Genetic variation at the calcium-sensing receptor (CASR) locus: Implications for clinical molecular diagnostics

Yun, Francisco; Wong, Betty; Chase, Maretta; Shuen, Andrew Y.; Canaff, Lucie; Thongthai, Kansuda; Siminovitch, Katherine A.; Hendy, Geoffrey N.; Cole, David E. C.

doi:10.1016/j.clinbiochem.2006.12.011

Cited by 44 publications

(47 citation statements)

References 50 publications

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“…This could stem from the long history of low vitamin D intake, as occurs among Europeans at higher latitudes, causing natural selection in favor of those with 'hypercalcemic' S alleles. Yet the frequency of the S allele in our study (11.7%) was lower than the previously reported S allele frequency in a cohort of Caucasian ethnicity (16.5%) [46] .…”

Section: Discussioncontrasting

confidence: 54%

“…In addition, our study suggested that the A986S polymorphism may not contribute to BMD, which is in congruence with the results of some Hungarian [23] and Italian [24] studies. The R990G CaSR polymorphism which has been shown to be associated with calcium excretion [45] is in linkage disequilibrium with the A986S polymorphism [46] . Thus, the R990G polymorphism , which contributes to higher than normal Ca 2+ levels without suppression in PTH secretion [47] .…”

Section: Discussionmentioning

confidence: 99%

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Associations of Vitamin D Receptor, Calcium-Sensing Receptor and Parathyroid Hormone Gene Polymorphisms with Calcium Homeostasis and Peripheral Bone Density in Adult Finns

Laaksonen

Outila²,

Kärkkäinen³

et al. 2009

Lifestyle Genomics

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Background: Thus far the search for osteoporosis candidate genes has focused less attention on the regulation of calcium homeostasis. Associations of vitamin D receptor (VDR) FokI, calcium-sensing receptor (CaSR) A986S and parathyroid hormone (PTH) BstBI polymorphisms with calcium homeostasis and peripheral bone density were investigated in adult Finns. Methods: The subgroup of the population-based FINRISK survey consists of 339 healthy adults aged 31–43 years. Lifestyle data were assessed with questionnaires and food diaries. DNA was isolated from blood, and biochemical determinants of calcium metabolism were measured from blood and 24-hour urine samples. Bone mineral density (BMD) was measured using the DXA method at the distal forearm and by quantitative ultrasound (broadband ultrasound attenuation and speed of sound) at the calcaneus. Subjects were genotyped for VDR FokI, CaSR A986S and PTH BstBI polymorphisms. Results: The CaSR 986S allele was associated with higher serum ionized calcium (p = 0.014). Forearm BMD was lowest for the PTH BstBI genotype bb in males (p = 0.023). VDR FokI and PTH BstBI polymorphisms showed a significant interaction on serum PTH (p = 0.010). The other gene–gene or diet–gene interactions studied showed no significant results. Conclusions: VDR, CaSR and PTH contribute to the genetic regulation of calcium homeostasis and peripheral bone density.

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Section: Discussioncontrasting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

Associations of Vitamin D Receptor, Calcium-Sensing Receptor and Parathyroid Hormone Gene Polymorphisms with Calcium Homeostasis and Peripheral Bone Density in Adult Finns

Laaksonen

Outila²,

Kärkkäinen³

et al. 2009

Lifestyle Genomics

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“…This drug is incorporated into bone matrix at the similar rate as calcium (with a long half life), and it has been hypothesized that could act as an agonist of the extracellular Ca-sensing receptor (CASR) that is expressed at all stages of osteoblast development [114]. Thus, it is likely that polymorphisms in the CASR gene (associated with BMD and calcium homeostasis in some studies) [115], as well as in different proteins of the bone matrix may affect the skeletal response to this compound. In this context, a preliminary study suggested that patients homozygous for glycine at the 990 position in exon 7 of the CASR may be more sensitive to the calcimimetic drug cinacalcet (acting on the CASR) compared to those who are homozygous for arginine at that location [116].…”

Section: Other Pharmacogenomic Implications Of Antiresorptive and Anamentioning

confidence: 98%

Pharmacogenomics of Osteoporosis

Gennari

2010

Clinic Rev Bone Miner Metab

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Pharmacogenomics and pharmacogenetics are emerging interdisciplinary areas recently defined, respectively as ''the investigation of variations of DNA and RNA characteristics as related to drug response'', and the study of ''the influence of variations in DNA sequence on drug efficacy and toxicity''. A major challenge of future genetic studies in complex disorders such as osteoporosis is the development of specific genetic tests to identify responders from non-responders as well as to identify patients at higher risk to develop adverse reactions. Even though the knowledge of the genetic determinants of bone fragility and fracture risk has consistently increased over the past decade and despite the parallel development of multiple drugs with antiresorptive or anabolic activity in bone, there is still relatively little known about pharmacogenomics and pharmacogenetics of osteoporosis. This review provides an overview of available information and identifies potential targets for future studies in this field.

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“…Various polymorphic variants have been identified in the CASR gene (Yun et al 2007). Of note, three single nucleotide polymorphisms in exon 7 encode nonconservative amino acid changes (A986S, R990G, and Q1011E) in the COOH-terminal tail of the CASR protein.…”

Section: Introductionmentioning

confidence: 99%

Calcium-sensing receptor mutations and denaturing high performance liquid chromatography

Cole¹,

Yun²,

Wong³

et al. 2009

Journal of Molecular Endocrinology

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The calcium-sensing receptor (CASR), a plasma membrane G-protein-coupled receptor, is expressed in parathyroid gland and kidney, and controls systemic calcium homeostasis. Inactivating CASR mutations are associated with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism, and activating mutations cause autosomal dominant hypocalcemia (ADH). CASR mutation identification plays an important role in the clinical management of mineral metabolism disorders. We describe here a high-throughput method using screening with denaturing high performance liquid chromatography (DHPLC) to initially interrogate 12 amplicons covering translated exons and exon/intron boundaries, followed by sequencing of any amplicon with a modified melting curve relative to wild type, and direct sequencing of a 13th amplicon encoding the COOH-terminal tail to distinguish causative mutations from three common missense single nucleotide polymorphisms. A blinded analysis of 32 positive controls representing mutations throughout the CASR sequence, as well as 22 negative controls, yielded a concordance rate of 100%. We report eight novel and five recurrent FHH mutations, along with six novel and two recurrent ADH mutations. Thus, DHPLC provides a rapid and effective means to screen for CASR mutations.

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Genetic variation at the calcium-sensing receptor (CASR) locus: Implications for clinical molecular diagnostics

Cited by 44 publications

References 50 publications

Associations of Vitamin D Receptor, Calcium-Sensing Receptor and Parathyroid Hormone Gene Polymorphisms with Calcium Homeostasis and Peripheral Bone Density in Adult Finns

Associations of Vitamin D Receptor, Calcium-Sensing Receptor and Parathyroid Hormone Gene Polymorphisms with Calcium Homeostasis and Peripheral Bone Density in Adult Finns

Pharmacogenomics of Osteoporosis

Calcium-sensing receptor mutations and denaturing high performance liquid chromatography

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