P51795 (CLCN5_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	746 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	Antiport Ion transport Transport
Cellular component	Cell membrane Endosome Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	CBS domain Repeat Transmembrane Transmembrane helix
Ligand	ATP-binding Chloride Nucleotide-binding
PTM	Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	endocytosis Inferred from electronic annotation. Source: Compara excretion Traceable author statement Ref.10. Source: ProtInc
Cellular_component	Golgi 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 to plasma membrane Traceable author statement Ref.10. Source: ProtInc
Molecular_function	ATP 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: InterPro
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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 746

746

H(+)/Cl(-) exchange transporter 5

PRO_0000094446

Regions

Topological domain

1 – 54

54

Cytoplasmic By similarity

Transmembrane

55 – 92

38

Helical; By similarity

Transmembrane

138 – 161

24

Helical; By similarity

Intramembrane

170 – 177

8

Helical; By similarity

Transmembrane

186 – 205

20

Helical; By similarity

Transmembrane

211 – 230

20

Helical; By similarity

Intramembrane

242 – 254

13

Helical; By similarity

Intramembrane

258 – 266

9

Helical; By similarity

Transmembrane

278 – 296

19

Helical; By similarity

Transmembrane

319 – 345

27

Helical; By similarity

Transmembrane

352 – 372

21

Helical; By similarity

Transmembrane

428 – 448

21

Helical; By similarity

Transmembrane

453 – 472

20

Helical; By similarity

Intramembrane

500 – 514

15

Helical; By similarity

Intramembrane

515 – 517

3

Note=Loop between two helices; By similarity

Intramembrane

518 – 529

12

Helical; By similarity

Intramembrane

530 – 534

5

Note=Loop between two helices; By similarity

Transmembrane

535 – 552

18

Helical; By similarity

Topological domain

553 – 746

194

Cytoplasmic By similarity

Domain

586 – 650

65

CBS 1

Domain

682 – 742

61

CBS 2

Nucleotide binding

617 – 619

3

ATP

Nucleotide binding

724 – 727

4

ATP

Motif

167 – 171

5

Selectivity filter part_1 By similarity

Motif

209 – 213

5

Selectivity filter part_2 By similarity

Motif

453 – 457

5

Selectivity filter part_3 By similarity

Sites

Binding site

168

1

Chloride By similarity

Binding site

455

1

Chloride; via amide nitrogen By similarity

Binding site

558

1

Chloride By similarity

Binding site

596

1

ATP; via amide nitrogen and carbonyl oxygen

Site

211

1

Mediates proton transfer from the outer aqueous phase to the interior of the protein; involved in linking H(+) and Cl(-) transport By similarity

Site

268

1

Mediates proton transfer from the protein to the inner aqueous phase By similarity

Natural variations

Alternative sequence

1

1

M → MAMWQGAMDNRGFQQGSFSS FQNSSSDEDLMDIPATAMDF SMRDDVPPLDREVGEDKSYN GGGIGSSNRIM in isoform 2.

VSP_042046

Natural variant

30

1

R → RH in NPHL2. Ref.12

VAR_001615

Natural variant

57

1

G → V in NPHL2; alters targeting to endosomes. Ref.12 Ref.14 Ref.22

VAR_001616

Natural variant

142

1

M → I.
Corresponds to variant rs34800648 [ dbSNP | Ensembl ].

VAR_048694

Natural variant

179

1

G → D in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23

VAR_065591

Natural variant

200

1

L → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.10 Ref.23

VAR_001617

Natural variant

203

1

S → L in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23

VAR_065592

Natural variant

212

1

G → 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 variant

219

1

C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.21 Ref.23

VAR_065594

Natural variant

221

1

C → R in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.17 Ref.23

VAR_065595

Natural variant

225

1

L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.24

VAR_065596

Natural variant

244

1

S → 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 variant

260

1

G → 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 variant

267

1

E → A in NPHL2. Ref.17

VAR_065598

Natural variant

267

1

Missing in NPHL2. Ref.19

VAR_065599

Natural variant

270

1

S → G in NPHL2. Ref.17

VAR_065600

Natural variant

270

1

S → R in NPHL2; retained in the endoplasmic reticulum; alters protein stability; associated with an abolishment of chloride current. Ref.15 Ref.22

VAR_065601

Natural variant

272

1

Y → 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 variant

273

1

F → L in NPHL2. Ref.21

VAR_065603

Natural variant

278

1

L → 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 variant

280

1

R → P in LMWPHN; 70% reduction in chloride transport activity and alters targeting to endosomes. Ref.13 Ref.22

VAR_001619

Natural variant

340

1

N → K in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.19 Ref.24

VAR_065605

Natural variant

462

1

G → D in NPHL2. Ref.17

VAR_065606

Natural variant

469

1

L → P in NPHL2; retained in the endoplasmic reticulum; improperly N-glycosylated and non-functional. Ref.23

VAR_065607

Natural variant

506

1

G → E in NPHL1. Ref.10

VAR_001620

Natural variant

512

1

G → R in NPHL2; abolishes the chloride currents. Ref.12

VAR_001621

Natural variant

513

1

G → E in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.22

VAR_065608

Natural variant

513

1

G → R in NPHL2. Ref.17 Ref.24

VAR_065609

Natural variant

516

1

R → W in NPHL2; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.17 Ref.22

VAR_065610

Natural variant

520

1

S → P in NPHL2. Ref.10

VAR_001622

Natural variant

524

1

I → K in LMWPHN; causes retention in the endoplasmic reticulum and alters protein stability; total loss of function. Ref.16 Ref.22

VAR_065611

Natural variant

527

1

E → D in NPHL2; abolishes the chloride currents; total loss of function. Ref.12 Ref.22

VAR_001623

Natural variant

545

1

S → N in NPHL2. Ref.17

VAR_065612

Natural variant

546

1

K → 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 variant

547

1

W → 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 variant

657

1

T → S in NPHL2. Ref.17

VAR_065615

Experimental info

Mutagenesis

211

1

E → A: Abolishes proton transport, but not chloride transport. Ref.9

Mutagenesis

617

1

Y → A: Strongly decreased affinity for ATP, but no effect on chloride transport. Ref.9

Mutagenesis

618

1

S → A: No effect ATP binding or chloride transport. Ref.9

Mutagenesis

672

1

Y → A: Abolishes interaction with NEDD4 and NEDD4L. Ref.8

Mutagenesis

727

1

D → A: Strongly decreased affinity for ATP, but no effect on chloride transport. Ref.9

Sequence conflict

732

1

I → V in BAG51748. Ref.2

Secondary structure

1

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746

Helix Strand Turn

Details...

Helix

582 – 585

4

Beta strand

586 – 588

3

Beta strand

598 – 601

4

Helix

605 – 614

10

Beta strand

618 – 624

7

Turn

626 – 628

3

Beta strand

630 – 636

7

Helix

637 – 648

12

Beta strand

659 – 661

3

Beta strand

663 – 665

3

Helix

680 – 682

3

Beta strand

683 – 686

4

Beta strand

689 – 691

3

Helix

696 – 706

11

Beta strand

709 – 715

7

Beta strand

718 – 724

7

Helix

725 – 735

11

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: EF913C5BA40C85D8	FASTA	746	83,147
	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
	Isoform 2 [UniParc]. Checksum: C9C63CC222959F35	FASTA	816	90,785
	10 20 30 40 50 60 MAMWQGAMDN RGFQQGSFSS FQNSSSDEDL MDIPATAMDF SMRDDVPPLD REVGEDKSYN 70 80 90 100 110 120 GGGIGSSNRI MDFLEEPIPG VGTYDDFNTI DWVREKSRDR DRHREITNKS KESTWALIHS 130 140 150 160 170 180 VSDAFSGWLL MLLIGLLSGS LAGLIDISAH WMTDLKEGIC TGGFWFNHEH CCWNSEHVTF 190 200 210 220 230 240 EERDKCPEWN SWSQLIISTD EGAFAYIVNY FMYVLWALLF AFLAVSLVKV FAPYACGSGI 250 260 270 280 290 300 PEIKTILSGF IIRGYLGKWT LVIKTITLVL AVSSGLSLGK EGPLVHVACC CGNILCHCFN 310 320 330 340 350 360 KYRKNEAKRR EVLSAAAAAG VSVAFGAPIG GVLFSLEEVS YYFPLKTLWR SFFAALVAAF 370 380 390 400 410 420 TLRSINPFGN SRLVLFYVEF HTPWHLFELV PFILLGIFGG LWGALFIRTN IAWCRKRKTT 430 440 450 460 470 480 QLGKYPVIEV LVVTAITAIL AFPNEYTRMS TSELISELFN DCGLLDSSKL CDYENRFNTS 490 500 510 520 530 540 KGGELPDRPA GVGVYSAMWQ LALTLILKIV ITIFTFGMKI PSGLFIPSMA VGAIAGRLLG 550 560 570 580 590 600 VGMEQLAYYH QEWTVFNSWC SQGADCITPG LYAMVGAAAC LGGVTRMTVS LVVIMFELTG 610 620 630 640 650 660 GLEYIVPLMA AAMTSKWVAD ALGREGIYDA HIRLNGYPFL EAKEEFAHKT LAMDVMKPRR 670 680 690 700 710 720 NDPLLTVLTQ DSMTVEDVET IISETTYSGF PVVVSRESQR LVGFVLRRDL IISIENARKK 730 740 750 760 770 780 QDGVVSTSII YFTEHSPPLP PYTPPTLKLR NILDLSPFTV TDLTPMEIVV DIFRKLGLRQ 790 800 810 CLVTHNGRLL GIITKKDVLK HIAQMANQDP DSILFN

References

	« Hide 'large scale' referencesShow '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. , 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. , 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.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X91906 mRNA. Translation: CAA63000.1.
AK056560 mRNA. Translation: BAG51748.1.
AL663118 Genomic DNA. Translation: CAI41555.1.
BC130429 mRNA. Translation: AAI30430.1.
BC130431 mRNA. Translation: AAI30432.1.
X81836 mRNA. Translation: CAA57430.1.
BK000969 mRNA. Translation: DAA01544.1.

IPI

IPI00294056.

PIR

I37277.

RefSeq

NP_000075.1. NM_000084.3.
NP_001121370.1. NM_001127898.2.

UniGene

Hs.166486.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2J9L	X-ray	2.30	A/B/C/D/E/F	571-746	[»]
2JA3	X-ray	3.05	A/B/C/D/E/F	571-746	[»]

ProteinModelPortal

P51795.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29263N.

MINT

MINT-1524912.

STRING

9606.ENSP00000365256.

Polymorphism databases

DMDM

1705908.

Proteomic databases

PaxDb

P51795.

PRIDE

P51795.

Protocols and materials databases

DNASU

1184.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000307367; ENSP00000304257; ENSG00000171365.
ENST00000376088; ENSP00000365256; ENSG00000171365.
ENST00000376091; ENSP00000365259; ENSG00000171365.
ENST00000376108; ENSP00000365276; ENSG00000171365.
ENST00000594930; ENSP00000470026; ENSG00000269240.
ENST00000598870; ENSP00000469532; ENSG00000269240.
ENST00000600725; ENSP00000470125; ENSG00000269240.
ENST00000601418; ENSP00000471330; ENSG00000269240.

GeneID

1184.

KEGG

hsa:1184.

UCSC

uc004doq.1. human.
uc004dos.1. human.

Organism-specific databases

CTD

1184.

GeneCards

GC0XP049687.

HGNC

HGNC:2023. CLCN5.

HPA

HPA000401.

MIM

300008. gene.
300009. phenotype.
300554. phenotype.
308990. phenotype.
310468. phenotype.

neXtProt

NX_P51795.

Orphanet

93622. Dent disease type 1.

PharmGKB

PA26550.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0038.

HOGENOM

HOG000164493.

HOVERGEN

HBG050984.

InParanoid

P51795.

KO

K05012.

OMA

SYNGGGI.

OrthoDB

EOG4XD3QH.

PhylomeDB

P51795.

Gene expression databases

Bgee

P51795.

CleanEx

HS_CLCN5.

Genevestigator

P51795.

GermOnline

ENSG00000171365. Homo sapiens.

Family and domain databases

Gene3D

1.10.3080.10. 3 hits.

InterPro

IPR014743. Cl-channel_core.
IPR001807. Cl-channel_volt-gated.
IPR002247. Cl_channel-5.
IPR000644. Cysta_beta_synth_core.
[Graphical view]

Pfam

PF00571. CBS. 2 hits.
PF00654. Voltage_CLC. 1 hit.
[Graphical view]

PRINTS

PR00762. CLCHANNEL.
PR01116. CLCHANNEL5.

SMART

SM00116. CBS. 2 hits.
[Graphical view]

SUPFAM

SSF81340. Cl-channel_core. 1 hit.

PROSITE

PS51371. CBS. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P51795.

GenomeRNAi

1184.

NextBio

4894.

SOURCE

Search...

Entry information

Entry name

CLCN5_HUMAN

Accession

Primary (citable) accession number: P51795
Secondary accession number(s): A1L475 , B3KPN6, Q5JQD5, Q7RTN8

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 29, 2013
This is version 129 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.