Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia
Authors' conclusion
This study provides functional validation of the pathogenicity of a novel nonsense CASR variant, resulting in an abnormally hyperfunctioning protein consistent with the patient's phenotype. Functional analyses indicate that mutant receptor is constitutively active and poorly sensitive to increasing concentrations of extracellular calcium, suggesting that the cytoplasmic tail may contain elements regulating signal transduction.
Study context
- Population
- Adolescent patient with chronic hypocalcemia carrying a novel nonsense calcium-sensing receptor (CASR) variant; HEK293T cells transfected with wild-type (WT) or mutant CASR
- Comparison
- Q967* mutant vs WT CASR
- Outcome
- Functional characterisation of Q967* vs WT CaSR
Methodological detailsin vitro, transient transfection in HEK293T cells
- In vitro
- Transient transfection in HEK293T cells
Main finding
As reported in the abstract
- Mutant CaSR protein had lower molecular weight than WT, consistent with loss of the last 122 amino acids of the intracellular domain
- Mutant receptor had higher baseline activity than WT (MAPK activation and SRE luciferase assays)
- ERK/JNK phosphorylation consistently high in the mutant, without significant modulation with increasing Ca2+o
Original publication
Functional evaluation of a novel nonsense variant of the calcium-sensing receptor gene leading to hypocalcemia. Eur J Endocrinol. Published 2 April 2024. doi:10.
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