Complexity of the 5′UTR region of the CLCN5gene: eleven 5′UTR ends are differentially expressed in the human kidney

Tosetto, Enrica; Casarin, Alberto; Salviati, Leonardo; Familiari, A.; Lieske, John C.; Anglani, Franca

doi:10.1186/1755-8794-7-41

Cited by 8 publications

(21 citation statements)

References 35 publications

(53 reference statements)

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“…The significant direct correlation between the CLCN5 translated region and variants 4 and 7 also supports the involvement of these isoforms in upregulating the CLCN5 transcript in these biopsies. It has been demonstrated that variant 7 is kidney-specific,7 so its higher expression could indicate a particular renal response to proteinuria-induced insult. Weak promoters can be turned on by various stimuli 11.…”

Section: Discussionmentioning

confidence: 99%

“…Data were analyzed according to the ΔΔCt method, normalizing on GAPDH expression levels. Primer sequences were as reported elsewhere 7…”

Section: Methodsmentioning

confidence: 99%

“…An aliquot of 2 µL of cDNA was used to amplify these variants in a final volume of 25 µL containing 0.2 mM dNTP, 0.4 µM of each primer, 0.04 U JumpStart Taq (Sigma-Aldrich, Milan Italy) in 50 mM KCl, and 10 mM Tris HCl pH 8.3. The amplification profile for each primer set consisted of an initial denaturation at 95°C for 5 min, followed by several amplification cycles (45 s at 94°C, 45 s at specific Ta °C, 1 min at 72°C), and an extension at 72°C for 7 min 7. Primer sequences were as reported elsewhere 7.…”

Section: Methodsmentioning

confidence: 99%

“…The amplification profile for each primer set consisted of an initial denaturation at 95°C for 5 min, followed by several amplification cycles (45 s at 94°C, 45 s at specific Ta °C, 1 min at 72°C), and an extension at 72°C for 7 min 7. Primer sequences were as reported elsewhere 7. PCR conditions are given in online supplementary table S2.…”

Section: Methodsmentioning

confidence: 99%

“…Open reading frame analysis suggested that all except three isoforms (variants 1, 2 and 4) code for the canonical 746 amino acid ClC-5 protein. In healthy kidney tissue, variant 3 mRNA was found to be predominantly expressed, and variant 6 and 7 mRNAs were exclusively expressed 7. The presence of many different 5’UTR ends of CLCN5 mRNA in the kidney underscores the complexity of this gene’s molecular structure and regulatory apparatus.…”

Section: Introductionmentioning

confidence: 99%

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CLCN5 5'Utr Isoforms in Human Kidneys: Differential Expression Analysis between Controls and Patients with Glomerulonephritis

Ceol

Gianesello

Tosetto

et al. 2020

Journal of Investigative Medicine

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ClC-5, the electrogenic chloride/proton exchanger strongly expressed in renal proximal tubules, belongs to the endocytic macromolecular complex responsible for albumin and low-molecular-weight protein uptake. ClC-5 was found to be overexpressed in glomeruli of glomerulonephritis and in cultured human podocytes under albumin overload. The transcriptional regulation of human ClC-5 is not fully understood. Three functional promoters of various strengths and 11 different 5’ untranslated region (5’UTR) isoforms of CLCN5 messenger RNA (mRNA) were detected in the human kidney (variants 1–11). The aim of this study was to investigate the expression pattern of CLCN5 5’UTR variants and the CLCN5 common translated region in glomerulonephritis. The 5’UTR ends and the translated region of CLCN5 mRNA were analyzed using quantitative relative real-time PCR or quantitative comparative endpoint PCR with GAPDH as housekeeping gene in 8 normal kidneys and 12 renal biopsies from patients with glomerulonephritis. The expression profile for all variants in normal and glomerulonephritis biopsies was similar, and variant 3 and alternative variant 4 were the most abundantly expressed in both sets. In glomerulonephritis biopsies, isoforms under the control of a weak promoter (variants 4, 6 and 7) showed an increased expression leading to an increase in the CLCN5 translated region, underscoring their importance in kidney pathophysiology. Since weak promoters can be turned on by different stimuli, these data support the hypothesis that proteinuria could be one of the stimuli capable of starting a signaling pathway that induces an increase in CLCN5 transcription.

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Section: Discussionmentioning

confidence: 99%

“…Data were analyzed according to the ΔΔCt method, normalizing on GAPDH expression levels. Primer sequences were as reported elsewhere 7…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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CLCN5 5'Utr Isoforms in Human Kidneys: Differential Expression Analysis between Controls and Patients with Glomerulonephritis

Ceol

Gianesello

Tosetto

et al. 2020

Journal of Investigative Medicine

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Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

et al. 2020

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Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are known to cause Dent disease, no such mutations are found in about 25-35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Starting from the history of Dent disease, and reviewing the clinical details of patients with and without a genetic characterization, we discuss the phenotypic and genetic heterogeneity that typifies this disease. We focus particularly on all those confounding clinical signs and symptoms that can lead to a misdiagnosis. We also try to shed light on a concealed aspect of Dent disease. Although it is a proximal tubulopathy, its misdiagnosis may lead to patients undergoing kidney biopsy. In fact, some individuals with Dent disease have high-grade proteinuria, with or without hematuria, as in the clinical setting of glomerulopathy, or chronic kidney disease of uncertain origin. Although glomerular damage is frequently documented in Dent disease patients' biopsies, there is currently no reliable evidence of renal biopsy being of either diagnostic or prognostic value. We review published histopathology reports of tubular and glomerular damage in these patients, and discuss current knowledge regarding the role of CLCN5 and OCRL genes in glomerular function.

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MEF2C orthologues from zebrafish: Evolution, expression and promoter regulation

Adrião

Conceição

Cancela

2016

Archives of Biochemistry and Biophysics

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Complexity of the 5′UTR region of the CLCN5gene: eleven 5′UTR ends are differentially expressed in the human kidney

Cited by 8 publications

References 35 publications

CLCN5 5'Utr Isoforms in Human Kidneys: Differential Expression Analysis between Controls and Patients with Glomerulonephritis

CLCN5 5'Utr Isoforms in Human Kidneys: Differential Expression Analysis between Controls and Patients with Glomerulonephritis

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

MEF2C orthologues from zebrafish: Evolution, expression and promoter regulation

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