An Inherited Mutation Associated with Functional Deficiency of the α-Subunit of the Guanine Nucleotide-Binding Protein Gs in Pseudo- and Pseudopseudohypoparathyroidism1

Abstract

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 ␣ 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 ␣ in two female patients with pseudo-PSP and in six of their offspring with PSP. The pathogenesis of clinical hypoparathyroidism remains to be clarified. (J Clin Endocrinol Metab 83: 935-938, 1998) P SEUDOHYPOPARATHYROIDISM Ia (PSP) is a disorder with clinical hypoparathyroidism and the phenotype of Albright's osteodystrophy, but raised plasma levels of bioactive and immunoreactive PTH (1; see Ref. 2 for additional references). Patients with PSP frequently present raised serum levels of TSH and excessive TSH response to TRH with sometimes overt clinical hypothyroidism (3 and references cited therein). The diagnosis of PSP-Ia was established on the basis of resistance of the urinary cAMP excretion to exogenous PTH, and decreased guanine nucleotidebinding protein G s activity (4 -10). G s activity was decreased in the PSP patients reported here, but it was similarly decreased in their mothers with pseudo-PSP (8). The latter responded normally to exogenous PTH with raised urinary cAMP excretion; secondary hyperparathyroidism and excessive TSH response to TRH were not observed. A functional deficiency of G s has been reported in PSP and pseudo-PSP (8 -10).A genetic deficiency of G s ␣ has been revealed in familial PSP and pseudo-PSP (11-15; for additional mutations, see Ref. 16). As shown here, the patients with PSP-Ia as well as those with pseudo-PSP carry a novel deletion in one G s ␣ allele resulting in reduced G s ␣ activity. In healthy siblings with no signs of Albright's osteodystrophy, both G s ␣ alleles were normal. It would seem, therefore, that the described genetic defect, resulting in reduced G s ␣ activity, is not an obvious cause of the resistance to exogenous PTH in the kindred reported here.

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A

“…A similar deletion, c.119_139 + 17del, was previously described in another family and it is reported in ClinVar as pathogenic, resulting in a splice junction loss with the predicted formation of an inactive protein with an altered carboxyl-terminus [ 25 ].…”

“…These data confirm what was previously reported by Mantovani et al [ 5 ]. Fisher et al [ 25 ] described another series of familial cases with PHP1A characterized by a high incidence of elevated TSH (5 out of 6 cases) and hypocalcaemia (4 out of 6 cases). However, these authors reported insufficient clinical and biochemical information to describe the disease phenotype and therefore insufficient to be compared with the other familial cases analyzed in our literature review.…”

Heterotopic Ossification of the Mesentery: A Rare Postoperative Complication

“…In progressive osseous heteroplasia, patients can acquire heterotopic bone formation in the skin and subcutis. Progressive osseous heteroplasia pathomechanisms are thought to be related to pseudopseudohypoparathyroidism, which clinically presents as Albright hereditary osteodystrophy 2,12 …”

“…Progressive osseous heteroplasia pathomechanisms are thought to be related to pseudopseudohypoparathyroidism, which clinically presents as Albright hereditary osteodystrophy. 2,12 While a definitive molecular basis has yet to be established, the most supported hypothesis is that this condition occurs as the result of immature multipotent mesenchymal cells differentiating into osteoblasts or chondroblasts as a reaction to local injury and under the influence of certain factors such as venous stasis, edema, local trauma, and inflammation. The expression patterns of bone morphogenetic proteins have been studied in their ability to induce bone formation in vivo with varying results.…”

G Protein Defects in Signal Transduction

“…In many cases the mutations result in abnormal RNA processing and lack of expression of the mutant allele, i.e. base substitution at a splice junction site; coding frameshift mutations, premature stop codons, and large deletions [12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24]; Weinstein LS, unpublished data]. One specific 4 base pair (bp) deletion within exon 7 of GNAS1 has been identified in affected members from multiple unrelated PHP Ia kindreds [13, 19, 20, 21, 22].…”