Autosomal Dominant Hypocalcemia: A Novel Activating Mutation (E604K) in the Cysteine-Rich Domain of the Calcium-Sensing Receptor

We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomat...

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Bibliographic Details
Published in:The journal of clinical endocrinology and metabolism 2003-02, Vol.88 (2), p.605-610
Main Authors: Tan, Y. M, Cardinal, J, Franks, A. H, Mun, H.-C, Lewis, N, Harris, L. B, Prins, J. B, Conigrave, A. D
Format: Article
Language:English
Subjects:
Adult
Aequorin
Biological and medical sciences
Calcium - metabolism
Cysteine - genetics
DNA Mutational Analysis
Endocrinopathies
Female
Genes, Dominant
Humans
Hypocalcemia - genetics
Luminescent Measurements
Male
Medical sciences
Mitogen-Activated Protein Kinases - metabolism
Non tumoral diseases. Target tissue resistance. Benign neoplasms
Parathyroids. Parafollicular cells. Cholecalciferol. Phosphocalcic homeostasis (diseases)
Pedigree
Point Mutation
Protein Structure, Tertiary
Receptors, Calcium-Sensing
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
Restriction Mapping
Signal Transduction - genetics
Tropical medicine
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Summary:We report a novel activating mutation (E604K) of the calcium-sensing receptor in a family with autosomal dominant hypocalcemia. Whereas all affected individuals exhibited marked hypocalcemia, some cases with untreated hypocalcemia exhibited seizures in infancy, whereas others were largely asymptomatic from birth into adulthood. The missense mutation E604K (G2182A; GenBank accession no. U20759), which affects an amino acid residue in the C terminus of the cysteine-rich domain of the extracellular head, cosegregated with hypocalcemia in all seven individuals for whom DNA was available. Two unaffected, normocalcemic members of the family did not exhibit the mutation. The molecular impact of the mutation on two key components of the signaling response was assessed in HEK-293 cells transiently transfected with cDNA corresponding to either the wild-type calcium-sensing receptor or the E604K mutation derived by site-directed mutagenesis. There was a significant leftward shift in the concentration response curves for the effects of extracellular Ca2+ on both intracellular Ca2+ mobilization (determined by aequorin luminescence) and MAPK activity (determined by luciferase expression). The C terminus of the cysteine-rich domain of the extracellular head may normally act to suppress receptor activity in the presence of low extracellular Ca2+ concentrations.
ISSN:0021-972X
1945-7197
DOI:10.1210/jc.2002-020081