An inherited mutation associated with functional deficiency of the α-subunit of the guanine nucleotide-binding protein Gs in pseudo- and pseudohypoparathyroidism

Pseudohypoparathyroidism type Ia (PSP) is a disorder characterized by Albright's osteodystrophy, secondary hyperparathyroidism, lowered G(s) activity, and resistance of the urinary cAMP excretion to exogenous PTH. The patients had raised basal serum levels of TSH and/or excessive TSH response to TRH. Here we have described a 38-bp deletion at the exon 1/intron 1 boundary of one G(s) alpha allele in two mothers with pseudo-PSP and in six offsprings with PSP of a kindred with Albright's osteodystrophy. The deletion eliminates the splice donor site of exon 1. The pseudo-PSP patients presented decreased G(s) activity, but normal urinary cAMP responses to PTH and normal TSH levels and responses to TRH. As monitored during 22 yr, they had normal serum levels of calcium and PTH. The findings demonstrate the same inherited functional defect of G(s) alpha in two female patients with pseudo-PSP and in six of their offspring with PSP. The pathogenesis of clinical hypoparathyroidism remains to be clarified.