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CLDN6 (claudin 6)

Written2012-12Erika Patricia Rendon-Huerta, Ana C Torres-Martínez, Luis Montaño
Departamento de Bioquimica, Facultad de Medicina, UNAM, 04510, Mexico City, Mexico

(Note : for Links provided by Atlas : click)


LocusID (NCBI) 9074
Atlas_Id 50974
Location 16p13.3  [Link to chromosome band 16p13]
Location_base_pair Starts at 3014712 and ends at 3018183 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping CLDN6.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PKMYT1 (16p13.3) / CLDN6 (16p13.3)


Description 5360 base-pairs DNA linear, starts at 3064713 and ends at 3070072 bp from pter with minus strand orientation. This gene contains 2 exons.
Transcription The transcription produces 2 alternatively spliced mRNA variants:
- NM_021195.4: transcript length: 2139 bp,
- ENST00000396925: transcript length: 1739 bp.
Pseudogene Pseudogene of claudin 6 (LOC284620) is located on chromosome 1 (859 bp).


Description The transcription of this gene gives 1 spliced mRNA that encodes 1 protein isoform with 220 aa and 23292 Da of molecular weight.
Expression Claudin-6 expression is mainly found in mouse embryonic stem cells (ESC), epithelial lineage cells during early development and primitive germ cell tumours such as spermatocytic seminoma, embryonal carcinoma, yolk sac tumour, choriocarcinoma, immature teratoma, mature teratoma and classic seminoma. Its expression is very weak or absent in adult mouse. In rat choroid plexus development claudin-6 is expressed postnatal between day 6 and 9. Claudin-6 expression is associated to ERα expression in human breast cancer and is inactivated by CpG island DNA hypermethylation.
Localisation This transmembrane protein is located in the tight junction during embryogenesis and, in certain cancer pathologies. It can be found in the cell cytoplasm and in the nucleus.
Function Claudin-6 regulates chloride and sodium permeability, and increases transepithelial electrical resistance in MDCK cells. It also has a Ca2+ independent cell adhesion activity. Is one of the entry cofactors for hepatitis C virus. Claudin-6 gene methylation may be involved in esophageal tumorogenesis.
Homology The CLDN6 gene sequence is conserved in human, chimpanzee, monkey, wolf, cow, mouse, rat, and zebrafish.


Somatic A heterozygous substitution (p.T33T) in position 33 in ovarian serous carcinoma, and an homozygous substitution (p.T33T) in position 135 in stomach adenocarcinoma, have been reported.

Implicated in

Entity Breast cancer
Note Up-regulation of claudin-6 expression in MCF-7 cells suppressed their malignant phenotype and restored tight junction integrity. Claudin-6 down-regulation contributes to the malignant progression of certain types of breast cancers.
Claudin-6 mRNA was low or undetectable in two rat mammary cancer cell lines, two human breast cancer cell lines, and one breast cancer sample compared to normal breast tissue (Quan and Lu, 2003). Decreased expression of claudin-6 promotes cellular invasiveness, transendothelial migration and an increase in matrix metalloproteinase activity (Osanai et al., 2007). The methylated phenotype of claudin-6 contributes to enhanced tumorigenic and invasive properties of breast carcinoma cells. Claudin-6 may function as tumor suppressor, particularly for breast cancer.
Entity Gastric adenocarcinoma
Note Abnormal claudin expression has been documented in several malignancies. Strong claudin-6 expression was associated with higher mortality rate in the diffuse- vs the intestinal-type gastric adenocarcinoma after a 2-year follow-up (Rendón-Huerta et al., 2010). Claudin-6 expression is closely related to gastric carcinogenesis, and their detection is a useful prognostic marker in gastric adenocarcinoma.
Claudin-6 overexpression in AGS cells enhanced their invasive potential (1,6-fold), cell migration and proliferation rate (13,3%); it also increased claudin-1 and zonula occludens-1 levels (Zavala-Zendejas et al., 2011). Increased expression of claudin-6 is sufficient to enhance tumorigenic properties of a gastric adenocarcinoma cell line.
Entity Brain tumors
Note Claudin-6 is a positive marker for atypical teratoid/rhabdoid tumors (AT/RTs) (Birks et al., 2010). AT/RTs are highly aggressive pediatric brain tumors. CLDN6 showed moderate or higher mRNA expression in eight of nine AT/RTs, with little to no expression in 114 of 115 other tumors. CLDN6 may be a useful marker to identify atypical teratoid/rhabdoid tumors AT/RTs.
Entity Hepatitis C virus infection
Note Claudin-6 mediates the entry of HCV into target cells. Claudin-6 is expressed in the liver, the primary site of HCV replication. Claudin-6 expressed in CD81+ (tetraspanin) cells enables the entry of HCV pseudoparticles. Claudin-1 and -6 function equally well as entry cofactors in endothelial cells but claudin-1 is more efficient in hepatoma cells (Meertens et al., 2008). This suggests that additional cellular factors modulate the ability of claudins to function as HCV entry cofactors.
Entity Cornea
Note Epigenetic regulators such as TSA, 5-aza, and DMSO significantly enhance the expression of claudin-9 in corneal cells, changing transcriptional signals by demethylating CpG islands (Nishikiori et al., 2008); additionally, the epigenetic regulators increase transendothelial electrical resistance and suppress fluxes of corneal cells, thus enhancing the corneal barrier function, in murine experimental corneal trauma.
Entity Adipogenesis
Note Claudin-6 mRNA is differentially expressed in four different adipose tissues, and up regulated in each fat depot of mice fed a high-fat diet as compared to a normal-fat diet. Levels of claudin-6 transcripts were increased during differentiation of 3T3-L1 cells in vitro but small interfering RNA-mediated reduction of claudin-6 mRNA inhibited its differentiation (Hong et al., 2005). Claudin-6 is an important regulator of adipogenesis and fat deposition.
Entity Neonatal development
Note Claudin-6 is a global marker of definitive endoderm and the development of the pancreas, lung and liver; CLDN6 null mice are viable and with no obvious phenotypic abnormalities (Anderson et al., 2008). Homozygous mice overexpressing claudin-6 exhibit a perturbation in the epidermal differentiation program leading to a defective epidermal permeability barrier (EPB); Inv-Cldn6 transgenic animals die within 2 days of birth, due to the lack of an intact EPB, inversely heterozygous Inv-Cldn6 mice exhibit a distinct coat phenotype and mild epidermal hyperkeratosis (Troy et al., 2005). A defective EPB has been shown in premature birth neonates (Turksen and Troy, 2002). Claudin 6 has a major role in epithelial differentiation and EPB assembly/maintenance.
Claudin-6 expression is fundamental for the formation of the trophectoderm (TE), the first epithelium generated during mammalian early development that isolates the inner cell mass from the uterine environment and provides the turgidity of the blastocyst through elevated hydrostatic pressure (Moriwaki et al., 2007). Claudin-6 was absent from TE tight junctions, and thus the barrier function of the TE was disrupted, when embryos were cultured in the presence of Clostridium perfringens enterotoxin.
Claudin-6 expression in the neonatal proximal tubule result in an increased transepithelial resistance, decreased chloride permeability, and decreased P(Na)/P(Cl) and P(HCO3)/P(Cl) (Sas et al., 2008).


Genetic targeting of the endoderm with claudin-6CreER.
Anderson WJ, Zhou Q, Alcalde V, Kaneko OF, Blank LJ, Sherwood RI, Guseh JS, Rajagopal J, Melton DA.
Dev Dyn. 2008 Feb;237(2):504-12. doi: 10.1002/dvdy.21437.
PMID 18213590
Claudin 6 is a positive marker for atypical teratoid/rhabdoid tumors.
Birks DK, Kleinschmidt-DeMasters BK, Donson AM, Barton VN, McNatt SA, Foreman NK, Handler MH.
Brain Pathol. 2010 Jan;20(1):140-50. doi: 10.1111/j.1750-3639.2008.00255.x. Epub 2009 Feb 9.
PMID 19220299
Up-regulation of the claudin-6 gene in adipogenesis.
Hong YH, Hishikawa D, Miyahara H, Nishimura Y, Tsuzuki H, Gotoh C, Iga T, Suzuki Y, Song SH, Choi KC, Lee HG, Sasaki S, Roh SG.
Biosci Biotechnol Biochem. 2005 Nov;69(11):2117-21.
PMID 16306693
The tight junction proteins claudin-1, -6, and -9 are entry cofactors for hepatitis C virus.
Meertens L, Bertaux C, Cukierman L, Cormier E, Lavillette D, Cosset FL, Dragic T.
J Virol. 2008 Apr;82(7):3555-60. doi: 10.1128/JVI.01977-07. Epub 2008 Jan 30.
PMID 18234789
Tight junctions containing claudin 4 and 6 are essential for blastocyst formation in preimplantation mouse embryos.
Moriwaki K, Tsukita S, Furuse M.
Dev Biol. 2007 Dec 15;312(2):509-22. Epub 2007 Oct 4.
PMID 17980358
Prevention of murine experimental corneal trauma by epigenetic events regulating claudin 6 and claudin 9.
Nishikiori N, Sawada N, Ohguro H.
Jpn J Ophthalmol. 2008 May-Jun;52(3):195-203. doi: 10.1007/s10384-008-0524-z. Epub 2008 Jul 27.
PMID 18661270
Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells.
Osanai M, Murata M, Chiba H, Kojima T, Sawada N.
Cancer Sci. 2007 Oct;98(10):1557-62. Epub 2007 Jul 23.
PMID 17645772
Identification of genes preferentially expressed in mammary epithelial cells of Copenhagen rat using subtractive hybridization and microarrays.
Quan C, Lu SJ.
Carcinogenesis. 2003 Oct;24(10):1593-9. Epub 2003 Aug 1.
PMID 12896909
Distribution and expression pattern of claudins 6, 7, and 9 in diffuse- and intestinal-type gastric adenocarcinomas.
Rendon-Huerta E, Teresa F, Teresa GM, Xochitl GS, Georgina AF, Veronica ZZ, Montano LF.
J Gastrointest Cancer. 2010 Mar;41(1):52-9. doi: 10.1007/s12029-009-9110-y. Epub 2009 Dec 4.
PMID 19960275
Effect of claudins 6 and 9 on paracellular permeability in MDCK II cells.
Sas D, Hu M, Moe OW, Baum M.
Am J Physiol Regul Integr Comp Physiol. 2008 Nov;295(5):R1713-9. doi: 10.1152/ajpregu.90596.2008. Epub 2008 Sep 10.
PMID 18784328
Delayed epidermal permeability barrier formation and hair follicle aberrations in Inv-Cldn6 mice.
Troy TC, Rahbar R, Arabzadeh A, Cheung RM, Turksen K.
Mech Dev. 2005 Jun;122(6):805-19. Epub 2005 Apr 21.
PMID 15908185
Permeability barrier dysfunction in transgenic mice overexpressing claudin 6.
Turksen K, Troy TC.
Development. 2002 Apr;129(7):1775-84.
PMID 11923212
[Effects of stable up-regulation of tight junction protein claudin-6 upon biological phenotypes of breast cancer cell MCF-7].
Wu Q, Liu YF, Ren Y, Xu XM, Yu LN, Li YL, Quan CS.
Zhonghua Yi Xue Za Zhi. 2010 Feb 9;90(6):407-12.
PMID 20367941
Claudin-6, 7, or 9 overexpression in the human gastric adenocarcinoma cell line AGS increases its invasiveness, migration, and proliferation rate.
Zavala-Zendejas VE, Torres-Martinez AC, Salas-Morales B, Fortoul TI, Montano LF, Rendon-Huerta EP.
Cancer Invest. 2011 Jan;29(1):1-11. doi: 10.3109/07357907.2010.512594. Epub 2010 Sep 27.
PMID 20874001
Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus.
Zheng A, Yuan F, Li Y, Zhu F, Hou P, Li J, Song X, Ding M, Deng H.
J Virol. 2007 Nov;81(22):12465-71. Epub 2007 Sep 5.
PMID 17804490


This paper should be referenced as such :
Rendon-Huerta, EP ; Torres-Martinez, AC ; Montao, L
CLDN6 (claudin 6)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(6):396-399.
Free journal version : [ pdf ]   [ DOI ]

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 1 ]
  PKMYT1/CLDN6 (16p13)

External links

HGNC (Hugo)CLDN6   2048
Entrez_Gene (NCBI)CLDN6    claudin 6
GeneCards (Weizmann)CLDN6
Ensembl hg19 (Hinxton)ENSG00000184697 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000184697 [Gene_View]  ENSG00000184697 [Sequence]  chr16:3014712-3018183 [Contig_View]  CLDN6 [Vega]
ICGC DataPortalENSG00000184697
TCGA cBioPortalCLDN6
Genatlas (Paris)CLDN6
SOURCE (Princeton)CLDN6
Genetics Home Reference (NIH)CLDN6
Genomic and cartography
GoldenPath hg38 (UCSC)CLDN6  -     chr16:3014712-3018183 -  16p13.3   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CLDN6  -     16p13.3   [Description]    (hg19-Feb_2009)
GoldenPathCLDN6 - 16p13.3 [CytoView hg19]  CLDN6 - 16p13.3 [CytoView hg38]
genome Data Viewer NCBICLDN6 [Mapview hg19]  
Gene and transcription
Genbank (Entrez)AF125306 AK075329 AY358480 BC008934 BT007399
RefSeq transcript (Entrez)NM_021195
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CLDN6
Alternative Splicing GalleryENSG00000184697
Gene ExpressionCLDN6 [ NCBI-GEO ]   CLDN6 [ EBI - ARRAY_EXPRESS ]   CLDN6 [ SEEK ]   CLDN6 [ MEM ]
Gene Expression Viewer (FireBrowse)CLDN6 [ Firebrowse - Broad ]
GenevisibleExpression of CLDN6 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9074
GTEX Portal (Tissue expression)CLDN6
Human Protein AtlasENSG00000184697-CLDN6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP56747   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP56747  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP56747
Splice isoforms : SwissVarP56747
Domaine pattern : Prosite (Expaxy)CLAUDIN (PS01346)   
Domains : Interpro (EBI)Claudin    Claudin6    Claudin_CS    PMP22/EMP/MP20/Claudin   
Domain families : Pfam (Sanger)PMP22_Claudin (PF00822)   
Domain families : Pfam (NCBI)pfam00822   
Conserved Domain (NCBI)CLDN6
Blocks (Seattle)CLDN6
Human Protein Atlas [tissue]ENSG00000184697-CLDN6 [tissue]
Peptide AtlasP56747
Protein Interaction databases
IntAct (EBI)P56747
Ontologies - Pathways
Ontology : AmiGOvirus receptor activity  structural molecule activity  protein binding  plasma membrane  plasma membrane  bicellular tight junction  bicellular tight junction  cell adhesion  integral component of membrane  apicolateral plasma membrane  calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules  identical protein binding  viral entry into host cell  bicellular tight junction assembly  
Ontology : EGO-EBIvirus receptor activity  structural molecule activity  protein binding  plasma membrane  plasma membrane  bicellular tight junction  bicellular tight junction  cell adhesion  integral component of membrane  apicolateral plasma membrane  calcium-independent cell-cell adhesion via plasma membrane cell-adhesion molecules  identical protein binding  viral entry into host cell  bicellular tight junction assembly  
Pathways : KEGGCell adhesion molecules (CAMs)    Tight junction    Leukocyte transendothelial migration    Hepatitis C   
REACTOMEP56747 [protein]
REACTOME PathwaysR-HSA-420029 [pathway]   
NDEx NetworkCLDN6
Atlas of Cancer Signalling NetworkCLDN6
Wikipedia pathwaysCLDN6
Orthology - Evolution
GeneTree (enSembl)ENSG00000184697
Phylogenetic Trees/Animal Genes : TreeFamCLDN6
Homologs : HomoloGeneCLDN6
Homology/Alignments : Family Browser (UCSC)CLDN6
Gene fusions - Rearrangements
Fusion : MitelmanPKMYT1/CLDN6 [16p13.3/16p13.3]  
Fusion PortalPKMYT1 16p13.3 CLDN6 16p13.3 BRCA
Fusion : Fusion_HubCLDN6--GABPB2    CLDN6--PKMYT1    PKMYT1--CLDN6   
Fusion : QuiverCLDN6
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCLDN6 [hg38]
Exome Variant ServerCLDN6
GNOMAD BrowserENSG00000184697
Varsome BrowserCLDN6
Genomic Variants (DGV)CLDN6 [DGVbeta]
DECIPHERCLDN6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCLDN6 
ICGC Data PortalCLDN6 
TCGA Data PortalCLDN6 
Broad Tumor PortalCLDN6
OASIS PortalCLDN6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCLDN6  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DCLDN6
Mutations and Diseases : HGMDCLDN6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CLDN6
DgiDB (Drug Gene Interaction Database)CLDN6
DoCM (Curated mutations)CLDN6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CLDN6 (select a term)
NCG6 (London) select CLDN6
Cancer3DCLDN6(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry CLDN6
NextProtP56747 [Medical]
Target ValidationCLDN6
Huge Navigator CLDN6 [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTD
Pharm GKB GenePA26574
Clinical trialCLDN6
canSAR (ICR)CLDN6 (select the gene name)
DataMed IndexCLDN6
PubMed62 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Feb 19 17:48:07 CET 2021

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