Mutational analysis of GNAS1 in patients with pseudohypoparathyroidism: Identification of two novel mutations

Pseudohypoparathyroidism (PHP) refers to two major variants that generally coexist in the same family, PHP type Ia (PHP Ia), in which both PTH resista nce and a constellation of physical features, termed Albright's hereditary osteodystrophy (AHO), are present, and pseudopseudohypoparathyroidism (PPHP ), in which AHO occurs without PTH resistance. Most patients with PHP Ia sh ow a partial deficiency (50%) of G(s) activity, due to loss of function mut ations in G(s)alpha gene (GNAS1). The present study reports clinical, bioch emical, and molecular data of 8 unrelated families with PHP Ia and PPHP. Th e 13 exons of GNAS1 were screened for mutations by PCR and direct sequencin g of the amplified products. We detected heterozygous mutations in the affe cted members of the 4 families in which PHP Ia was present. In 2 families 2 previously reported deletions in exons 5 and 7 were found, whereas in the other 2 families, 2 novel frameshift deletions were identified in exons 1 a nd 11, causing a premature stop codon in the mutant allele. No mutation was detected in the families in which PPHP was the only clinical manifestation . In conclusion, we report the first mutational analysis of Italian patients with PHP Ia and PPHP, and we describe two novel deletions in GNAS1. Further more, we confirm that these mutations cannot be detected in families with i solated PPHP, suggesting that these forms of AHO are genetically distinct f rom PHP Ia.