A variant in a Cis-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones
| Autor: | Megan E Ure, Sabah Rehman, Henrik Dimke, Robin L. Erickson, Ajay Ramesh, Wanling Pan, Maury Pinsk, Mathieu Lemaire, Johannes M. Herrmann, Catherine Morgan, Michael A. Walter, R. Todd Alexander, Emmanuelle Cordat, Emma Heydari |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male endocrine system diseases 030232 urology & nephrology Genome-wide association study urologic and male genital diseases Binding Sites/genetics 0302 clinical medicine Polymorphism (computer science) Gene expression pediatric kidney stones Hypercalciuria Kidney Calculi/complications Child Genetics (clinical) hypercalciuria claudin-14 Calcium/blood Claudins/genetics Polymorphism Single Nucleotide/genetics Child Preschool Female Protein Binding medicine.medical_specialty Adolescent Hypercalciuria/complications Biology Polymorphism Single Nucleotide Gene Expression Regulation/genetics Protein Binding/genetics 03 medical and health sciences Kidney Calculi Internal medicine Genetics medicine Journal Article SNP Humans Genetic Predisposition to Disease Risk factor Repressor Proteins/genetics Binding Sites Haplotype Infant medicine.disease Repressor Proteins 030104 developmental biology Endocrinology Gene Expression Regulation Haplotypes Claudins Kidney stones Calcium |
| Zdroj: | Ure, M E, Heydari, E, Pan, W, Ramesh, A, Rehman, S, Morgan, C, Pinsk, M, Erickson, R, Herrmann, J M, Dimke, H, Cordat, E, Lemaire, M, Walter, M & Alexander, R T 2017, ' A variant in a Cis-regulatory element enhances claudin-14 expression and is associated with pediatric-onset hypercalciuria and kidney stones ', Human Mutation, vol. 38, no. 6, pp. 649–657 . https://doi.org/10.1002/humu.23202 |
| DOI: | 10.1002/humu.23202 |
| Popis: | The greatest risk factor for kidney stones is hypercalciuria, the etiology of which is largely unknown. A recent genome-wide association study (GWAS) linked hypercalciuria and kidney stones to a claudin-14 (CLDN14) risk haplotype. However, the underlying molecular mechanism was not delineated. Recently, renal CLDN14 expression was found to increase in response to increased plasma calcium, thereby inducing calciuria. We hypothesized therefore that some children with hypercalciuria and kidney stones harbor a CLDN14 variant that inappropriately increases gene expression. To test this hypothesis, we sequenced the CLDN14 risk haplotype in a cohort of children with idiopathic hypercalciuria and kidney stones. An intronic SNP was more frequent in affected children. Dual luciferase and cell-based assays demonstrated increased reporter or CLDN14 expression when this polymorphism was introduced. In silico studies predicted the SNP introduced a novel insulinoma-associated 1 (INSM1) transcription factor binding site. Consistent with this, repeating the dual luciferase assay in the presence of INSM1 further increased reporter expression. Our data suggest that children with the INSM1 binding site within the CLDN14 risk haplotype have a higher likelihood of hypercalciuria and kidney stones. Enhanced CLDN14 expression may play a role in the pathophysiology of their hypercalciuria. |
| Databáze: | OpenAIRE |
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