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Abstract

Background

Autosomal Dominant Hypocalcemia (ADH) is an endocrine disorder due to activating mutations of the calcium-sensing receptor (CASR) gene that encodes for a plasma membrane G protein-coupled receptor. This protein plays a central role in maintaining calcium homeostasis. ADH is characterized by hypocalcemia and hypercalciuria with inappropriately low serum concentration of parathyroid hormone (PTH). We report on a young boy who presented hypocalcemia with hypercalciuria, hyperphosphatemia and low serum concentration of PTH.

Materials and Methods

Genomic DNA was extracted from peripheral venous blood of a pediatric patient with ADH. Molecular screening of the CASR coding sequence was performed by sequence analysis with an ABI PRISM® 3100 Avant Genetic Analyzer. Site-directed mutagenesis was performed directly on CASR wild type cDNA, cloned in pCR3.1 plasmid to obtain CASR mutant plasmid. Functional properties of mutant receptor were studied in transiently transfected HEK-293 cells with the wild-type or mutated CASR. The ERK phosphorylation levels were measured by western blot analysis.

Results

We detected a novel heterozygous deletion of a cytosine (c.2682delC) causing a frameshift and a premature stop codon resulting in a truncation of the CaSR's C-tail. HEK-293 cells transfection with CASR Mutant increased significantly (P = 0.02) p-ERK levels by 3.8 fold versus CASR wild type.

Conclusion

We identified a novel CASR gene mutation in a young boy with ADH. Although the mutation leads to a truncation of the protein, it leads to a constitutive gain-of-function of the receptor. This finding is in line with the clinical phenotype observed in our patient.

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/content/papers/10.5339/qfarc.2016.HBPP2064
2016-03-21
2020-09-27
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