GNAS – Pseudohypoparathyroidism Type 1C

Pseudohypoparathyroidism type 1C (PHPIc) presents with resistance to parathyroid hormone (PTH) in vivo despite normal in vitro Gsα activity. PHPIc falls within the spectrum of GNAS-related imprinting disorders and is distinguished from type 1A/Ib by preservation of erythrocyte Gsα function. Clinical diagnosis relies on endocrine resistance and mild Albright hereditary osteodystrophy features without demonstrable GNAS coding mutations in most cases.

A single multi-center study evaluated the methylation status of GNAS DMRs (exons A/B, AS, XL, NESP) in 26 unrelated PHPIc patients by bisulfite pyrosequencing. Six individuals displayed one of three distinct epigenetic signatures: one had isolated loss of methylation at exon A/B co-occurring with a 3-kb STX16 deletion; four showed combined loss at XL and AS with gain at NESP; and one exhibited partial methylation alterations across all four DMRs (n = 26 probands) ([PMID:24878042]).

No pathogenic point mutations or small indels in GNAS exons 1–13 were identified in this cohort, and only one patient carried the known STX16 microdeletion, implicating primary imprinting defects rather than GNAS coding changes in the majority of PHPIc cases. Genetic segregation analysis is limited by imprinting effects and incomplete familial transmission data.

Mechanistically, loss or gain of methylation at maternal GNAS DMRs disrupts allele-specific expression of Gsα and its splice variants, leading to hormone resistance in target tissues. STX16 deletions act in cis to abrogate exon A/B methylation, while more complex methylation gains at NESP and losses at XL/AS further underscore locus heterogeneity.

Functional evidence is robust: bisulfite pyrosequencing reliably distinguishes PHPIc from other PHP subtypes by quantifying methylation levels at four GNAS DMRs, confirming pathogenic imprinting alterations. No discordant reports dispute the central role of GNAS epigenetic defects in PHPIc.

In summary, PHPIc is a heterogeneous imprinting disorder of GNAS characterized by maternal-allele methylation abnormalities, with or without STX16 deletion. Methylation analysis of GNAS DMRs is essential for accurate diagnosis and subclassification of pseudohypoparathyroidism, guiding genetic counseling and management.

References

• The Journal of clinical endocrinology and metabolism • 2014 • 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 PMID:24878042

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