Molecular analysis of the GNAS1 gene for the correct diagnosis of Albright hereditary osteodystrophy and pseudohypoparathyroidism.
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.
De Sanctis
Luisa
L
Department of Pediatric Sciences, 94, Piazza Polonia, 10126 Torino, Italy; ldesanct@pediatria.unito.it
Romagnolo
Damiano
D
Olivero
Martina
M
Buzi
Fabio
F
Maghnie
Mohamad
M
Scirè
Giuseppe
G
Crino
Antonio
A
Baroncelli
Giampiero Igli
GI
Salerno
Mariacarolina
M
Di Maio
Salvatore
S
Cappa
Marco
M
Grosso
Salvatore
S
Rigon
Franco
F
Lala
Roberto
R
De Sanctis
Carlo
C
Dianzani
Irma
I
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*
D002864:Chromogranins; D018389:Codon, Nonsense; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs