title: Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.
abstract: Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show Gsalpha protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the Gsalpha protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for Gsalpha activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia.
authors.affiliation: Department of Pediatric Sciences, 94, Piazza Polonia, 10126 Torino, Italy; ldesanct@pediatria.unito.it
authors.forename: Luisa
authors.initials: L
authors.lastname: De Sanctis
authors.forename: Damiano
authors.initials: D
authors.lastname: Romagnolo
authors.forename: Martina
authors.initials: M
authors.lastname: Olivero
authors.forename: Fabio
authors.initials: F
authors.lastname: Buzi
authors.forename: Mohamad
authors.initials: M
authors.lastname: Maghnie
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scirè
authors.forename: Antonio
authors.initials: A
authors.lastname: Crino
authors.forename: Giampiero Igli
authors.initials: GI
authors.lastname: Baroncelli
authors.forename: Mariacarolina
authors.initials: M
authors.lastname: Salerno
authors.forename: Salvatore
authors.initials: S
authors.lastname: Di Maio
authors.forename: Marco
authors.initials: M
authors.lastname: Cappa
authors.forename: Salvatore
authors.initials: S
authors.lastname: Grosso
authors.forename: Franco
authors.initials: F
authors.lastname: Rigon
authors.forename: Roberto
authors.initials: R
authors.lastname: Lala
authors.forename: Carlo
authors.initials: C
authors.lastname: De Sanctis
authors.forename: Irma
authors.initials: I
authors.lastname: Dianzani
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002864:Chromogranins; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011547:Pseudohypoparathyroidism / Q000235:genetics*
chemical_list: D002864:Chromogranins; D018389:Codon, Nonsense; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs