Background:CaSR gene is a candidate for calcium nephrolithiasis. SNPs encompassing its regulatory region were associated with calcium nephrolithiasis.Aims:To test SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney.Subjects and Methods:167 idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load oral was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype.Results:Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, p=0.001). A reduced strontium excretion was observed in GG homozygous stone formers.Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele.CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects.Conclusion:Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Decreased transcriptional activity of Calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis / G. Vezzoli, A. Terranegra, A. Aloia, T. Arcidiacono, L. Milanesi, E. Mosca, A. Mingione, D. Spotti, D. Cusi, J. Hou, G.N. Hendy, L. Soldati. - In: THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM. - ISSN 0021-972X. - 98:9(2013 Jul 17), pp. 3839-3847. [Epub ahead of print] [10.1210/jc.2013-1834]

Decreased transcriptional activity of Calcium-sensing receptor gene promoter 1 is associated with calcium nephrolithiasis

G. Vezzoli
Primo
;
A. Terranegra
Secondo
;
A. Aloia;A. Mingione;D. Cusi;L. Soldati
Ultimo
2013-07-17

Abstract

Background:CaSR gene is a candidate for calcium nephrolithiasis. SNPs encompassing its regulatory region were associated with calcium nephrolithiasis.Aims:To test SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney.Subjects and Methods:167 idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load oral was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype.Results:Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, p=0.001). A reduced strontium excretion was observed in GG homozygous stone formers.Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele.CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects.Conclusion:Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.
CASR ; Claudin ; Nephrolitiasis
Settore MED/14 - Nefrologia
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/224486
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