Alternative titles; symbols
HGNC Approved Gene Symbol: CLCN5
SNOMEDCT: 444645005, 717789008;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:49,922,596-50,099,230 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Dent disease 1 | 300009 | X-linked recessive | 3 |
| Hypophosphatemic rickets | 300554 | X-linked recessive | 3 | |
| Nephrolithiasis, type I | 310468 | X-linked recessive | 3 | |
| Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis | 308990 | X-linked recessive | 3 |
The CLCN5 gene encodes a voltage-gated chloride ion channel that belongs to a distinct branch of the chloride channel (CLC) family, which also includes CLCN3 (600580) and CLCN4 (302910) (Fisher et al., 1995).
By positional cloning of a microdeletion at chromosome Xp11.22 identified in a family with Dent disease (DENT1; 300009), Fisher et al. (1994) isolated a coding sequence from a human kidney cDNA library. Sequence analysis suggested that CLCN5, which they termed CLCK2, encoded a new member of the CLC family of voltage-gated chloride channels. A 9.5-kb mRNA transcript was expressed predominantly in the kidney.
Fisher et al. (1995) described the isolation and characterization of the complete open reading frame of CLCN5, which encodes a deduced 746-amino acid protein with significant homology to all known members of the family of voltage-gated chloride channels.
Fisher et al. (1995) determined that the CLCN5 gene contains 12 exons and spans 25 to 30 kb of genomic DNA.
By positional cloning, Fisher et al. (1994) identified the CLCN5 gene within the minimum candidate region for Dent disease (DENT1; 300009) on Xp11.22.
In the course of high-resolution comparative mapping of the proximal region of the mouse X chromosome, Blair et al. (1995) demonstrated the location of the Clcn5 gene in relation to others.
Dutzler et al. (2002) presented the x-ray structures of 2 prokaryotic CLC chloride channels, from Salmonella typhimurium and E. coli, at 3.0 and 3.5 angstroms, respectively. Both structures revealed 2 identical pores, each pore being formed by a separate subunit contained within a homodimeric membrane protein.
Gunther et al. (1998) showed that the CLCN5 gene was expressed in renal proximal tubule cells, which normally endocytose proteins passing the glomerular filter. Expression was highest below the brush border in a region densely packed with endocytotic vesicles, where CLC5 colocalizes with the H(+)-ATPase and with internalized proteins early after uptake. CLCN5 localized to apical intracellular vesicles in intercalated cells of the collecting duct, and colocalized with the proton pump in alpha-intercalated cells. In transfected cells, CLC5 colocalized with endocytosed alpha-2-macroglobulin. Cotransfection with a GTPase-deficient rab5 mutant led to enlarged early endosomes that stained for CLC5. Gunther et al. (1998) suggested that CLC5 may be essential for proximal tubular endocytosis by providing an electrical shunt necessary for the efficient acidification of vesicles in the endocytotic pathway, explaining the proteinuria observed in Dent disease.
Devuyst et al. (1999) raised specific antisera against human CLC5 and identified by immunoblotting an 83-kD band corresponding to CLC5 in human kidney cortex and medulla. Immunohistochemistry revealed CLC5 expression in the epithelial cells lining the proximal tubules and the thick ascending limbs of the Henle loop, and in the intercalated cells of the collecting ducts. Subcellular fractionation studies of human kidney established that CLC5 distribution was most closely associated with that of Rab4, a marker of recycling early endosomes. Confocal microscopy using the proximal tubular cell model of opossum kidney cells, which endogenously express CLC5, revealed that CLC5 colocalized with the albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway. The expression of CLC5 at multiple sites in the kidney explained the proteinuria and hypercalciuria which characterize Dent disease.
As described by Novarino et al. (2010), CLC5 is a 2-chloride (Cl-)/proton (H+) exchanger rather than a chloride channel (see Picollo and Pusch, 2005, Scheel et al., 2005, and Zifarelli and Pusch, 2009).
Lloyd et al. (1996) identified 11 mutations in the CLCN5 gene in affected members of 8 kindreds with Dent disease-1 (300009) (see, e.g., 300008.0001-300008.0004), 2 families with X-linked recessive nephrolithiasis (XRN; 310468; 300008.0005-300008.0006), and 1 family with X-linked recessive hypophosphatemic rickets (XLHRR; 300554; 300008.0007). All 4 missense mutations were confined to the predicted transmembrane domains. In vitro functional expression studies showed that the mutations markedly reduced or abolished outwardly rectifying chloride currents.
In affected members from 4 unrelated Japanese kindreds with low molecular weight proteinuria (308990), Lloyd et al. (1997) identified 4 different mutations in the CLCN5 gene (300008.0001; 300008.0008-300008.0010). Nakazato et al. (1997) identified mutations in the CLCN5 gene in affected members of 2 Japanese families with low molecular weight proteinuria. Akuta et al. (1997) identified mutations in the CLCN5 gene in 7 of 10 unrelated Japanese patients with low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. They estimated that over 70% of Japanese patients with the disorder have mutations in the CLCN5 gene.
In 8 unrelated patients with Dent disease, Cox et al. (1999) found 3 nonsense mutations, 4 deletions of single codons, and 1 acceptor splice consensus sequence mutation in the CLCN5 gene. None of these mutations was found in a study of unrelated normal individuals. All of the mutations predicted truncated chloride channels that were likely to result in a functional loss.
After heterologous expression of various mutant CLCN5 cDNAs in Xenopus oocytes, Ludwig et al. (2005) observed that except for the R516W and R648X (300008.0002) variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. The tested missense mutations were distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper CLCN5 function but also for Golgi exit. The R648X mutant, although functionally compromised (30% of wildtype current), displayed a significant increase in surface expression.
Tosetto et al. (2009) identified mutations in the CLCN5 gene, including 15 novel mutations (see, e.g., 300008.0014), in 16 (53%) of 30 mostly Italian patients with a clinical suspicion of Dent disease. Most of the missense mutations were predicted to occur in the helix regions involved in the CLCN5 dimer interface.
Piwon et al. (2000) created a mouse model of Dent disease by targeted disruption of the Clcn5 gene. Clcn5 -/- mice had proteinuria due to strong reduction of apical proximal tubular endocytosis. Both receptor-mediated and fluid-phase endocytosis were affected, and the internalization of the apical transporters NaPi2 and Nhe3 (182307) was slowed. At steady state, however, both proteins were redistributed from the plasma membrane to intracellular vesicles. Piwon et al. (2000) postulated that this may have been caused by an increased stimulation of luminal parathyroid hormone (PTH; 168450) receptors (see 168468) owing to the observed decreased tubular endocytosis of PTH. The rise in luminal PTH concentration should also have stimulated the hydroxylation of 25-hydroxyvitamin D3 to the active hormone. However, this would be counteracted by a urinary loss of the precursor 25-hydroxyvitamin D3. The balance between these opposing effects, both of which are secondary to the defect in proximal tubular endocytosis, probably determined whether there would be hypercalciuria and kidney stones. Piwon et al. (2000) showed that CLC5 is crucial for efficient endocytosis in the proximal tubule. CLC5 was the first intracellular chloride channel for which a role in vesicle trafficking was established. Piwon et al. (2000) argued that their mouse model strongly suggested that alterations in hormones involved in calcium homeostasis, and hyperphosphaturia and hypocalciuria, are indirect effects of defective apical endocytosis of PTH and 25-hydroxyvitamin D3; this may explain how a defect in a chloride channel could lead to kidney stones.
In Xenopus oocytes, Schwake et al. (2001) found that mutations introduced into the C-terminal internalization PY motif of the Clcn5 gene increased surface expression and currents of the channel by about 2-fold. Further studies with the wildtype and mutant ubiquitin-protein ligase WWP2 (602308) and Rab5 (179512) indicated that the prolonged surface expression of PY-mutant Clcn5 resulted from changes in cellular trafficking of the channel, and that endocytosis of Clcn5 depended on the interaction of the internalization signal with these other endocytic proteins.
Christensen et al. (2003) tested whether the endocytic failure that results from loss of the CLCN5 channel in Dent disease and knockout mice primarily reflects a loss of reabsorption by the multiligand receptors megalin (600073) and cubilin (602997) caused by a trafficking defect. Impaired protein endocytosis in kidney proximal tubule cells of Clcn5 knockout mice was demonstrated by a major decreased uptake of (125)I-labeled beta-2-microglobulin (109700), but not of the fluid-phase tracer FITC-dextran; reduced labeling of endosomes by injected peroxidase and reduced labeling for the endogenous megalin/cubilin ligands vitamin D- and retinol-binding proteins; and urinary appearance of low molecular mass proteins and the selective cubilin ligand transferrin (190000). An overall decrease of megalin and cubilin in proximal tubule cells and their selective loss at the brush border was demonstrated. In contrast, total contents of the rate-limiting endocytic catalysts Rab5a and Rab7 (602298) were unaffected. Thus, impaired protein endocytosis caused by invalidation of Clcn5 primarily reflects a trafficking defect of megalin and cubilin in proximal tubule cells.
Novarino et al. (2010) generated mice that carry the uncoupling E211A mutation that converts ClC5 into a pure chloride conductor. ATP-dependent acidification of renal endosomes was reduced in mice in which ClC5 was knocked out, but normal in mice carrying the E211A mutation. However, their proximal tubular endocytosis was also impaired. Novarino et al. (2010) concluded that endosomal chloride concentration, which is raised by ClC5 in exchange for protons accumulated by the proton ATPase, may play a role in endocytosis.
Alex et al. (2010) showed that loss of Clcn5 in mice exacerbated dextran sodium sulfate (DSS)-induced ulcerative colitis (266600), as measured by disease and histologic activity indices and myeloperoxidase (MPO; 606989) activity. Multiplex serum cytokine analysis, as well as immunofluorescence and Western blot analyses of colonic mucosa, demonstrated a heightened Th1/Th17 profile with increased systemic and local expression of Tnfa (191160), Il6 (147620), and Il17 (603149) in Clcn5 -/- mice with DSS-induced ulcerative colitis. Baseline Il6 and phospho-Ikb (NFKBIA; 164008) were high in Clcn5 -/- mice. Colitis in Clcn5 -/- mice could be attenuated by a high vitamin D diet. Alex et al. (2010) concluded that CLCN5 is involved in the immunopathogenesis of ulcerative colitis.
In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a G-to-A transition in the CLCN5 gene, resulting in a trp279-to-ter (W279X) substitution. The mutation was predicted to result in a loss of 469 amino acids from the D6 region to the C terminus.
Lloyd et al. (1997) identified the W279X mutation in affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990).
In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in an arg648-to-ter (R648X) substitution. The mutation was predicted to result in a loss of 100 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins.
Lloyd et al. (1997) identified the R648X mutation in another family with Dent disease.
In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a T-to-G transversion in the CLCN5 gene, resulting in a leu200-to-arg (L200R) substitution. The mutation was predicted to disrupt the charge distribution within domain D3 of the protein.
In affected members of a family with Dent disease (DENT1; 300009), Lloyd et al. (1996) identified a T-to-C transition in the CLCN5 gene, resulting in a ser520-to-pro (S520P) substitution. The mutation was predicted to disrupt a helix in D11.
In affected members of a family with X-linked recessive nephrolithiasis (XRN; 310468), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in an arg704-to-ter (R704X) substitution. The mutation was predicted to result in a loss of 42 amino acids from the cytoplasmic C terminus of the protein, deleting domain D13, which is conserved in all eukaryotic chloride channel proteins.
In affected members of a family with X-linked recessive nephrolithiasis, Lloyd et al. (1996) identified a G-to-A transition in the CLCN5 gene, resulting in a gly506-to-glu (G506E) substitution. The mutation was predicted to disrupt a charge within domain D11.
In affected members of an Italian family with X-linked recessive hypophosphatemic rickets (XLHRR; 300554) reported by Bolino et al. (1993), Lloyd et al. (1996) identified a C-to-T transition in the CLCN5 gene, resulting in a ser244-to-leu (S244L) substitution. The mutation was predicted to disrupt a helix in D5. Functional expression studies showed that the mutant S244L channel had reduced, but not abolished, chloride conductance.
Oudet et al. (1997) reported a second family with the S244L mutation but with a milder phenotype than that in the family reported by Lloyd et al. (1996). The family reported by Oudet et al. (1997) had neither nephrocalcinosis nor nephrolithiasis. However, the affected individuals were significantly younger than those of the family reported by Lloyd et al. (1996).
In affected members of a Japanese family with low molecular weight proteinuria associated with hypercalciuria and nephrocalcinosis (308990), Lloyd et al. (1997) identified a G-to-A transition in the CLCN5 gene, resulting in a trp343-to-ter (W343X) substitution.
In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990), Lloyd et al. (1997) identified a 1-bp deletion (2085delC) in the CLCN5 gene, resulting in a frameshift and premature termination of the protein at codon 699.
In affected members of a Japanese family with idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis (308990), Lloyd et al. (1997) identified an arg280-to-pro (R280P) mutation in the CLCN5 gene. Heterologous expression of this mutation in Xenopus oocytes demonstrated a 70% reduction in channel activity when compared with the wildtype.
In 2 half-brothers, born of the same mother, with X-linked recessive nephrolithiasis (XRN; 310468), Schurman et al. (1998) identified a mutation in the CLCN5 gene, resulting in a gly57-to-val (G57V) substitution. The boys had been referred because of microhematuria and proteinuria noted on screening urinalysis. Family history showed renal failure after recurrent nephrolithiasis in a maternal grandfather and male cousin, and recurrent nephrolithiasis in an older brother.
Claverie-Martin et al. (2003) studied a Spanish patient with Dent disease (DENT1; 300009) and found, by PCR amplification of the CLCN5 exons, an abnormally large exon 11. Sequence analysis showed an insertion in codon 650 of a 345-bp Alu element that had arisen de novo on the maternal chromosome. Polymorphism analysis indicated that the insertion occurred in the germline of the maternal grandfather. The presence of a long poly(A) tract and evidence for a 16-bp target-site duplication implied that the Alu element was integrated by retrotransposition. The mutation predicted a truncated CLC5 protein.
Claverie-Martin et al. (2005) reported further studies of the Alu insertion in the family previously reported by Claverie-Martin et al. (2003). PCR amplification of blood DNA showed that the Alu insertion resulted in aberrant splicing of the CLCN5 pre-mRNA and skipping of exon 11. The resultant truncated protein lacks part of the C terminus, including the PY and CBS2 domains, which are critical for sorting and chloride channel function. In addition, there were 2 conserved exonic splicing enhancer sequences in the site of insertion.
Tosetto et al. (2006) identified a 1070G-T transversion in exon 7 of the CLCN5 gene, resulting in a gly260-to-val (G260V) substitution, in 1 of 25 men from northern Italy with end-stage renal disease and renal stones. The findings were consistent with Dent disease (DENT1; 300009). Examination of the family identified the G260V mutation in 2 additional young male relatives. Both had mild proteinuria, and one also had hypercalciuria.
In a patient with Dent disease (DENT1; 300009), Tosetto et al. (2009) identified a G-to-T transversion in intron 8 of the CLCN5, resulting in a splice site mutation and generation of an mRNA transcript lacking part of exon 8, which was confirmed by RT-PCR analysis. The mutation truncated the protein at codon 361.
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