AN INHERITED MUTATION ASSOCIATED WITH FUNCTIONAL DEFICIENCY OF THE ALPHA-SUBUNIT OF THE GUANINE-NUCLEOTIDE-BINDING PROTEIN G(S) IN PSEUDOPARATHYROIDISM 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 P TH. 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 e xon 1/intron 1 boundary of one G(s) alpha allele in two mothers with p seudo-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 norm al urinary cAMP responses to PTH and normal TSH levels and responses t o TRH. As monitored during 22 yr, they had normal serum levels of calc ium and PTH. The findings demonstrate the same inherited functional de fect of G(s) alpha in two female patients with pseudo-PSP and in six o f their offspring with PSP. The pathogenesis of clinical hypoparathyro idism remains to be clarified.