Pseudohypoparathyroidism Type Ia and Pseudo-Pseudohypoparathyroidism: The Growing Spectrum ofGNASInactivating 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.

Screening of PRKAR1A and PDE4D in a Large Italian Series of Patients Clinically Diagnosed With Albright Hereditary Osteodystrophy and/or Pseudohypoparathyroidism

“…The presence of genetic/epigenetic defects affecting GNAS locus had been previously excluded in all samples by Sanger sequencing of Gsa coding exons 1 to 13 and methylation specific-multiplex ligand-dependent probe amplification (MS-MLPA) of STX16 and GNAS loci, both methods previously described (22,23) Informed consent was obtained from all patients (or legal guardians for minors) and relatives included in the present study.…”

“…Direct sequencing was performed with the AmpliTaq BigDye Terminator Kit and the 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, USA), as previously described. (22) The mutation nomenclature follows the guidelines indicated by Human Genome Variation Society (HGVS; available at http://www.hgvs.org/mutnomen/). Nucleotide numbering is based on the PRKAR1A transcript ENST00000392711/NM_002734, and the PDE4D gene is based on the LRG sequence (available at www.lovd.nl/PDE4D) corresponding to the PDE4D transcript ENST00000502484/ NM_001165899.…”

“…edu/pph2/), sort intolerant from tolerant human protein (SIFT human protein program; available at http://sift.jcvi.org/www/ SIFT_enst_submit.html), and Mutation Taster (available at http://www.mutationtaster.org/). (22) …”

Calcification of Soft Tissues in a Family, Case Report and Review of Pseudohypoparathyroidism

“…In a routine visit of a 17 month old boy, asymptomatic multiple subcutaneous calcifications in trunk, limb and neck, which was sized maximum one centimeter in diameter were founded Navaeifar MR 1 and Zamanfar D 2 ( Figure 1). The lesions were painless and they didn't have history of trauma.…”

“…Pseudo-pseudohypoparathyroidism (PPHP; OMIM #612463) is the more rare disorder of calcium metabolism [1]. These conditions could be seen separately or concomitant together in kindred [2].…”