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Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation
M R Pollak1, E M Brown, H L Estep
1Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115.
Nature Genetics
|November 1, 1994
Summary
A novel mutation in the calcium-sensing receptor gene causes familial hypocalcemia. This extracellular domain mutation enhances receptor activity, leading to low calcium levels in affected individuals.
Area of Science:
- Genetics
- Molecular Biology
- Endocrinology
Background:
- Genetic defects in the calcium-sensing receptor (CaSR) are linked to calcium metabolism disorders.
- Previously identified CaSR mutations cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.
Purpose of the Study:
- To investigate the role of a specific CaSR missense mutation (Glu128Ala) in familial hypocalcemia.
- To characterize the functional consequences of the Glu128Ala mutation on CaSR activity.
Main Methods:
- Genetic analysis of affected family members.
- Expression of wild-type and mutant CaSR in Xenopus oocytes.
- Measurement of inositol 1,4,5-triphosphate production in response to calcium stimulation.
Main Results:
- A missense mutation, Glu128Ala, in the CaSR gene was identified in a family with hypocalcemia.
- Xenopus oocytes expressing the mutant CaSR showed an exaggerated inositol 1,4,5-triphosphate response to calcium compared to wild-type.
- The Glu128Ala mutation was found to increase CaSR activity at low extracellular calcium concentrations.
Conclusions:
- The Glu128Ala extracellular domain mutation in the CaSR gene is a cause of familial hypocalcemia.
- This mutation leads to increased receptor sensitivity to calcium, resulting in hypocalcemia in heterozygous carriers.