Genetic evidence linking the promoter region and 5'-UTR deletion of GNAS with pseudohypoparathyroidism type 1 C.

Authors

Chung Lee, Yoon Ji Ahn, Sung-Chul Jung, Saeyoung Park, Ji Yeon Kim, Chang-Seok Ki, Woong-Yang Park, Sung Yoon Cho

Published in

BMC medical genomics. Volume 19. Issue 1. Jul 28, 2026. Epub Jul 28, 2026.

Abstract

Pseudohypoparathyroidism (PHP) is a heterogeneous disorder caused by genetic or epigenetic changes at the GNAS locus on chromosome 20q13.3 leading to impaired cyclic adenosine monophosphate (cAMP)-dependent signaling pathway via the alpha-subunit of the stimulatory G protein (G_sα). Unlike PHP type 1 A (PHP1A), which occurs due to GNAS variant and low G_sα activity, the activity of G_sα is normal in PHP type 1 C (PHP1C) despite the same phenotypic characteristics as PHP1A. However, the genetic cause of PHP1C is unknown.
The likely causative variant of PHP1C was investigated using next-generation sequencing, and G_sα protein levels and function were assessed in patient-derived cells by immunoblotting, immunocytochemistry and cAMP measurement.
We identified a de novo genomic deletion in a promoter region and 5' untranslated region (UTR) of GNAS (5' deletion of GNAS), in a participant with PHP1C. Furthermore, although the mRNA and protein levels of GNAS were maintained, cAMP production was impaired in PHP1C, implicating a functional abnormality rather than quantitative changes.
This novel 5'-UTR deletion of GNAS may underlie PHP1C and highlights the importance of assessing non-coding regions of GNAS in participants with PHP1C or PHP1A who lack pathogenic variants in conventional genetic tests.

PMID:
42919396
Bibliographic data and abstract were imported from PubMed on 24 Oct 2026.

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