Different pattern of epigenetic changes of the GNAS gene locus in patients with pseudohypoparathyroidism type Ic confirm the heterogeneity of underlying pathomechanisms in this subgroup of pseudohypoparathyroidism and the demand for a new classification of GNAS-related disorders.

Context: Disorders characterized by PTH resistance are grouped within the term pseudohypoparathyroidism type I (PHPI). Most subtypes of this disease are caused by genetic or epigenetic changes of the GNAS locus leading to deficiency of the α-subunit of stimulatory G proteins (Gsα). Because the in vitro measured Gsα protein activity is normal in pseudohypoparathyroidism Ic (PHPIc), it had previously been postulated that this subtype is caused by impairment of distinct components of the G protein-signaling pathway. However, recently, pathogenic GNAS mutations in a subset of PHPIc patients were found.

Objective: To clarify the underlying pathogenic mechanism of GNAS exon 1-13 mutation-negative PHPIc cases by investigating the differentially methylated regions of GNAS for epigenetic abnormalities.

Patients And Methods: The methylation pattern of GNAS exons A/B, AS, XL, and NESP from blood-derived leukocytes of 26 PHPIc patients was assessed by pyrosequencing of bisulfite-converted DNA.

Results: Six patients presented with three different patterns of epigenetic changes. One patient had an exclusive loss of methylation of exon A/B associated with a STX16 deletion; four patients had an additional loss of methylation in XL and AS and a gain of methylation in NESP; and one patient presented with partial GNAS methylation changes concerning all differentially methylated regions.

Conclusions: Our results confirm that PHPIc is a heterogeneous entity caused in part by impaired Gsα function, not only due to mutations, but also due to abnormal imprinting of GNAS. However, in the majority of cases of PHPIc, the underlying etiopathogenesis remains elusive.