title: Pseudohypoparathyroidism type Ia and pseudo-pseudohypoparathyroidism: the growing spectrum of GNAS inactivating mutations.
abstract: Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP-Ia), when maternally inherited, or pseudo-pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60-70% of affected subjects, most patients/families harbor private mutations and no genotype-phenotype correlation has been found to date. We investigated Gsα-coding GNAS exons in a large panel of PHP-Ia-PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, we identified 15 novel mutations in 19 patients. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS-locus-specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.
authors.affiliation: Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Francesca Marta
authors.initials: FM
authors.lastname: Elli
authors.forename: Luisa
authors.initials: L
authors.lastname: deSanctis
authors.forename: Barbara
authors.initials: B
authors.lastname: Ceoloni
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Barbieri
authors.forename: Paolo
authors.initials: P
authors.lastname: Bordogna
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Anna
authors.initials: A
authors.lastname: Spada
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mantovani
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002864:Chromogranins; D005091:Exons; D005260:Female; D005359:Fibrous Dysplasia, Polyostotic / Q000235:genetics; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D056726:Genetic Association Studies; D005817:Genetic Counseling; D056426:Genetic Loci; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011547:Pseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*; D011556:Pseudopseudohypoparathyroidism / Q000175:diagnosis / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D002864:Chromogranins; D005819:Genetic Markers; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs