Endocrinopathies in patients with hypocalcemia and hyperphosphatemia that share resistance to
parathyroid hormone (PTH) are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP
type Ia (PHP-Ia) often present with additional hormonal resistance and show characteristic physical features
that are jointly termed as having an Albright's hereditary osteodystrophy (AHO) phenotype. Alternatively, PHPIb
patients predominantly have PTH and sometimes TSH resistance but do not present with AHO features.
Most of these PHP forms are caused by defects in GNAS, an imprinted gene locus consisting of maternal,
paternal and biallelic transcripts. PHP-Ia is caused by heterozygous inactivating mutations in those exons of
GNAS encoding the alpha subunit of the stimulatory guanine nucleotide-binding protein (Gsalpha) while PHPIb
results from epigenetic GNAS defects. Familial and sporadic forms of PHP-Ib have distinct GNAS imprinting
patterns: familial PHP-Ib patients have an exon A/B-only imprinting defect whereas sporadic PHP-Ib cases
have abnormal imprinting of the three differentially methylated regions (DMRs) in GNAS. This classification of
PHP was made years ago but was recently questioned since different studies showed GNAS epigenetic
defects in PHP-Ia patients. In this review, we focus on the epigenetic description and screening methods of
GNAS, the associated pathology and the recent need for a PHP reclassification.
Keywords: DNA methylation, GNAS cluster, imprinting, pseudohypoparathyroidism
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