Genetic variation at the calcium-sensing receptor (CASR) locus: implications for clinical molecular diagnostics.
OBJECTIVE
The calcium-sensing receptor (CASR) is critical for maintenance of blood calcium in a narrow physiologic range. Naturally occurring mutations in the calcium-sensing receptor gene (CASR) cause hypocalcaemia or hypercalcaemia, and molecular diagnosis of these mutations is clinically important. Knowledge of SNP frequency and haplotype structure is essential in understanding molecular test results.


METHODS
Genotyping and haplotype analysis of 26 CASR SNPs (and a tetranucleotide insertion/deletion polymorphism) in control cohorts of Caucasian, Asian and African-American origin (n=1136, 88 and 104 chromosomes, respectively).


RESULTS
The three SNPs in exon 7 (A986S, R990G, Q1011E) are the only common exonic variants in our cohorts, and synonymous exonic SNPs are uncommon. Linkage disequilibrium analysis of the Caucasian cohort (Haploview) showed that the CASR locus is divided into three haplotype blocks, coincident with 5' regulatory, coding, and 3' regulatory domains.


CONCLUSIONS
These analyses provide an important framework for appropriate interpretation of CASR mutation screening now offered by a number of laboratories for the diagnosis of calcium disorders. They will assist in the study of CASR polymorphisms as predictors of complex disease states.
Yun
Francisco H J
FH
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Wong
Betty Y L
BY
Chase
Maretta
M
Shuen
Andrew Y
AY
Canaff
Lucie
L
Thongthai
Kansuda
K
Siminovitch
Katherine
K
Hendy
Geoffrey N
GN
Cole
David E C
DE
D001741:Black or African American / Q000235:genetics; D000483:Alleles; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006934:Hypercalcemia / Q000175:diagnosis / Q000235:genetics; D006996:Hypocalcemia / Q000175:diagnosis / Q000235:genetics; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D044169:Receptors, Calcium-Sensing / Q000235:genetics*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D044465:White People / Q000235:genetics
D044169:Receptors, Calcium-Sensing