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

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 (G s α). Unlike PHP type 1 A (PHP1A), which occurs due to GNAS variant and low G s α activity, the activity of G s α 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 G s α 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.