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Published on: March 14, 2017
Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism
J Baron1, K K Winer, J A Yanovski
1Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862, USA.
Abstract:
Parathyroid hormone secretion is negatively regulated by a 7-transmembrane domain, G-protein coupled Ca(2+)-sensing receptor. We hypothesized that activating mutations in this receptor might cause autosomal dominant hypoparathyroidism (ADHP). Consistent with this hypothesis, we identified, in two families with ADHP, heterozygous missense mutations in the Ca(2+)-sensing receptor gene that cosegregated with the disorder. None of 50 normal controls had either mutation. We also identified a de novo, missense Ca(2+)-sensing receptor mutation in a child with severe sporadic hypoparathyroidism. The amino acid substitution in one ADHP family affected the N-terminal, extracellular domain of the receptor. The other mutations involved the transmembrane region. Unlike patients with acquired hypoparathyroidism, patients with these mutations had hypercalciuria even at low serum calcium concentrations. Their greater hypercalciuria presumably reflected activation of Ca(2+)-sensing receptors in kidney cells, where the receptor negatively regulates calcium reabsorption. This augmented hypercalciuria increases the risk of renal complications and thus has implications for the choice of therapy.
Insights
Activating mutations in the calcium-sensing receptor gene cause autosomal dominant hypoparathyroidism. These genetic mutations lead to hypercalciuria, increasing renal complication risks in affected individuals.
Area of Science:
- Endocrinology
- Genetics
- Molecular Biology
Background:
- Parathyroid hormone secretion is regulated by the calcium-sensing receptor (CaSR), a G-protein coupled receptor.
- Activating mutations in CaSR are hypothesized to cause autosomal dominant hypoparathyroidism (ADHP).
Purpose of the Study:
- To investigate the role of CaSR mutations in autosomal dominant hypoparathyroidism and sporadic hypoparathyroidism.
- To analyze the clinical and genetic features of patients with CaSR mutations.
Main Methods:
- Genetic analysis of the CaSR gene in families with ADHP and patients with sporadic hypoparathyroidism.
- Segregation analysis to confirm cosegregation of mutations with the disorder.
- Comparison of clinical features, including serum calcium levels and urinary calcium excretion, with normal controls and patients with acquired hypoparathyroidism.
Main Results:
- Heterozygous missense mutations in the CaSR gene were identified in two families with ADHP, cosegregating with the disorder.
- A de novo missense CaSR mutation was found in a child with severe sporadic hypoparathyroidism.
- Patients with CaSR mutations exhibited hypercalciuria, even at low serum calcium concentrations, due to enhanced CaSR activation in renal cells.
Conclusions:
- Activating CaSR mutations are a cause of ADHP and can lead to severe sporadic hypoparathyroidism.
- The resulting hypercalciuria has significant implications for renal health and therapeutic strategies in affected individuals.
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