Activating Calcium-Sensing Receptor Mutation in the Mouse Is Associated with Cataracts and Ectopic Calcification

• Published in: Proceedings of the National Academy of Sciences - PNAS 2004-09, Vol.101 (37), p.13566-13571
• Main Authors: Hough, Tertius A., Bogani, Debora, Cheeseman, Michael T., Favor, Jack, Nesbit, M. Andrew, Thakker, Rajesh V., Lyon, Mary F.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Arteries; Biological Sciences; Blood plasma; Calcification, Physiologic; Calcium; Cataract - genetics; Cataract - metabolism; Cataract - pathology; Cataracts; Cell Line; Chromosomes, Mammalian - genetics; Exons - genetics; Female; Genetic mutation; Genetics; HEK293 cells; Heterozygote; Homozygote; Humans; Hypocalcemia; Male; Medical disorders; Mice; Mice, Knockout; Molecular Sequence Data; Mutation; Mutation - genetics; Organ Specificity; Phenotype; Phenotypes; Physical Chromosome Mapping; Proteins; Receptors, Calcium-Sensing - chemistry; Receptors, Calcium-Sensing - genetics; Receptors, Calcium-Sensing - metabolism; Sequence Alignment; Tongue
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0405516101

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 EC50. 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.