While all family members carrying this lossof-function mutation in one G s โฃ allele had AHO, neither the presence of the mutation nor the degree of reduction of erythrocyte G s โฃ bioactivity allowed prediction of phenotype (AHO alone versus AHO and PHP-Ia). Paternal transmission of the mutation (from the patriarch of the first generation to three members of the second generation) was not associated with concurrent PHP-Ia, but maternal transmission (from two women in the second generation to four children in the third generation) was invariably associated with PHP-Ia. No expansion of an upstream short CCG nucleotide repeat region was detected, nor was there evidence of uniparental disomy by polymorphism analysis. This report, the first to document the effects across three generations of both paternal and maternal transmission of a specific G s โฃ mutation, strongly supports the hypothesis that a maternal factor determines full expression of G s โฃ dysfunction as PHP-Ia. Am.