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P51795 (CLCN5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
H(+)/Cl(-) exchange transporter 5
Alternative name(s):
Chloride channel protein 5
Short name=ClC-5
Chloride transporter ClC-5
Gene names
Name:CLCN5
Synonyms:CLCK2
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length746 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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.

Subunit structure

Interacts with NEDD4 and NEDD4L. Ref.8

Subcellular location

Golgi apparatus membrane; Multi-pass membrane protein. Endosome membrane; Multi-pass membrane protein. Cell membrane; Multi-pass membrane protein Ref.22.

Tissue specificity

Kidney. Moderately expressed in aortic vascular smooth muscle and endothelial cells, and at a slightly higher level in the coronary vascular smooth muscle. Ref.7

Post-translational modification

Ubiquitinated by NEDD4L in the presence of albumin; which promotes endocytosis and proteasomal degradation. Ref.8

Involvement in disease

Hypophosphatemic rickets, X-linked recessive (XLRHR) [MIM:300554]: 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.24

Nephrolithiasis 2 (NPHL2) [MIM:300009]: An X-linked recessive 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. Nephrolithiasis type 2 patients manifest hypercalciuria, hypophosphatemia, aminoaciduria, nephrocalcinosis and nephrolithiasis, renal insufficiency leading to renal failure in adulthood, rickets (33% of patients) and osteomalacia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.11 Ref.12 Ref.14 Ref.15 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.23 Ref.24

Nephrolithiasis 1 (NPHL1) [MIM:310468]: An X-linked recessive 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. Nephrolithiasis type 1 presents with hypercalciuria, nephrocalcinosis, renal stones and renal insufficiency. Patients lack urinary acidification defects, rickets, and osteomalacia.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10

Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis (LMWPHN) [MIM:308990]: An X-linked 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. LMWPHN is a slowly progressive disorder. Patients tend to have hypercalciuric nephrocalcinosis without rickets or renal failure.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.13 Ref.16 Ref.22

Miscellaneous

The CLC channel family contains both chloride channels and proton-coupled anion transporters that exchange chloride or another anion for protons. The absence of conserved gating glutamate residues is typical for family members that function as channels.

Sequence similarities

Belongs to the chloride channel (TC 2.A.49) family. ClC-5/CLCN5 subfamily. [View classification]

Contains 2 CBS domains.

Ontologies

Keywords
   Biological processAntiport
Ion transport
Transport
   Cellular componentCell membrane
Endosome
Golgi apparatus
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainCBS domain
Repeat
Transmembrane
Transmembrane helix
   LigandATP-binding
Chloride
Nucleotide-binding
   PTMUbl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processchloride transmembrane transport

Traceable author statement Ref.10. Source: GOC

endocytosis

Inferred from electronic annotation. Source: Ensembl

excretion

Traceable author statement Ref.10. Source: ProtInc

ion transmembrane transport

Traceable author statement. Source: Reactome

transmembrane transport

Traceable author statement. Source: Reactome

transport

Traceable author statement Ref.10. Source: ProtInc

   Cellular_componentGolgi membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

apical part of cell

Inferred from direct assay PubMed 14675051. Source: UniProtKB

endosome membrane

Traceable author statement. Source: Reactome

integral component of plasma membrane

Traceable author statement Ref.10. Source: ProtInc

lysosomal membrane

Inferred from direct assay PubMed 17897319. Source: UniProtKB

membrane

Inferred from direct assay PubMed 14675051. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

antiporter activity

Inferred from electronic annotation. Source: UniProtKB-KW

chloride channel activity

Traceable author statement Ref.10. Source: ProtInc

voltage-gated chloride channel activity

Inferred from electronic annotation. Source: Ensembl

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P51795-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P51795-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MAMWQGAMDNRGFQQGSFSSFQNSSSDEDLMDIPATAMDFSMRDDVPPLDREVGEDKSYNGGGIGSSNRIM

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 746746H(+)/Cl(-) exchange transporter 5
PRO_0000094446

Regions

Topological domain1 – 5454Cytoplasmic By similarity
Transmembrane55 – 9238Helical; By similarity
Transmembrane138 – 16124Helical; By similarity
Intramembrane170 – 1778Helical; By similarity
Transmembrane186 – 20520Helical; By similarity
Transmembrane211 – 23020Helical; By similarity
Intramembrane242 – 25413Helical; By similarity
Intramembrane258 – 2669Helical; By similarity
Transmembrane278 – 29619Helical; By similarity
Transmembrane319 – 34527Helical; By similarity
Transmembrane352 – 37221Helical; By similarity
Transmembrane428 – 44821Helical; By similarity
Transmembrane453 – 47220Helical; By similarity
Intramembrane500 – 51415Helical; By similarity
Intramembrane515 – 5173Note=Loop between two helices; By similarity
Intramembrane518 – 52912Helical; By similarity
Intramembrane530 – 5345Note=Loop between two helices; By similarity
Transmembrane535 – 55218Helical; By similarity
Topological domain553 – 746194Cytoplasmic By similarity
Domain586 – 65065CBS 1
Domain682 – 74261CBS 2
Nucleotide binding617 – 6193ATP
Nucleotide binding724 – 7274ATP
Motif167 – 1715Selectivity filter part_1 By similarity
Motif209 – 2135Selectivity filter part_2 By similarity
Motif453 – 4575Selectivity filter part_3 By similarity

Sites

Binding site1681Chloride By similarity
Binding site4551Chloride; via amide nitrogen By similarity
Binding site5581Chloride By similarity
Binding site5961ATP; via amide nitrogen and carbonyl oxygen
Site2111Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transport By similarity
Site2681Mediates proton transfer from the protein to the inner aqueous phase By similarity

Natural variations

Alternative sequence11M → MAMWQGAMDNRGFQQGSFSS FQNSSSDEDLMDIPATAMDF SMRDDVPPLDREVGEDKSYN GGGIGSSNRIM in isoform 2.
VSP_042046
Natural variant301R → RH in NPHL2. Ref.12
VAR_001615
Natural variant571G → V in NPHL2; alters targeting to endosomes. Ref.12 Ref.14 Ref.22
VAR_001616
Natural variant1421M → I.
Corresponds to variant rs34800648 [ dbSNP | Ensembl ].
VAR_048694
Natural variant1791G → D in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23
VAR_065591
Natural variant2001L → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.10 Ref.23
VAR_001617
Natural variant2031S → L in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23
VAR_065592
Natural variant2121G → A in NPHL2; trafficks normally to the cell surface and to early endosomes; endergoes complex glycosylation at the cell surface like wild-type protein but exhibits significant reductions in outwardly rectifying ion currents. Ref.23
VAR_065593
Natural variant2191C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.21 Ref.23
VAR_065594
Natural variant2211C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.17 Ref.23
VAR_065595
Natural variant2251L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.24
VAR_065596
Natural variant2441S → L in XLRHR; trafficks normally to the cell surface and to early endosomes; displays complex glycosylation at the cell surface like wild-type protein; exhibits reduced current. Ref.10 Ref.11 Ref.17 Ref.19 Ref.20 Ref.24
VAR_001618
Natural variant2601G → V in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. Ref.18 Ref.19 Ref.20 Ref.24
VAR_065597
Natural variant2671E → A in NPHL2. Ref.17
VAR_065598
Natural variant2671Missing in NPHL2. Ref.19
VAR_065599
Natural variant2701S → G in NPHL2. Ref.17
VAR_065600
Natural variant2701S → R in NPHL2; retained in the endoplasmic reticulum; alters protein stability; associated with an abolition of chloride current. Ref.15 Ref.22
VAR_065601
Natural variant2721Y → C in NPHL2; trafficks normally to the cell surface and to early endosomes and displays complex glycosylation at the cell surface like wild-type protein; exhibits no current. Ref.19 Ref.24
VAR_065602
Natural variant2731F → L in NPHL2. Ref.21
VAR_065603
Natural variant2781L → F in NPHL2; associated with a marked reduction to about 30% of wild-type chloride currents; no significant differences between the expression of the mutated and wild-type protein. Ref.15 Ref.24
VAR_065604
Natural variant2801R → P in LMWPHN; 70% reduction in chloride transport activity and alters targeting to endosomes. Ref.13 Ref.22
VAR_001619
Natural variant3401N → K in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.19 Ref.24
VAR_065605
Natural variant4621G → D in NPHL2. Ref.17
VAR_065606
Natural variant4691L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23
VAR_065607
Natural variant5061G → E in NPHL1. Ref.10
VAR_001620
Natural variant5121G → R in NPHL2; abolishes the chloride currents. Ref.12
VAR_001621
Natural variant5131G → E in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.22
VAR_065608
Natural variant5131G → R in NPHL2. Ref.17 Ref.24
VAR_065609
Natural variant5161R → W in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.17 Ref.22
VAR_065610
Natural variant5201S → P in NPHL2. Ref.10
VAR_001622
Natural variant5241I → K in LMWPHN; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.16 Ref.22
VAR_065611
Natural variant5271E → D in NPHL2; abolishes the chloride currents; total loss of function. Ref.12 Ref.22
VAR_001623
Natural variant5451S → N in NPHL2. Ref.17
VAR_065612
Natural variant5461K → E in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows abolished current at the plasma membrane. Ref.17 Ref.24
VAR_065613
Natural variant5471W → G in NPHL2; delayed in processing of the protein and decrease in the stability of the mature complex glycosylated form causing lower cell surface expression; the early endosome distribution is normal; shows reduced current at the plasma membrane. Ref.21 Ref.24
VAR_065614
Natural variant6571T → S in NPHL2. Ref.17
Corresponds to variant rs144207967 [ dbSNP | Ensembl ].
VAR_065615

Experimental info

Mutagenesis2111E → A: Abolishes proton transport, but not chloride transport. Ref.9
Mutagenesis6171Y → A: Strongly decreased affinity for ATP, but no effect on chloride transport. Ref.9
Mutagenesis6181S → A: No effect ATP binding or chloride transport. Ref.9
Mutagenesis6721Y → A: Abolishes interaction with NEDD4 and NEDD4L. Ref.8
Mutagenesis7271D → A: Strongly decreased affinity for ATP, but no effect on chloride transport. Ref.9
Sequence conflict7321I → V in BAG51748. Ref.2

Secondary structure

............................... 746
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified October 1, 1996. Version 1.
Checksum: EF913C5BA40C85D8

FASTA74683,147
        10         20         30         40         50         60 
MDFLEEPIPG VGTYDDFNTI DWVREKSRDR DRHREITNKS KESTWALIHS VSDAFSGWLL 

        70         80         90        100        110        120 
MLLIGLLSGS LAGLIDISAH WMTDLKEGIC TGGFWFNHEH CCWNSEHVTF EERDKCPEWN 

       130        140        150        160        170        180 
SWSQLIISTD EGAFAYIVNY FMYVLWALLF AFLAVSLVKV FAPYACGSGI PEIKTILSGF 

       190        200        210        220        230        240 
IIRGYLGKWT LVIKTITLVL AVSSGLSLGK EGPLVHVACC CGNILCHCFN KYRKNEAKRR 

       250        260        270        280        290        300 
EVLSAAAAAG VSVAFGAPIG GVLFSLEEVS YYFPLKTLWR SFFAALVAAF TLRSINPFGN 

       310        320        330        340        350        360 
SRLVLFYVEF HTPWHLFELV PFILLGIFGG LWGALFIRTN IAWCRKRKTT QLGKYPVIEV 

       370        380        390        400        410        420 
LVVTAITAIL AFPNEYTRMS TSELISELFN DCGLLDSSKL CDYENRFNTS KGGELPDRPA 

       430        440        450        460        470        480 
GVGVYSAMWQ LALTLILKIV ITIFTFGMKI PSGLFIPSMA VGAIAGRLLG VGMEQLAYYH 

       490        500        510        520        530        540 
QEWTVFNSWC SQGADCITPG LYAMVGAAAC LGGVTRMTVS LVVIMFELTG GLEYIVPLMA 

       550        560        570        580        590        600 
AAMTSKWVAD ALGREGIYDA HIRLNGYPFL EAKEEFAHKT LAMDVMKPRR NDPLLTVLTQ 

       610        620        630        640        650        660 
DSMTVEDVET IISETTYSGF PVVVSRESQR LVGFVLRRDL IISIENARKK QDGVVSTSII 

       670        680        690        700        710        720 
YFTEHSPPLP PYTPPTLKLR NILDLSPFTV TDLTPMEIVV DIFRKLGLRQ CLVTHNGRLL 

       730        740 
GIITKKDVLK HIAQMANQDP DSILFN 

« Hide

Isoform 2 [UniParc].

Checksum: C9C63CC222959F35
Show »

FASTA81690,785

References

« Hide 'large scale' references
[1]"Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis)."
Fisher S.E., van Bakel I., Lloyd S.E., Pearce S.H.S., Thakker R.V., Craig I.W.
Genomics 29:598-606(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Kidney.
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
[3]"The DNA sequence of the human X chromosome."
Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. expand/collapse author list , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R.
Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[5]"Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis)."
Fisher S., Black G.C.M., Lloyd S.E., Hatchwell E., Wrong O., Thakker R.V., Craig I.W.
Hum. Mol. Genet. 3:2053-2059(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 487-746.
Tissue: Kidney.
[6]"Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent's phenotype in patients without mutations in the short variant."
Ludwig M., Waldegger S., Nuutinen M., Bokenkamp A., Reissinger A., Steckelbroeck S., Utsch B.
Kidney Blood Press. Res. 26:176-184(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION (ISOFORM 2), ALTERNATIVE SPLICING.
[7]"Expression of CLCN voltage-gated chloride channel genes in human blood vessels."
Lamb F.S., Clayton G.H., Liu B.-X., Smith R.L., Barna T.J., Schutte B.C.
J. Mol. Cell. Cardiol. 31:657-666(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY.
Tissue: Aortic endothelium and Vascular smooth muscle.
[8]"Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells."
Hryciw D.H., Ekberg J., Lee A., Lensink I.L., Kumar S., Guggino W.B., Cook D.I., Pollock C.A., Poronnik P.
J. Biol. Chem. 279:54996-55007(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH NEDD4 AND NEDD4L, UBIQUITINATION, MUTAGENESIS OF TYR-672.
[9]"Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5."
Meyer S., Savaresi S., Forster I.C., Dutzler R.
Nat. Struct. Mol. Biol. 14:60-67(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 570-746 IN COMPLEXES WITH ATP AND ADP, MUTAGENESIS OF GLU-211; TYR-617; SER-618 AND ASP-727.
[10]"A common molecular basis for three inherited kidney stone diseases."
Lloyd S.E., Pearce S.H.S., Fisher S.E., Steinmeyer K., Schwappach B., Schelnman 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.
Nature 379:445-449(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT XLRHR LEU-244, VARIANT NPHL1 GLU-506, VARIANTS NPHL2 ARG-200 AND PRO-520.
[11]"A second family with XLRH displays the mutation S244L in the CLCN5 gene."
Oudet C., Martin-Coignard D., Pannetier S., Praud E., Champion G., Hanauer A.
Hum. Genet. 99:781-784(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT NPHL2 LEU-244.
[12]"Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders."
Lloyd S.E., Guenther W., Pearce S.H.S., Thomson A., Bianchi M.L., Bosio M., Craig I.W., Fisher S.E., Scheinman S.J., Wrong O., Jentsch T.J., Thakker R.V.
Hum. Mol. Genet. 6:1233-1239(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 HIS-30 INS; VAL-57; ARG-512 AND ASP-527.
[13]"Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5)."
Lloyd S.E., Pearce S.H.S., Guenther W., Kawaguchi H., Igarashi T., Jentsch T.J., Thakker R.V.
J. Clin. Invest. 99:967-974(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LMWPHN PRO-280.
[14]"X-linked recessive nephrolithiasis: presentation and diagnosis in children."
Schurman S.J., Norden A.G., Scheinman S.J.
J. Pediatr. 132:859-862(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT NPHL2 VAL-57.
[15]"Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent'sJapan disease."
Igarashi T., Gunther W., Sekine T., Inatomi J., Shiraga H., Takahashi S., Suzuki J., Tsuru N., Yanagihara T., Shimazu M., Jentsch T.J., Thakker R.V.
Kidney Int. 54:1850-1856(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 ARG-270 AND PHE-278, CHARACTERIZATION OF VARIANTS NPHL2 ARG-270 AND PHE-278.
[16]"Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent's disease)."
Takemura T., Hino S., Ikeda M., Okada M., Igarashi T., Inatomi J., Yoshioka K.
Am. J. Kidney Dis. 37:138-143(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT LMWPHN LYS-524.
[17]"Evidence for genetic heterogeneity in Dent's disease."
Hoopes R.R. Jr., Raja K.M., Koich A., Hueber P., Reid R., Knohl S.J., Scheinman S.J.
Kidney Int. 65:1615-1620(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 ARG-221; LEU-244; ALA-267; GLY-270; ASP-462; ARG-513; TRP-516; ASN-545; GLU-546 AND SER-657.
[18]"Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy."
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.
J. Hum. Genet. 51:25-30(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT NPHL2 VAL-260.
[19]"Phenotypic and genetic heterogeneity in Dent's disease -- the results of an Italian collaborative study."
Tosetto E., Ghiggeri G.M., Emma F., Barbano G., Carrea A., Vezzoli G., Torregrossa R., Cara M., Ripanti G., Ammenti A., Peruzzi L., Murer L., Ratsch I.M., Citron L., Gambaro G., D'angelo A., Anglani F.
Nephrol. Dial. Transplant. 21:2452-2463(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 LEU-244; VAL-260; GLU-267 DEL; CYS-272 AND LYS-340.
[20]"Family history may be misleading in the diagnosis of Dent's disease."
Anglani F., Bernich P., Tosetto E., Cara M., Lupo A., Nalesso F., D'Angelo A., Gambaro G.
Urol. Res. 34:61-63(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 LEU-244 AND VAL-260.
[21]"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."
Ramos-Trujillo E., Gonzalez-Acosta H., Flores C., Garcia-Nieto V., Guillen E., Gracia S., Vicente C., Espinosa L., Maseda M.A., Santos F., Camacho J.A., Claverie-Martin F.
J. Hum. Genet. 52:255-261(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 ARG-219; LEU-273 AND GLY-547.
[22]"Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure."
Smith A.J., Reed A.A., Loh N.Y., Thakker R.V., Lippiat J.D.
Am. J. Physiol. 296:F390-F397(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS NPHL2 VAL-57; ARG-270; GLU-513; TRP-516 AND ASP-527, CHARACTERIZATION OF VARIANTS LMWPHN PRO-280 AND LYS-524, SUBCELLULAR LOCATION.
[23]"Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing."
Grand T., Mordasini D., L'Hoste S., Pennaforte T., Genete M., Biyeyeme M.J., Vargas-Poussou R., Blanchard A., Teulon J., Lourdel S.
Kidney Int. 76:999-1005(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHL2 ASP-179; LEU-203; ALA-212 AND PRO-469, CHARACTERIZATION OF VARIANTS NPHL2 ASP-179; ARG-200; LEU-203; ALA-212; ARG-219; ARG-221 AND PRO-469.
[24]"Heterogeneity in the processing of CLCN5 mutants related to Dent disease."
Grand T., L'Hoste S., Mordasini D., Defontaine N., Keck M., Pennaforte T., Genete M., Laghmani K., Teulon J., Lourdel S.
Hum. Mutat. 32:476-483(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS NPHL2 PRO-225; VAL-260; CYS-272; PHE-278; LYS-340; ARG-513; GLU-546 AND GLY-547, CHARACTERIZATION OF VARIANT XLRHR LEU-244.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X91906 mRNA. Translation: CAA63000.1.
AK056560 mRNA. Translation: BAG51748.1.
FO393402 Genomic DNA. No translation available.
BC130429 mRNA. Translation: AAI30430.1.
BC130431 mRNA. Translation: AAI30432.1.
X81836 mRNA. Translation: CAA57430.1.
BK000969 mRNA. Translation: DAA01544.1.
CCDSCCDS14328.1. [P51795-1]
CCDS48115.1. [P51795-2]
PIRI37277.
RefSeqNP_000075.1. NM_000084.4. [P51795-1]
NP_001121370.1. NM_001127898.3. [P51795-2]
NP_001121371.1. NM_001127899.3. [P51795-2]
NP_001269092.1. NM_001282163.1.
UniGeneHs.166486.
Hs.745501.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2J9LX-ray2.30A/B/C/D/E/F571-746[»]
2JA3X-ray3.05A/B/C/D/E/F571-746[»]
ProteinModelPortalP51795.
SMRP51795. Positions 124-737.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid107598. 3 interactions.
DIPDIP-29263N.
MINTMINT-1524912.
STRING9606.ENSP00000365256.

Proteomic databases

MaxQBP51795.
PaxDbP51795.
PRIDEP51795.

Protocols and materials databases

DNASU1184.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000307367; ENSP00000304257; ENSG00000171365. [P51795-1]
ENST00000376088; ENSP00000365256; ENSG00000171365. [P51795-2]
ENST00000376091; ENSP00000365259; ENSG00000171365. [P51795-2]
ENST00000376108; ENSP00000365276; ENSG00000171365. [P51795-1]
ENST00000594930; ENSP00000470026; ENSG00000269240. [P51795-2]
ENST00000598870; ENSP00000469532; ENSG00000269240. [P51795-1]
ENST00000600725; ENSP00000470125; ENSG00000269240. [P51795-2]
ENST00000601418; ENSP00000471330; ENSG00000269240. [P51795-1]
GeneID1184.
KEGGhsa:1184.
UCSCuc004doq.1. human. [P51795-2]
uc004dos.1. human. [P51795-1]

Organism-specific databases

CTD1184.
GeneCardsGC0XP049687.
GeneReviewsCLCN5.
HGNCHGNC:2023. CLCN5.
HPAHPA000401.
MIM300008. gene.
300009. phenotype.
300554. phenotype.
308990. phenotype.
310468. phenotype.
neXtProtNX_P51795.
Orphanet93622. Dent disease type 1.
PharmGKBPA26550.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0038.
HOGENOMHOG000164493.
HOVERGENHBG050984.
InParanoidP51795.
KOK05012.
OMALMDIPGT.
OrthoDBEOG7MWGXT.
PhylomeDBP51795.
TreeFamTF313867.

Enzyme and pathway databases

ReactomeREACT_15518. Transmembrane transport of small molecules.

Gene expression databases

BgeeP51795.
CleanExHS_CLCN5.
GenevestigatorP51795.

Family and domain databases

Gene3D1.10.3080.10. 3 hits.
InterProIPR000644. CBS_dom.
IPR014743. Cl-channel_core.
IPR001807. Cl-channel_volt-gated.
IPR002247. Cl_channel-5.
[Graphical view]
PfamPF00571. CBS. 2 hits.
PF00654. Voltage_CLC. 1 hit.
[Graphical view]
PRINTSPR00762. CLCHANNEL.
PR01116. CLCHANNEL5.
SMARTSM00116. CBS. 2 hits.
[Graphical view]
SUPFAMSSF81340. SSF81340. 3 hits.
PROSITEPS51371. CBS. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP51795.
GeneWikiCLCN5.
GenomeRNAi1184.
NextBio4894.
PROP51795.
SOURCESearch...

Entry information

Entry nameCLCN5_HUMAN
AccessionPrimary (citable) accession number: P51795
Secondary accession number(s): A1L475 expand/collapse secondary AC list , B3KPN6, Q5JQD5, Q7RTN8
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: July 9, 2014
This is version 142 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome X

Human chromosome X: entries, gene names and cross-references to MIM