Calcium-sensing receptor gene polymorphism affects the parathyroid response to moderate hypercalcemic suppression in patients with end-stage renal disease

Yokoyama, Keitaro; Shigematsu, Takeshi; Tsukada, Toshihiko; Yamada, Akiteru; Kawaguchi, Yoshindo; Hosoya, Tatsuo

doi:10.5414/cnp57131

Cited by 29 publications

(25 citation statements)

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“…In agreement with the in vitro phenotype, patients with primary or secondary hyperparathyroidism (PHPT and SHPT) with the 990G allele were found to have lower levels of serum PTH (Yamauchi et al 2001, Scillitani et al 2004, Corbetta et al 2007a, Wang et al 2007) and ionized calcium (Yano et al 2000). Accordingly, the 990R allele was found to be associated with higher levels of both PTH and ionized calcium in comparison with 990G carriers in healthy Chinese women (Yokoyama et al 2002). Although most studies obtained in different populations confirmed the gain-of-function of the CASR 990G allele, a few studies failed to find this association (Harding et al 2006, Kelly et al 2006.…”

Section: Introductionsupporting

confidence: 50%

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

Terranegra¹,

Ferraretto²,

Dogliotti³

et al. 2010

Journal of Molecular Endocrinology

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Previous studies have demonstrated a gain-of-function of the calcium-sensing receptor (CASR) gene R990G polymorphism. In this study, activation of the R990G CASR stably transfected in HEK-293 (HEK-990G) cells compared with that of the common variant (HEK-wild-type (WT)) by increasing concentrations of CaCl 2 or calcimimetic R-568 caused significantly higher intracellular free calcium concentration ([Ca 2C ] i ) and lower Ca-EC 50 . Moreover, the [Ca 2C ] i oscillation percentage was higher with a larger sinusoidal pattern in HEK-990G. R-568 induced a shift of the oscillatory events from 4 to 2 mmol/l extracellular calcium concentration in HEK-990G cells and increased the sinusoidal oscillation percentage in comparison with HEK-WT. Preincubation with thapsigargin or phospholipase C inhibitors completely prevented oscillations in both cell lines, consistent with the involvement of the inositol trisphosphate pathway, while protein kinase C inhibitor prevented oscillations in HEK-WT cells only. Finally, CaCl 2 and R-568 caused a significant increase in p44/42 extracellular signaling-regulated kinase phosphorylation, with the mean Ca-EC 50 values being significantly lower in HEK-990G. Our findings demonstrated that the 990G allele is associated with high sensitivity to R-568, which provided new evidence for differences in CASR signaling.

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Section: Introductionsupporting

confidence: 50%

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

Terranegra¹,

Ferraretto²,

Dogliotti³

et al. 2010

Journal of Molecular Endocrinology

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“…The hypothesis that G at position 990 might make the receptor more sensitive to calcium is supported by some clinical observations (34,35). In particular, it has been reported that a moderate increase of extracellular calcium in patients with end-stage renal disease on regular hemodialysis caused a significant reduction of PTH levels only in patients bearing the 990G allele (34).…”

Section: Discussionmentioning

confidence: 53%

“…In particular, it has been reported that a moderate increase of extracellular calcium in patients with end-stage renal disease on regular hemodialysis caused a significant reduction of PTH levels only in patients bearing the 990G allele (34). Moreover, in a small series of patients with secondary hyperparathyroidism, it has been observed that subjects homozygous for 990G showed a more marked inhibition of PTH levels in response to treatment with the calcimimetic drug Cinacalcet compared with those homozygous for R at that location (35).…”

Section: Discussionmentioning

confidence: 99%

R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism

Corbetta

Eller-Vainicher²,

Filopanti³

et al. 2006

eur j endocrinol

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Context: Primary hyperparathyroidism (PHPT) shows a great variability in clinical course and severity. Data concerning the association between polymorphic variants of the gene encoding the calciumsensing receptor (CaSR) and clinical characteristics of PHPT are not conclusive. Objective: To evaluate the frequency of three polymorphisms; A986S, R990G, and Q1011E of CaSR in patients with PHPT and to correlate the genotypes with clinical and biochemical parameters. Patients and methods: The study included 94 consecutive unrelated patients referred to our Departments for PHPT diagnosis and management between 2000 and 2005 and 137 age and sexmatched healthy subjects. Patients and controls were genotyped according to standard procedures. Due to the rarity of 990G allele, homozygous and heterozygous subjects were grouped in R/GCG/G set. All PHPT patients were studied for calcium metabolism parameters and renal and bone complications. Results: The proportion of CaSRvariants was similar in PHPT patients and controls. In PHPT patients, only R990G polymorphism was associated with disease parameters; in comparison with R/R, R/GCG/G patients showed lower mean serum parathyroid hormone (PTH) and phosphate levels (139.9G62.2 vs 199.9G136.3 pg/ml, P!0.05 and 0.69G0.12 vs 0.81G0.18 mmol/l, PZ0.031 respectively), higher mean 24-h urine calcium concentration and calcium excretion (9.05G2.05 vs 6.77G4.31 mmol/24 h, PZ0.012 and 67G20 vs 51G26 mmol/l GF, PZ0.039), and increased prevalence of nephrolithiasis (90.0 vs 44.2%, PZ0.007). Conclusions: The study showed that patients with PHPT, bearing the 990G allele, had lower serum PTH levels and higher urinary calcium excretion in comparison with the other genotype, suggesting an increased sensitivity of the variant receptor to extracellular calcium. Since this variant was associated with increased occurrence of nephrolithiasis, analysis of this polymorphism might help to predict renal complication of the disease.European Journal of Endocrinology 155 687-692

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“…It is important to note that allele frequencies of this SNP are reversed between East Asians and Blacks/Whites, i.e., 5-10% of Blacks and Whites carry the glycine allele, while 5-10% of East Asians carry the arginine allele [2]. Cell culture data back this up: in transfected HEK cells, Vezzoli et al [3] showed that rs1042636 causes indeed a gain-of-function in the CaSR molecule, the allele dose of one glycine allele equalling about 30 mg once daily of cinacalcet.…”

Section: To the Editormentioning

confidence: 99%

Cinacalcet HCl therapy in East Asian patients and rs1042636 carriers

Rothe

2018

Clin Exp Nephrol

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Calcium-sensing receptor gene polymorphism affects the parathyroid response to moderate hypercalcemic suppression in patients with end-stage renal disease

Cited by 29 publications

References 0 publications

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

Calcimimetic R-568 effects on activity of R990G polymorphism of calcium-sensing receptor

R990G polymorphism of the calcium-sensing receptor and renal calcium excretion in patients with primary hyperparathyroidism

Cinacalcet HCl therapy in East Asian patients and rs1042636 carriers

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