Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification

Abstract

The extracellular calcium-sensing receptor (CaSR) plays a pivotal role in the regulation of extracellular calcium such that abnormalities, which result in a loss or gain of function, lead to hypercalcemia or hypocalcemia, respectively, in patients. Mice carrying CaSR knockout alleles develop hypercalcemia that mimics the disorders observed in humans. To date, there is no mouse model for an activating CaSR mutation. Here, we describe such a mouse model, named Nuf, originally identified for having opaque flecks in the nucleus of the lens in a screen for eye mutants. Nuf mice also display ectopic calcification, hypocalcemia, hyperphosphatemia, and inappropriately reduced levels of plasma parathyroid hormone. These features are similar to those observed in patients with autosomal dominant hypocalcemia. Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal-dominant manner, and mapping studies located the locus to chromosome 16, in the vicinity of the CaSR gene (Mouse Genome Database symbol Gprc2a). DNA sequence analysis revealed the presence of a Gprc2a missense mutation, Leu723Gln. Transient expression of wild-type and mutant CaSRs in human embryonic kidney 293 cells demonstrated that the mutation resulted in a gain of function of the CaSR, which had a significantly lower EC 50. Thus, our results have identified a mouse model for an activating CaSR mutation, and the development of ectopic calcification and cataract formation, which tended to be milder in the heterozygote Nuf mice, indicates that an evaluation for such abnormalities in autosomal dominant hypocalcemia patients who have activating CaSR mutations is required.

Arterial calcifications and increased expression of vitamin D receptor targets in mice lacking TIF1α

“…The association of ectopic calcifications in arteries, arterioles, vibrissae capsules, and lung alveoli appears to be unique to TIF1␣ Ϫ/Ϫ mutants (present report) and mouse mutants carrying an activating mutation of the Casr gene (41). The latter encodes a G-coupled seven-transmembrane domain protein that plays a central role in controlling calcium homeostasis (42).…”

Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2)

“…These ADH‐associated Gα 11 mutations have been demonstrated to enhance CaSR‐mediated signaling in cellular studies, consistent with a gain‐of‐function 3, 7. ADH1 patients have calcitropic phenotypes, such as hypocalcemia with inappropriately low or normal PTH concentrations and a relative hypercalciuria that is characterized by urinary calcium to creatinine ratios that are within or above the reference range,1, 8, 9 and mice with a gain‐of‐function CaSR mutation, that are representative of ADH1, have been reported to also have non‐calcitropic phenotypes such as cataracts 10. Although these features are similar to hypoparathyroidism, ADH1 is considered to represent a distinct disease entity from hypoparathyroidism, because affected individuals generally have PTH concentrations that are detectable and within the reference range 1, 8.…”

Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH)

“…The content of Ca, phosphorus (P), and vitamin D in this diet is 1.2% Ca, 0.8% P, and vitamin D 400 IU/100 g. (37) Serum and urinary biochemistry All mice were housed in metabolic cages to collect urine samples. Twenty-four-hour urine was collected under a layer of mineral oil to prevent evaporation.…”