A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Ho C; Conner DA; Pollak MR; Ladd DJ; Kifor O; Warren HB; Brown EM; Seidman JG; Seidman CE

doi:10.1038/ng1295-389

Abstract

Mice lacking the calcium-sensing receptor (Casr) were created to examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human Casr gene defects cause diseases. Casr+/- mice, analogous to humans with familial hypocalciuric hypercalcemia, had benign and modest elevations of serum calcium, magnesium and parathyroid hormone levels as well as hypocalciuria. In contrast, Casr-/- mice, like humans with neonatal severe hyperparathyroidism, had markedly elevated serum calcium and parathyroid hormone levels, parathyroid hyperplasia, bone abnormalities, retarded growth and premature death. Our findings suggest that Casr mutations cause these human disorders by reducing the number of functional receptor molecules on the cell surface.

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References

Articles referenced by this article (24)

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Heterogeneous Transcriptional Landscapes in Human Sporadic Parathyroid Gland Tumors.
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Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G.
Sinigaglia B, Escudero J, Biagini SA, Garcia-Calleja J, Moreno J, Dobon B, Acosta S, Mondal M, Walsh S, Aguileta G, Vallès M, Forrow S, Martin-Caballero J, Migliano AB, Bertranpetit J, Muñoz FJ, Bosch E
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Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.
Ward BK, Loffell KA, Walsh JP, Howe WD, Brown SJ, Wilson SG
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Molecular and Clinical Spectrum of Primary Hyperparathyroidism.
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Diseases in OMIM (2)

CALCIUM-SENSING RECEPTOR; CASR(OMIM - 601199)
HYPOCALCIURIC HYPERCALCEMIA, FAMILIAL, TYPE I; HHC1(OMIM - 145980)

Proteins in UniProt (Showing 5 of 6)

Receptor ligand binding region domain-containing protein(UniProt - O88982)
Extracellular calcium-sensing receptor(UniProt - Q8CDP3)
G-protein coupled receptors family 3 profile domain-containing protein(UniProt - L7N2B8)
Extracellular calcium-sensing receptor(UniProt - Q9QY96)
G-protein coupled receptors family 3 profile domain-containing protein(UniProt - A0A3B2WBC8)

Go to all (6) records in UniProt

GlyGen is an international glycobioinformatics knowledgebase funded by The National Institutes of Health to facilitate glycoscience research by integrating diverse kinds of information, including glycomics, genomics, proteomics (and glycoproteomics), cell biology, developmental biology and biochemistry.

https://www.glygen.org/publication/MED/7493018

Mouse Genome Informatics (MGI)

http://www.informatics.jax.org/reference/7493018

The Rat Genome Database (RGD) was established in 1999 and rapidly became the premier site for genetic, genomic, phenotype, and disease-related data generated from rat research. In addition, RGD has expanded to include a large body of structured and standardized data for eight species (rat, mouse, human, chinchilla, bonobo, 13-lined ground squirrel, dog and pig). Much of this data is the result of manual curation work by RGD curators. In other instances, it has been imported into RGD from other databases through custom ELT (Extract, Load and Transform) pipelines giving RGD users integrated access to a wide variety of data to support their research efforts. RGD also offers a growing suite of innovative tools for querying, analyzing and visualizing this data making it a valuable resource for researchers worldwide. (4)

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NIDDK NIH HHS (3)

Grant ID: DK46422
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Grant ID: DK41415
89 publications
Grant ID: DK02138
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A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

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References

Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

Cloning and functional expression of a rat kidney extracellular calcium/polyvalent cation-sensing receptor.

Calcium sensing receptor: molecular cloning in rat and localization to nerve terminals.

Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds.

Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families.

Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia.

Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes.

Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

Citations & impact

Impact metrics

Citations of article over time

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Article citations

Heterogeneous Transcriptional Landscapes in Human Sporadic Parathyroid Gland Tumors.

A novel mouse model for familial hypocalciuric hypercalcemia (FHH1) reveals PTH-dependent and independent CaSR defects.

Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G.

Case Presentation: Functional Assessment of a CASR Variant Identified in a Patient with Hypercalcaemia Confirms Familial Hypocalciuric Hypercalcaemia in the Patient and a Sister Previously Misdiagnosed with Primary Hyperparathyroidism.

Molecular and Clinical Spectrum of Primary Hyperparathyroidism.

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Diseases in OMIM (2)

Proteins in UniProt (Showing 5 of 6)

Mouse Genome Informatics (MGI)

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A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

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