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Background  Dent disease 1 represents a hereditary disorder of renal tubular epithelial function associated with mutations in the  CLCN5  gene that encoded the ClC-5 Cl - /H +  antiporter. All of the reported disease-causing mutations are localized in the coding region except for one recently identified in the 5 ’ UTR region of a single patient. This finding highlighted the possible role for genetic variability in this region in the pathogenesis of Dent disease 1.  The structural complexity of the  CLCN5  5 ’ UTR region has not yet been fully characterized. To date 6 different 5 ’  alternatively used exons - 1a, 1b, 1b1 and I-IV with an alternatively spliced exon II (IIa, IIb) - have been described, but their significance and differential expression in the human kidney have not been investigated. Therefore our aim was to better characterize the  CLCN5  5 ’ UTR region in the human kidney and other tissues.    Methods  To clone more of the 5 ’  end portion of the human  CLCN5  cDNA, total human kidney RNA was utilized as template and RNA ligase-mediated rapid amplification of cDNA 5 ’  ends was applied.  The expression of the different  CLCN5  isoforms was studied in the kidney, leucocytes and in different tissues by quantitative comparative RT/PCR and Real -Time RT/PCR.    Results  Eleven transcripts initiating at 3 different nucleotide positions having 3 distinct promoters of varying strength were identified. Previously identified 5 ’ UTR isoforms were confirmed, but their ends were extended. Six additional 5 ’ UTR ends characterized by the presence of new untranslated exons (c, V and VI) were also identified. Exon c originates exon c.1 by alternative splicing. The kidney uniquely expresses all isoforms, and the isoform containing exon c appears kidney specific. The most abundant isoforms contain exon 1a, exon IIa and exons 1b1 and c. ORF analysis predicts that all isoforms except 3 encode for the canonical 746 amino acid ClC-5 protein.    Conclusions  Our results confirm the structural complexity of the  CLCN5  5 ’ UTR region. Characterization of this crucial region could allow a clear genetic classification of a greater number of Dent disease patients, but also provide the basis for highlighting some as yet unexplored functions of the ClC-5 proton exchanger.

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