Alternative titles; symbols
SNOMEDCT: 717789008; ORPHA: 1652, 93622; DO: 0050699, 0081453;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.23 | Dent disease 1 | 300009 | X-linked recessive | 3 | CLCN5 | 300008 |
A number sign (#) is used with this entry because of evidence that Dent disease-1 (DENT1) is caused by mutation in the CLCN5 gene (300008) on chromosome Xp11.
The term 'X-linked hypercalciuric nephrolithiasis' comprises several related forms of hereditary renal tubular disorders caused by mutations in the CLCN5 gene, including Dent disease, X-linked recessive nephrolithiasis (310468), X-linked recessive hypophosphatemic rickets (300554), and low molecular weight proteinuria (308990). Although these disorders are allelic and are all characterized by progressive proximal renal tubulopathy with hypercalciuria, low molecular weight proteinuria, and nephrocalcinosis, they vary in degree of severity and were originally reported as separate disorders. Some have considered these disorders as phenotypic variants of a single disease, referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004).
Scheinman et al. (1999) provided a comprehensive review of genetic disorders of renal electrolyte transport.
Genetic Heterogeneity of Dent Disease
See also Dent disease-2 (DENT2; 300555), caused by mutation in the OCRL gene (300535) on chromosome Xq26.
Dent and Friedman (1964) reported 2 unrelated English boys with rickets associated with renal tubular damage characterized by hypercalciuria, hyperphosphaturia, proteinuria, and aminoaciduria. In a follow-up of these patients, Wrong et al. (1994) reported that they had developed nephrolithiasis and renal failure.
Wrong et al. (1990, 1994) reported a total of 5 families with X-linked inheritance of a renal Fanconi syndrome with proximal renal tubular defects, including low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, and progressive renal failure. They termed the disorder 'Dent disease.' In general, female carriers were asymptomatic, but all had low molecular weight proteinuria and approximately half had hypercalciuria. Approximately one-third of affected males had rickets.
Wrong et al. (1992) suggested that Dent disease could be distinguished from the disorder reported by Frymoyer et al. (1991) as X-linked recessive nephrolithiasis by the presence of microglobulinuria. Microglobulinuria in Dent disease involved particularly beta-2-microglobulin (B2M; 109700), alpha-1-microglobulin (AMBP; 176870), and retinol-binding protein (RBP; 180250). However, the total amount of these abnormal urinary proteins was not always sufficient to yield a positive dipstick test for protein. Wrong et al. (1992) also reported affected women: one died of nephrocalcinosis and renal failure, and another was asymptomatic but had microglobulinuria, suggesting that carrier females may manifest some symptoms. Wrong et al. (1992) noted other families with microglobulinuria and male predominance who may have had Dent disease (Buckalew et al., 1974; Carey and Hopfer, 1987; Long et al., 1990).
By linkage analysis of 2 families with Dent disease, including 1 family reported by Dent and Friedman (1964), Pook et al. (1993) identified a locus on chromosome Xp11. In 1 family, a microdeletion involving DXS255 permitted fine localization of the gene to a 4-cM interval on chromosome Xp11.22 flanked by TFE3 (314310) telomerically and DXS988 centromerically. Pook et al. (1993) noted that X-linked recessive nephrolithiasis had been mapped to the same region.
In affected members of 8 British families with Dent disease, Lloyd et al. (1996) identified different mutations in the CLCN5 gene (see, e.g., 300008.0001-300008.0004).
Hoopes et al. (2004) found that 19 (60%) of 32 families with a clinical diagnosis of Dent disease had mutations in the CLCN5 gene.
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. Almost all of the patients had the classic triad of low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis.
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.
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.
Before the causative gene was identified, the locus responsible for X-linked recessive nephrolithiasis described by Frymoyer et al. (1991) was considered to be at a locus separate from that responsible for Dent disease; hence they were treated as separate entities and given the symbols NPHL1 and NPHL2, respectively, on the recommendation of the human gene nomenclature committee.
Buckalew, V. M., Jr., Purvis, M. L., Shulman, M. G., Herndon, C. N., Rudman, D. Hereditary renal tubular acidosis: report of a 64 member kindred with variable clinical expression including idiopathic hypercalciuria. Medicine 53: 229-254, 1974. [PubMed: 4834851] [Full Text: https://doi.org/10.1097/00005792-197407000-00001]
Carey, D. E., Hopfer, S. M. Hypophosphatemic rickets with hypercalciuria and microglobulinuria. J. Pediat. 111: 860-863, 1987. [PubMed: 3316563] [Full Text: https://doi.org/10.1016/s0022-3476(87)80206-8]
Christensen, E. I., Devuyst, O., Dom, G., Nielsen, R., Van Der Smissen, P., Verroust, P., Leruth, M., Guggino, W. B., Courtoy, P. J. Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules. Proc. Nat. Acad. Sci. 100: 8472-8477, 2003. [PubMed: 12815097] [Full Text: https://doi.org/10.1073/pnas.1432873100]
Dent, C. E., Friedman, M. Hypercalciuric rickets associated with renal tubular damage. Arch. Dis. Child. 39: 240-249, 1964. [PubMed: 14169453] [Full Text: https://doi.org/10.1136/adc.39.205.240]
Frymoyer, P. A., Scheinman, S. J., Dunham, P. B., Jones, D. B., Hueber, P., Schroeder, E. T. X-linked recessive nephrolithiasis with renal failure. New Eng. J. Med. 325: 681-686, 1991. [PubMed: 1908057] [Full Text: https://doi.org/10.1056/NEJM199109053251003]
Gambaro, G., Vezzoli, G., Casari, G., Rampoldi, L., D'Angelo, A., Borghi, L. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am. J. Kidney Dis. 44: 963-986, 2004. [PubMed: 15558518] [Full Text: https://doi.org/10.1053/j.ajkd.2004.06.030]
Hoopes, R. R., Jr., Raja, K. M., Koich, A., Hueber, P., Reid, R., Knohl, S. J., Scheinman, S. J. Evidence for genetic heterogeneity in Dent's disease. Kidney Int. 65: 1615-1620, 2004. [PubMed: 15086899] [Full Text: https://doi.org/10.1111/j.1523-1755.2004.00571.x]
Lloyd, S. E., Pearce, S. H. S., Fisher, S. E., Steinmeyer, K., Schwappach, B., Scheinman, S. J., Harding, B., Bolino, A., Devoto, M., Goodyer, P., Rigden, S. P. A., Wrong, O., Jentsch, T. J., Craig, I. W., Thakker, R. V. A common molecular basis for three inherited kidney stone diseases. Nature 379: 445-449, 1996. [PubMed: 8559248] [Full Text: https://doi.org/10.1038/379445a0]
Long, W. S., Seashore, M. R., Siegel, N. J., Bia, M. J. Idiopathic Fanconi syndrome with progressive renal failure: a case report and discussion. Yale J. Biol. Med. 63: 15-28, 1990. [PubMed: 2356624]
Piwon, N., Gunther, W., Schwake, M., Bosl, M. R., Jentsch, T. J. ClC-5 Cl(-)-channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 408: 369-373, 2000. [PubMed: 11099045] [Full Text: https://doi.org/10.1038/35042597]
Pook, M. A., Wrong, O., Wooding, C., Norden, A. G. W., Feest, T. G., Thakker, R. V. Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. Hum. Molec. Genet. 2: 2129-2134, 1993. [PubMed: 8111383] [Full Text: https://doi.org/10.1093/hmg/2.12.2129]
Scheinman, S. J., Guay-Woodford, L. M., Thakker, R. V., Warnock, D. G. Genetic disorders of renal electrolyte transport. New Eng. J. Med. 340: 1177-1187, 1999. [PubMed: 10202170] [Full Text: https://doi.org/10.1056/NEJM199904153401507]
Scheinman, S. J. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int. 53: 3-17, 1998. [PubMed: 9452994] [Full Text: https://doi.org/10.1046/j.1523-1755.1998.00718.x]
Tosetto, E., Ceol, M,, Mezzabotta, F., Ammenti, A., Peruzzi, L., Caruso, M. R., Barbano, G., Vezzoli, G., Colussi, G., Vergine, G., Giordano, M., Glorioso, N., Degortes, S., Soldati, L., Sayer, J., D'Angelo, A., Anglani, F. Novel mutations of the CLCN5 gene including a complex allele and a 5-prime UTR mutation in Dent disease 1. (Letter) Clin. Genet. 76: 413-416, 2009. [PubMed: 19673950] [Full Text: https://doi.org/10.1111/j.1399-0004.2009.01212.x]
Wrong, O. M., Norden, A. G. W., Feest, T. G. Dent's disease: a familial renal tubular syndrome with hypercalciuria, tubular proteinuria, rickets, nephrocalcinosis and eventual renal failure. (Abstract) Quart. J. Med. 77: 1086-1087, 1990.
Wrong, O. M., Norden, A. G. W., Feest, T. G. Dent's disease: a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. Quart. J. Med. 87: 473-493, 1994. [PubMed: 7922301]
Wrong, O., Norden, A. G. W., Feest, T. G. X-linked recessive nephrolithiasis with renal failure. (Letter) New Eng. J. Med. 326: 1029, 1992. [PubMed: 1372109] [Full Text: https://doi.org/10.1056/NEJM199204093261516]