Lessons from pseudo(pseudo)hypoparathyroidism using platelets: (epi)genetic defects within and outside the imprinted GNAS cluster.

GNAS is an imprinted region that gives rise to several transcripts, including transcription of the alpha subunit of the stimulatory G protein (Gsalpha). The complexity of the GNAS cluster results in ubiquitous and tissue-specific genomic imprints and in multiple genotype-phenotype relationships. Phenotypes resulting from genetic and epigenetic abnormalities of GNAS include Albright Hereditary Osteodystrophy (AHO), pseudohypoparathyroidism types Ia (PHPIa) and Ib (PHPIb), and pseudopseudohypoparathyroidism (PPHP). Recently, it became clear that the old GNAS ‘genotype-phenotype ‘classification is not suitable for all patients since epigenetic defects were detected in PHPIa patients while always thought to be PHPIbspecific. In addition, we detected multilocus imprinting defects, including GNAS, in patients with an AHO-like phenotype. Also AHO is a phenotype that is present in patients with haploinsufficiency due to 2q37.2 deletions or mutations in the histone deacetylase HDAC4, which could point to a role in GNAS regulation. In this project, we will try to further unravel unknown molecular pathways that control the (epi)genetic status of GNAS or its expression in patients with AHO, PHPIa or PHPIb with/or without an abnormal Gsalpha platelet function but not fitting in the current genotype-phenotype classification. We expect to find defects within the GNAS cluster but also in other chromosomal regions as novel regulators of GNAS pathology. These factors could explain some contradictory results in (epi)genotype-phenotype findings and would improve our current knowledge of the regulation of this highly complex imprinted gene cluster to be able to also improve patient diagnosis.