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Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor
F De Luca1, K Ray, E E Mancilla
1Developmental Endocrinology Branch, National Institute of Child Health and Human Development Bethesda, Maryland 20892, USA. delucaF@cc1.nichd.nih.gov
Abstract:
Activating mutations of the Ca(2+)-sensing receptor (CaR) gene have been identified in families with autosomal dominant hypoparathyroidism and in one patient with sporadic hypoparathyroidism. Here, we describe two additional patients with sporadic hypoparathyroidism. One patient presented with mild symptoms at age 18 yr; the other was severely symptomatic from infancy. A heterozygous missense mutation was identified in each patient. One mutation (L773R) involved the fifth transmembrane domain of the CaR, the other (N118K) affected the amino-terminal, extracellular domain. In both cases, the probands' parents lacked the mutation, indicating that the mutations arose de novo. In expression studies the mutations shifted the concentration-response curve to the left and increased maximal activity. We conclude that 1) sporadic hypoparathyroidism can be caused by de novo gain-of-function mutations of the CaR; 2) the phenotype can vary from mild to life-threatening hypocalcemia; 3) gain-of-function mutations can involve not only extracellular regions, as previously reported, but also transmembrane domains of the CaR; and 4) the mechanism of activation can involve both increased receptor sensitivity to Ca2+ and increased maximal signal transduction.
Insights
Sporadic hypoparathyroidism can result from new activating mutations in the calcium-sensing receptor (CaR) gene. These CaR gene mutations can cause varying symptoms, from mild to severe, affecting calcium levels.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Activating mutations in the calcium-sensing receptor (CaR) gene are linked to autosomal dominant hypoparathyroidism.
- Sporadic cases of hypoparathyroidism are less understood regarding CaR gene involvement.
Observation:
- Two new patients with sporadic hypoparathyroidism were identified, one with mild symptoms and another with severe, early-onset disease.
- Each patient harbored a unique heterozygous missense mutation in the CaR gene: L773R in a transmembrane domain and N118K in the extracellular domain.
- These mutations were confirmed to be de novo, as they were absent in the probands' parents.
Findings:
- Expression studies revealed that the identified CaR mutations shift the concentration-response curve leftward and increase maximal receptor activity.
- This indicates a gain-of-function mechanism for the CaR in these sporadic hypoparathyroidism cases.
Implications:
- De novo gain-of-function mutations in the CaR gene are a cause of sporadic hypoparathyroidism.
- The clinical presentation of sporadic hypoparathyroidism due to CaR mutations can range from mild to life-threatening.
- Gain-of-function mutations can occur in both extracellular and transmembrane domains of the CaR, affecting receptor sensitivity and signal transduction.