NAR Molecular Biology Database Collection entry number 124
Hendy, G., Pidasheva, S.
Department of Medicine, McGill University, and Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada
Familial Hypocalciuric Hypercalcemia (FHH; MIM #145980) is an autosomal dominant disorder characterized by lifelong benign mild hypercalcemia, whereas Neonatal Severe Hyperparathyroidism (NSHPT; MIM #239200) occurs in infants who have marked and often severely symptomatic hypercalcemia with bony changes of hyperparathyroidism. Autosomal Dominant Hypocalcemia (ADH; MIM #601198) is characterized by mild hypocalcemia and inappropriately high urinary calcium excretion and low serum parathyroid hormone (PTH) levels. The calcium-sensing receptor (CASR) is a G protein coupled receptor expressed in the PTH producing chief cells of the parathyroid gland and the cells lining the kidney tubule. The extracellular domain (ECD) that binds calcium spans about 610 amino acids, the transmembrane domain (TMD) about 250 amino acids and the intracellular domain (ICD) about 200 amino acids. Heterozygous and homozygous inactivating mutations in the CASR gene cause FHH and NSHPT, respectively. Heterozygous activating mutations in the CASR gene cause ADH. We created a CASR locus-specific mutation database "CASRDB" which is available on the World Wide Web at http://data.mch.mcgill.ca/casrdb/. The initial entries described 53 different mutations (inactivating and activating) in 60 different families or individuals with FHH, NSHPT, or ADH. Of these, 46 are missense, two nonsense, three insertions, one a deletion/insertion, and one a splicesite mutation. Several polymorphisms have been identified. One of these, A986S, is associated with the serum calcium concentration in Caucasians. Recurrent inactivating mutations, found in more than one apparently unrelated family, are P55L, T138M, and R185Q. In addition, different inactivating missense mutations have been identified at three positions (R185X and R185Q; R220W and R220Q; R227L and R227Q). With the exceptions of R227L and R227Q, all these mutations are in CpG dinucleotide motifs. Recurrent activating mutations are N118K, T151M, and F612S. Only T151M is located in a CpG dinucleotide. The mutations are not evenly distributed throughout the CASR's sequence. They are found clustered in the first approximately 300 amino acids of the ECD and in the TMD region starting at amino acid 520 and continue to amino acid 881 in the ICD. The database allows on-line access to search mutation name, position and type, clinical and biochemical phenotype, functional analysis, and references. The CASRDB site provides a submission form allowing newly identified mutations to be added to the database, and we wish to encourage all interested investigators to send us new entries, corrections, and suggestions.
1. Pidasheva S, D'Souza-Li L, Canaff L, Cole DE, Hendy GN. CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia. Hum Mutat. 2004, 24: 107-111.
Category: Human Genes and Diseases
Subcategory: Gene-, system- or disease-specific databases
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