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Mutational Analysis of GNAS1 in Patients with Pseudohypoparathyroidism: Identification of Two Novel Mutations¹

Ospedale Maggiore IRCCS, Institute of Endocrine Sciences (G.M., R.R., P.B.-P., A.S.), and Pediatric Department, Endocrine Unit, Scientific Ospedale S. Raffaele (G.W., S.B.), University of Milan, and Pediatric Department, Ospedale Buzzi (V.B.), 20122 Milan; and First Divisione Medica, Ospedale Regionale Veneto (E.D.M.), 31100 Treviso, Italy

Address all correspondence and requests for reprints to: Dr. Anna Spada, Istituto di Scienze Endocrine, Padiglione Granelli, Ospedale Maggiore IRCCS, Via Francesco Sforza 35, 20122 Milan, Italy. E-mail: endosci{at}mailserver.unimi.it

Pseudohypoparathyroidism (PHP) refers to two major variants that generally coexist in the same family, PHP type Ia (PHP Ia), in which both PTH resistance 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 show a partial deficiency (50%) of G_s activity, due to loss of function mutations in G_s gene (GNAS1). The present study reports clinical, biochemical, and molecular data of 8 unrelated families with PHP Ia and PPHP. The 13 exons of GNAS1 were screened for mutations by PCR and direct sequencing of the amplified products. We detected heterozygous mutations in the affected 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 and 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. Furthermore, we confirm that these mutations cannot be detected in families with isolated PPHP, suggesting that these forms of AHO are genetically distinct from PHP Ia.

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