Get access

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

Authors

  • Francesca Marta Elli,

    1. Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Luisa deSanctis,

    1. Department of Public Health and Pediatrics, University of Turin, Regina Margherita Children's Hospital, Turin, Italy
    Search for more papers by this author
  • Barbara Ceoloni,

    1. Department of Public Health and Pediatrics, University of Turin, Regina Margherita Children's Hospital, Turin, Italy
    Search for more papers by this author
  • Anna Maria Barbieri,

    1. Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Paolo Bordogna,

    1. Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Paolo Beck-Peccoz,

    1. Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Anna Spada,

    1. Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Giovanna Mantovani

    Corresponding author
    • Department of Clinical Sciences and Community Health, University of Milan, Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author

  • Communicated by Daniel W. Nebert

  • Contract grant sponsor: Italian Ministry of Health (GR-2009-1608394).

Correspondence to: Giovanna Mantovani, Unità di Endocrinologia-Pad. Granelli, Fondazione IRCCS Ca’ Granda Policlinico, Via Francesco Sforza 35, Milan 20122 Italy. E-mail: giovanna.mantovani@unimi.it

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.

Get access to the full text of this article

Ancillary