Pseudohypoparathyroidism (PHP) is a rare endocrine disorder derived from the defective activation of the cAMP pathway by the parathyroid hormone secondary to GNAS molecular defects.
Short metacarpals and/or metatarsals are typically observed in pseudohypoparathyroidism (PHP) type Ia (PHP1A) or pseudo-PHP (PPHP), disorders caused by inactivating GNAS mutations involving exons encoding the alpha-subunit of the stimulatory G protein (Gsα).
Pseudohypoparathyroidism (PHP) is caused by mutations and epimutations in the GNAS locus, and characterized by the possibility of resistance to multiple hormones and Albright's hereditary osteodystrophy.
Genetic or epigenetic alterations in the complex imprinted GNAS locus, encoding the alpha-subunit of the stimulatory G protein (GSα) and several other transcripts, give rise to the different forms oh PHP, which can be differentiated according to the phenotype, the response to PTH infusion and in vitro assays testing Gsα activity.
Autosomal dominant PHP type Ib (AD-PHP1B) is caused by heterozygous maternal deletions within GNAS or STX16, which are associated with loss-of-methylation (LOM) at exon A/B alone or at all maternally methylated GNAS exons.
These are termed, starting from PTH receptor inactivation mutation (Eiken and Blomstrand dysplasia) as iPPSD1, inactivating Gsα mutations (PHP-Ia, PHP-Ic and pPHP) as iPPSD2, loss of methylation of GNAS DMRs (PHP-Ib) as iPPSD3, PRKAR1A mutations (acrodysostosis type 1) as iPPSD4, PDE4D mutations (acrodysostosis type 2) as iPPSD5 and PDE3A mutations (autosomal dominant hypertension with brachydactyly) as iPPSD6. iPPSDx is reserved for unknown molecular defects and iPPSDn+1 for new molecular defects which are yet to be described.
Interestingly, in contrast to the notion that all PHP patients share methylation defects in the A/B DMR while only PHP(Δstx16) patients have normal NESP, GNAS-AS1 and XL methylation, we found a novel DMR (named GNAS-AS2) in the GNAS-AS1 region that is significantly different in both PHP(Δstx16) and PHP(neg), as validated by Sequenom EpiTYPER in a larger PHP cohort.
A retrospective review of the medical records of children diagnosed by erythrocyte Gsα activity and/or GNAS1 gene study and followed-up for PHP type 1A.
Genetic and epigenetic alterations in the GNAS locus and clinical consequences in Pseudohypoparathyroidism: Italian common healthcare pathways adoption.
The term pseudohypoparathyroidism (PHP) was coined to describe the clinical condition resulting from end-organ resistance to parathormone (rPTH), caused by genetic and/or epigenetic alterations within or upstream of GNAS.
According to the growing knowledge on Gsα-cAMP signaling-linked disorders, we investigated our series of patients (n = 81) with a clinical diagnosis of PHP/AHO but negative forGNAS anomalies for the presence of novel genetic variants at PRKAR1A and PDE4D genes.
Despite the first description of this disorder dating back to 1942, later findings have unveiled complex epigenetic alterations in addition to classic mutations in GNAS underpining the molecular basis of the main subtypes of pseudohypoparathyroidism.
Due to monoallelic expression, heterozygous GNAS mutations affecting either paternally or maternally derived transcripts cause different forms of pseudohypoparathyroidism (PHP), including autosomal-dominant PHP type Ib (AD-PHP1B) associated with loss of methylation (LOM) at exon A/B alone or sporadic PHP1B (sporPHP1B) associated with broad GNAS methylation changes.
Pseudohypoparathyroidism (PHP) is associated with compromised signal transductions via PTH receptor (PTH-R) and other G-protein-coupled receptors including GHRH-R. To date, while GH deficiency (GHD) has been reported in multiple patients with PHP-Ia caused by mutations on the maternally expressed GNAS coding regions and in two patients with sporadic form of PHP-Ib accompanied by broad methylation defects of maternally derived GNAS differentially methylated regions (DMRs), it has not been identified in a patient with an autosomal dominant form of PHP-Ib (AD-PHP-Ib) accompanied by an STX16 microdeletion and an isolated loss of methylation (LOM) at exon A/B-DMR.
Loss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP).
Pseudohypoparathyroidism is a rare genetic disorder characterised by end-organ resistance to parathyroid hormone due to a defect of the guanine nucleotide-binding protein alpha that simulates activity of the polypeptide 1 (GNAS) gene.