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.
© 2012 Wiley Periodicals, Inc.