Pseudohypoparathyroidism Type Ia and Pseudo-Pseudohypoparathyroidism: The Growing Spectrum of GNAS Inactivating Mutations

• Published in: Human mutation Vol. 34; no. 3; pp. 411 - 416
• Main Authors: Elli, Francesca Marta, deSanctis, Luisa, Ceoloni, Barbara, Barbieri, Anna Maria, Bordogna, Paolo, Beck-Peccoz, Paolo, Spada, Anna, Mantovani, Giovanna
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.03.2013; John Wiley & Sons, Inc
• Subjects: Adolescent; Adult; Child; Child, Preschool; Chromogranins; Exons; Female; Fibrous Dysplasia, Polyostotic - genetics; Genetic Association Studies; Genetic Counseling; Genetic Loci; Genetic Markers; Genetic Predisposition to Disease; GNAS; GTP-Binding Protein alpha Subunits, Gs - genetics; Heterozygote; Humans; Infant; Male; Mutation, Missense; Phenotype; PHP-Ia; PPHP; pseudohypoparathyroidism; Pseudohypoparathyroidism - diagnosis; Pseudohypoparathyroidism - genetics; Pseudopseudohypoparathyroidism - diagnosis; Pseudopseudohypoparathyroidism - genetics; Sequence Analysis, DNA; type Ia; Young Adult
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.22265

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. Pseudohypoprathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end‐organ resistance to parathyroid hormone. Heterozygous inactivating GNAS mutations lead to either PHP type Ia or PPHP. The present work provides an updated collection of mutational and phenotypic data for both diagnostic and research purposes, as a step forward to a better understanding of PHP. The absence of genotype‐phenotype correlation supports the hypothesis of Gsα haploinsufficiency as the molecular mechanism underlying PHP, independently of the mutation type/localization.