| Structural highlights
Disease
[CLCN5_HUMAN] Defects in CLCN5 are a cause of hypophosphatemic rickets, X-linked recessive (XLRHR) [MIM:300554]. XLRHR is a renal disease belonging to the 'Dent disease complex', a group of disorders characterized by proximal renal tubular defect, hypercalciuria, nephrocalcinosis, and renal insufficiency. The spectrum of phenotypic features is remarkably similar in the various disorders, except for differences in the severity of bone deformities and renal impairment. XLRH patients present with rickets or osteomalacia, hypophosphatemia due to decreased renal tubular phosphate reabsorption, hypercalciuria, and low molecular weight proteinuria. Patients develop nephrocalcinosis with progressive renal failure in adulthood. Female carriers may have asymptomatic hypercalciuria or hypophosphatemia only.[1] [2] Defects in CLCN5 are the cause of nephrolithiasis type 2 (NPHL2) [MIM:300009]; also known as Dent disease 1. NPHL2 is an X-linked recessive renal disease belonging to the 'Dent disease complex'. NPHL2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia.[3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] Defects in CLCN5 are the cause of nephrolithiasis type 1 (NPHL1) [MIM:310468]; also designated XRN. NPHL1 is an X-linked recessive renal disease belonging to the 'Dent disease complex'. NPHL1 presents with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia.[16] Defects in CLCN5 are the cause of low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN) [MIM:308990]. LMWPHN is an X-linked renal disease belonging to the 'Dent disease complex'. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure.[17] [18] [19]
Function
[CLCN5_HUMAN] Proton-coupled chloride transporter. Functions as antiport system and exchanges chloride ions against protons. Important for normal acidification of the endosome lumen. May play an important role in renal tubular function.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The ubiquitous CBS domains, which are found as part of cytoplasmic domains in the ClC family of chloride channels and transporters, have previously been identified as building blocks for regulatory nucleotide-binding sites. Here we report the structures of the cytoplasmic domain of the human transporter ClC-5 in complex with ATP and ADP. The nucleotides bind to a specific site in the protein. As determined by equilibrium dialysis, the affinities for ATP, ADP and AMP are in the high micromolar range. Point mutations that interfere with nucleotide binding change the transport behavior of a ClC-5 mutant expressed in Xenopus laevis oocytes. Our results establish the structural and energetic basis for the interaction of ClC-5 with nucleotides and provide a framework for future investigations.
Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5.,Meyer S, Savaresi S, Forster IC, Dutzler R Nat Struct Mol Biol. 2007 Jan;14(1):60-7. Epub 2006 Dec 31. PMID:17195847[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature. 1996 Feb 1;379(6564):445-9. PMID:8559248 doi:http://dx.doi.org/10.1038/379445a0
- ↑ Grand T, L'Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T, Genete M, Laghmani K, Teulon J, Lourdel S. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat. 2011 Apr;32(4):476-83. doi: 10.1002/humu.21467. PMID:21305656 doi:10.1002/humu.21467
- ↑ Smith AJ, Reed AA, Loh NY, Thakker RV, Lippiat JD. Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol. 2009 Feb;296(2):F390-7. doi:, 10.1152/ajprenal.90526.2008. Epub 2008 Nov 19. PMID:19019917 doi:10.1152/ajprenal.90526.2008
- ↑ Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature. 1996 Feb 1;379(6564):445-9. PMID:8559248 doi:http://dx.doi.org/10.1038/379445a0
- ↑ Grand T, L'Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T, Genete M, Laghmani K, Teulon J, Lourdel S. Heterogeneity in the processing of CLCN5 mutants related to Dent disease. Hum Mutat. 2011 Apr;32(4):476-83. doi: 10.1002/humu.21467. PMID:21305656 doi:10.1002/humu.21467
- ↑ Oudet C, Martin-Coignard D, Pannetier S, Praud E, Champion G, Hanauer A. A second family with XLRH displays the mutation S244L in the CLCN5 gene. Hum Genet. 1997 Jun;99(6):781-4. PMID:9187673
- ↑ Lloyd SE, Gunther W, Pearce SH, Thomson A, Bianchi ML, Bosio M, Craig IW, Fisher SE, Scheinman SJ, Wrong O, Jentsch TJ, Thakker RV. Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet. 1997 Aug;6(8):1233-9. PMID:9259268
- ↑ Schurman SJ, Norden AG, Scheinman SJ. X-linked recessive nephrolithiasis: presentation and diagnosis in children. J Pediatr. 1998 May;132(5):859-62. PMID:9602200
- ↑ Igarashi T, Gunther W, Sekine T, Inatomi J, Shiraga H, Takahashi S, Suzuki J, Tsuru N, Yanagihara T, Shimazu M, Jentsch TJ, Thakker RV. Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease. Kidney Int. 1998 Dec;54(6):1850-6. PMID:9853249 doi:10.1046/j.1523-1755.1998.00203.x
- ↑ Hoopes RR Jr, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ. Evidence for genetic heterogeneity in Dent's disease. Kidney Int. 2004 May;65(5):1615-20. PMID:15086899 doi:10.1111/j.1523-1755.2004.00571.x
- ↑ Tosetto E, Graziotto R, Artifoni L, Nachtigal J, Cascone C, Conz P, Piva M, Dell'Aquila R, De Paoli Vitali E, Citron L, Nalesso F, Antonello A, Vertolli U, Zagatti R, Lupo A, D'Angelo A, Anglani F, Gambaro G. Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy. J Hum Genet. 2006;51(1):25-30. Epub 2005 Oct 25. PMID:16247550 doi:10.1007/s10038-005-0317-x
- ↑ Tosetto E, Ghiggeri GM, Emma F, Barbano G, Carrea A, Vezzoli G, Torregrossa R, Cara M, Ripanti G, Ammenti A, Peruzzi L, Murer L, Ratsch IM, Citron L, Gambaro G, D'angelo A, Anglani F. Phenotypic and genetic heterogeneity in Dent's disease--the results of an Italian collaborative study. Nephrol Dial Transplant. 2006 Sep;21(9):2452-63. Epub 2006 Jul 5. PMID:16822791 doi:10.1093/ndt/gfl274
- ↑ Anglani F, Bernich P, Tosetto E, Cara M, Lupo A, Nalesso F, D'Angelo A, Gambaro G. Family history may be misleading in the diagnosis of Dent's disease. Urol Res. 2006 Feb;34(1):61-3. Epub 2006 Jan 14. PMID:16416111 doi:10.1007/s00240-005-0005-5
- ↑ Ramos-Trujillo E, Gonzalez-Acosta H, Flores C, Garcia-Nieto V, Guillen E, Gracia S, Vicente C, Espinosa L, Maseda MA, Santos F, Camacho JA, Claverie-Martin F. A missense mutation in the chloride/proton ClC-5 antiporter gene results in increased expression of an alternative mRNA form that lacks exons 10 and 11. Identification of seven new CLCN5 mutations in patients with Dent's disease. J Hum Genet. 2007;52(3):255-61. Epub 2007 Jan 30. PMID:17262170 doi:10.1007/s10038-007-0112-y
- ↑ Grand T, Mordasini D, L'Hoste S, Pennaforte T, Genete M, Biyeyeme MJ, Vargas-Poussou R, Blanchard A, Teulon J, Lourdel S. Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney Int. 2009 Nov;76(9):999-1005. doi: 10.1038/ki.2009.305. Epub 2009 Aug 5. PMID:19657328 doi:10.1038/ki.2009.305
- ↑ Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV. A common molecular basis for three inherited kidney stone diseases. Nature. 1996 Feb 1;379(6564):445-9. PMID:8559248 doi:http://dx.doi.org/10.1038/379445a0
- ↑ Smith AJ, Reed AA, Loh NY, Thakker RV, Lippiat JD. Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol. 2009 Feb;296(2):F390-7. doi:, 10.1152/ajprenal.90526.2008. Epub 2008 Nov 19. PMID:19019917 doi:10.1152/ajprenal.90526.2008
- ↑ Lloyd SE, Pearce SH, Gunther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV. Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J Clin Invest. 1997 Mar 1;99(5):967-74. PMID:9062355 doi:10.1172/JCI119262
- ↑ Takemura T, Hino S, Ikeda M, Okada M, Igarashi T, Inatomi J, Yoshioka K. Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent's disease). Am J Kidney Dis. 2001 Jan;37(1):138-143. PMID:11136179
- ↑ Meyer S, Savaresi S, Forster IC, Dutzler R. Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5. Nat Struct Mol Biol. 2007 Jan;14(1):60-7. Epub 2006 Dec 31. PMID:17195847 doi:10.1038/nsmb1188
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