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Background <p>Pseudohypoparathyroidism (PHP) is a heterogeneous disorder caused by genetic or epigenetic changes at the <i>GNAS</i> 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<sub>s</sub>α). Unlike PHP type 1&#xa0;A (PHP1A), which occurs due to <i>GNAS</i> variant and low G<sub>s</sub>α activity, the activity of G<sub>s</sub>α is normal in PHP type 1&#xa0;C (PHP1C) despite the same phenotypic characteristics as PHP1A. However, the genetic cause of PHP1C is unknown.</p> Methods <p>The likely causative variant of PHP1C was investigated using next-generation sequencing, and G<sub>s</sub>α protein levels and function were assessed in patient-derived cells by immunoblotting, immunocytochemistry and cAMP measurement.</p> Results <p>We identified a <i>de novo</i> genomic deletion in a promoter region and 5’ untranslated region (UTR) of <i>GNAS (</i>5’ deletion of <i>GNAS)</i>, in a participant with PHP1C. Furthermore, although the mRNA and protein levels of <i>GNAS</i> were maintained, cAMP production was impaired in PHP1C, implicating a functional abnormality rather than quantitative changes.</p> Conclusions <p>This novel 5’-UTR deletion of <i>GNAS</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月28日

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

摘要

Background

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 (Gsα). Unlike PHP type 1 A (PHP1A), which occurs due to GNAS variant and low Gsα activity, the activity of Gsα is normal in PHP type 1 C (PHP1C) despite the same phenotypic characteristics as PHP1A. However, the genetic cause of PHP1C is unknown.

Methods

The likely causative variant of PHP1C was investigated using next-generation sequencing, and Gsα protein levels and function were assessed in patient-derived cells by immunoblotting, immunocytochemistry and cAMP measurement.

Results

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.

Conclusions

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.