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Atlas / Gene / TTYH2

TTYH2

gene
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Also known as C17orf29

Summary

TTYH2 (tweety family member 2, HGNC:13877) is a protein-coding gene on chromosome 17q25.1, encoding Protein tweety homolog 2 (Q9BSA4). Calcium-independent, swelling-dependent volume-regulated anion channel (VRAC-swell) which plays a pivotal role in the process of regulatory volume decrease (RVD) in the brain through the efflux of anions like chloride and organic osmolytes like glutamate.

This gene encodes a member of the tweety family of proteins. Members of this family function as chloride anion channels. The encoded protein functions as a calcium(2+)-activated large conductance chloride(-) channel, and may play a role in kidney tumorigenesis. Two transcript variants encoding distinct isoforms have been identified for this gene.

Source: NCBI Gene 94015 — RefSeq curated summary.

At a glance

  • GWAS associations: 1
  • Clinical variants (ClinVar): 103 total
  • MANE Select transcript: NM_032646

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:13877
Approved symbolTTYH2
Nametweety family member 2
Location17q25.1
Locus typegene with protein product
StatusApproved
AliasesC17orf29
Ensembl geneENSG00000141540
Ensembl biotypeprotein_coding
OMIM608855
Entrez94015

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000269346, ENST00000441391, ENST00000526858, ENST00000528128, ENST00000528152, ENST00000529107, ENST00000534039, ENST00000534346, ENST00000578825, ENST00000876769, ENST00000876770, ENST00000876771, ENST00000970580, ENST00000970581, ENST00000970582

RefSeq mRNA: 3 — MANE Select: NM_032646 NM_001330453, NM_032646, NM_052869

CCDS: CCDS32717, CCDS45770, CCDS82195

Canonical transcript exons

ENST00000269346 — 14 exons

ExonStartEnd
ENSE000011974867422248574222657
ENSE000011974957421357174213716
ENSE000034595937425308174253266
ENSE000034606877423088874230999
ENSE000034710257425026574250357
ENSE000034746607423729474237514
ENSE000035058677424337474243469
ENSE000035060707424934474249399
ENSE000035520457425223474252376
ENSE000035528257424901174249080
ENSE000035544127424993674250028
ENSE000036515377424397774244049
ENSE000036632627425375574253833
ENSE000037263697426012974262020

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4405 / max 883.7245, expressed in 1214 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter IDTPM avgSamples expressed
16258115.95781213
1625830.419590
1625820.026612
1625850.020911
1625840.01585

Top tissues by expression

254 total, by Bgee expression score (0-100, higher = more expressed):

TissueAnatomy IDExpression scoreQuality
inferior vagus X ganglionUBERON:000536399.43gold quality
lateral globus pallidusUBERON:000247699.16gold quality
corpus callosumUBERON:000233699.04gold quality
subthalamic nucleusUBERON:000190699.03gold quality
substantia nigra pars reticulataUBERON:000196698.92gold quality
medulla oblongataUBERON:000189698.86gold quality
ventral tegmental areaUBERON:000269198.71gold quality
substantia nigra pars compactaUBERON:000196598.65gold quality
dorsal plus ventral thalamusUBERON:000189798.57gold quality
ponsUBERON:000098898.55gold quality
superior vestibular nucleusUBERON:000722798.49gold quality
endothelial cellCL:000011598.16gold quality
lateral nuclear group of thalamusUBERON:000273697.71gold quality
spinal cordUBERON:000224097.48gold quality
C1 segment of cervical spinal cordUBERON:000646997.38gold quality
midbrainUBERON:000189196.41gold quality
left ventricle myocardiumUBERON:000656696.38silver quality
substantia nigraUBERON:000203896.11gold quality
Brodmann (1909) area 46UBERON:000648395.66gold quality
cardiac muscle of right atriumUBERON:000337995.27silver quality
globus pallidusUBERON:000187594.68gold quality
putamenUBERON:000187494.60gold quality
Ammon’s hornUBERON:000195494.37gold quality
pigmented layer of retinaUBERON:000178293.98gold quality
amygdalaUBERON:000187693.86gold quality
trigeminal ganglionUBERON:000167593.60gold quality
medial globus pallidusUBERON:000247793.52gold quality
occipital lobeUBERON:000202193.20gold quality
caudate nucleusUBERON:000187392.96gold quality
temporal lobeUBERON:000187192.59gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

ExperimentMarker?Max mean expression
E-ANND-3yes3.94

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

  • expressed most highly in brain and testis and at lower levels in heart, ovary, spleen, and peripheral blood leukocytes. Expression of this gene is upregulated in 13 of 16 (81%) renal cell carcinoma samples examined (PMID:11597145)
  • TTYH2 gene expression is significantly up-regulated in colon cancer. The TTYH2 gene may play an important role in regulating both proliferating and metastatic potentials of colorectal cancer. (PMID:17569141)
  • N-glycosylation is not the determining factor for TTYH2 trafficking to the plasma membrane. (PMID:18260827)
  • Nedd4-2 differentially interacts with and regulates TTYH1-3 (PMID:18577513)
  • data suggested that beta-COP plays a critical role in the trafficking of the TTYH2 channel to the plasma membrane (PMID:30670146)
  • TTYH2 may serve as a novel target for the treatment of osteosarcoma. (PMID:31230749)
  • SARS-CoV-2 exacerbates proinflammatory responses in myeloid cells through C-type lectin receptors and Tweety family member 2. (PMID:34048708)
  • Cryo-EM structures of the TTYH family reveal a novel architecture for lipid interactions. (PMID:34385445)

Cross-species orthologs

7 orthologs

OrganismSymbolGene ID
danio_reriottyh2lENSDARG00000010727
danio_reriottyh2ENSDARG00000016934
mus_musculusTtyh2ENSMUSG00000034714
rattus_norvegicusTtyh2ENSRNOG00000024578
drosophila_melanogasterttyFBGN0015558
drosophila_melanogasterCG3638FBGN0261444
caenorhabditis_elegansWBGENE00009632

Paralogs (2): TTYH3 (ENSG00000136295), TTYH1 (ENSG00000167614)

Protein

Protein identifiers

Protein tweety homolog 2 — Q9BSA4 (reviewed: Q9BSA4)

Alternative names: Volume-regulated anion channel subunit TTYH2

All UniProt accessions (4): B4DKD1, Q9BSA4, J3KRY9, J3KSH7

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-independent, swelling-dependent volume-regulated anion channel (VRAC-swell) which plays a pivotal role in the process of regulatory volume decrease (RVD) in the brain through the efflux of anions like chloride and organic osmolytes like glutamate. Probable large-conductance Ca(2+)-activated chloride channel.

Subunit / interactions. Homodimer. Forms cis-homodimers in the presence of Ca(+2) and forms monomers and trans-dimers in the absence of Ca(2+). Interacts with NEDD4L.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at higher level in brain and testis and at lower levels in heart, ovary, spleen and peripheral blood leukocytes. Up-regulated in 13 of 16 renal cell carcinoma samples examined. Up-regulated in colon carcinoma.

Post-translational modifications. N- Glycosylated. Contains high-mannose, hybrid and complex oligosaccharides. Ubiquitinated by NEDD4L, leading to its proteasomal degradation.

Similarity. Belongs to the tweety family.

Isoforms (2)

UniProt IDNamesCanonical?
Q9BSA4-11yes
Q9BSA4-22

RefSeq proteins (3): NP_001317382, NP_116035, NP_443101 (=MANE)

Domains & families (InterPro)

IDNameType
IPR006990TweetyFamily

Pfam: PF04906

Catalyzed reactions (Rhea), 2 shown:

  • chloride(in) = chloride(out) (RHEA:29823)
  • L-glutamate(out) = L-glutamate(in) (RHEA:66336)

UniProt features (61 total): helix 13, mutagenesis site 8, sequence variant 7, topological domain 6, transmembrane region 5, glycosylation site 4, sequence conflict 3, strand 3, short sequence motif 2, binding site 2, modified residue 2, disulfide bond 2, chain 1, site 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDBMethodResolution (Å)
9G71ELECTRON MICROSCOPY2.74
7P54ELECTRON MICROSCOPY3.3
9G6XELECTRON MICROSCOPY3.7
7P5MELECTRON MICROSCOPY3.92

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q9BSA4-F181.780.65

Antibody-complex structures (SAbDab): 1 — 9G6X

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 164 (essential for the formation of the channel-pore)

Ligand- & substrate-binding residues (2): 113; 116

Post-translational modifications (2): 199, 504

Disulfide bonds (2): 274–382, 300–367

Glycosylation sites (4): 31, 129, 283, 352

Mutagenesis-validated functional residues (8):

PositionPhenotype
31loss of glycosylation. no effect on cell membrane localization, increased ubiquitination and significant decrease in pro
129loss of glycosylation. no effect on cell membrane localization, increased ubiquitination and significant decrease in pro
283loss of glycosylation. no effect on cell membrane localization, increased ubiquitination and significant decrease in pro
352loss of glycosylation. no effect on cell membrane localization, increased ubiquitination and significant decrease in pro
444no effect on interaction with nedd4l and nedd4l-mediated ubiquitination.
504no effect on interaction with nedd4l and nedd4l-mediated ubiquitination.
509loss of interaction with nedd4l and almost complete loss of nedd4l-mediated ubiquitination. a 3-fold increase in its exp
510reduced interaction with nedd4l and reduced nedd4l-mediated ubiquitination. a 2-fold increase in its expression in the c

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-2672351Stimuli-sensing channels

MSigDB gene sets: 201 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GCM_MAP4K4, GCM_PTPRD, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT, AAACCAC_MIR140, GOBP_CHLORIDE_TRANSPORT, ROZANOV_MMP14_TARGETS_UP, HNF4_DR1_Q3, GOBP_AMINO_ACID_TRANSPORT, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_DICARBOXYLIC_ACID_TRANSPORT, GOBP_ACIDIC_AMINO_ACID_TRANSPORT

GO Biological Process (5): L-glutamate transmembrane transport (GO:0015813), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), chloride transmembrane transport (GO:1902476)

GO Molecular Function (6): intracellularly calcium-gated chloride channel activity (GO:0005229), calcium ion binding (GO:0005509), volume-sensitive chloride channel activity (GO:0072320), chloride channel activity (GO:0005254), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): plasma membrane (GO:0005886), chloride channel complex (GO:0034707), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Ion channel transport1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
chloride channel activity2
L-glutamate import1
L-alpha-amino acid transmembrane transport1
transport1
monoatomic anion transport1
inorganic anion transport1
monoatomic ion transport1
transmembrane transport1
chloride transport1
monoatomic anion transmembrane transport1
ligand-gated monoatomic anion channel activity1
intracellularly calcium-gated channel activity1
metal ion binding1
volume-sensitive anion channel activity1
monoatomic anion channel activity1
chloride transmembrane transporter activity1
binding1
cation binding1
membrane1
cell periphery1
monoatomic ion channel complex1
cellular anatomical structure1

Protein interactions and networks

STRING

448 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
TTYH2LRRC8CQ8TDW0664
TTYH2LRRC8EQ6NSJ5589
TTYH2LRRC8DQ7L1W4575
TTYH2LRRC8BQ6P9F7570
TTYH2KCPQ6ZWJ8564
TTYH2LRRC8AQ8IWT6548
TTYH2COPB1P53618521
TTYH2RPL38P23411513
TTYH2BTBD17A6NE02479
TTYH2DNAI2Q9GZS0473
TTYH2GPRC5CQ9NQ84421
TTYH2CD300AQ9UGN4418
TTYH2ASGR1P07306368
TTYH2ADAMTSL2Q86TH1363
TTYH2RER1O15258361

IntAct

23 interactions, top by confidence:

ABTypeScore
TTYH2COPB1psi-mi:“MI:0915”(physical association)0.620
TUSC5TTYH2psi-mi:“MI:0915”(physical association)0.560
MANSC1KLRG2psi-mi:“MI:0914”(association)0.530
GRB2SH3PXD2Bpsi-mi:“MI:0914”(association)0.530
TTYH2Dlg4psi-mi:“MI:0407”(direct interaction)0.440
TTYH2GPR37psi-mi:“MI:0915”(physical association)0.370
TTYH2TTYH2psi-mi:“MI:0407”(direct interaction)0.360
C11orf87KLRG2psi-mi:“MI:0914”(association)0.350
C5AR1TCAF2psi-mi:“MI:0914”(association)0.350
S1PR1STXBP3psi-mi:“MI:0914”(association)0.350
PILRBEI24psi-mi:“MI:0914”(association)0.350
SMAD4TTYH2psi-mi:“MI:2364”(proximity)0.270
TUSC5TTYH2psi-mi:“MI:0915”(physical association)0.000
TTYH2IKBKGpsi-mi:“MI:0407”(direct interaction)0.000

BioGRID (37): TTYH2 (Affinity Capture-MS), TTYH2 (Affinity Capture-MS), ERBB2 (FRET), FGFR4 (FRET), GRM1 (FRET), KAT2A (FRET), KDELR2 (FRET), NF2 (FRET), PDGFRA (FRET), TTYH2 (FRET), CCND2 (FRET), CDKN2B (FRET), IGF1R (FRET), COPB1 (Affinity Capture-Western), TTYH2 (Affinity Capture-Western)

ESM2 similar proteins: A0JPH4, A2AQW0, D3ZWZ9, O00322, O35099, O42281, O42282, O42581, O42582, O42583, O95859, P15499, P17438, P17810, P23942, P35906, P38572, P52204, Q08CE6, Q32LT7, Q3TDN0, Q3TH73, Q4V8I7, Q4V922, Q569A2, Q5PQZ7, Q5R8B5, Q5RH73, Q5T848, Q5U308, Q62147, Q6AXF6, Q6AZD1, Q6IQC7, Q6P1U2, Q6ZN16, Q7L1W4, Q80WG5, Q8BGR2, Q8BKT6

Diamond homologs: P0C5X8, Q0V9V9, Q2KJ98, Q32LT7, Q3TH73, Q6AX57, Q6GM04, Q6GPA5, Q6NUZ2, Q6P1U2, Q6P5F7, Q7ZWN9, Q9BSA4, Q9C0H2, Q9D3A9, Q9H313, Q9MZZ8

SIGNOR signaling

1 interactions.

AEffectBMechanism
NEDD4L“down-regulates quantity by destabilization”TTYH2polyubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

103 variants total. Per-class counts are floors (≥ shown; pagination cap):

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance86
Likely benign8
Benign0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2429 predictions. Top by Δscore:

VariantEffectΔscore
17:74213712:AGGAG:Adonor_gain1.0000
17:74213713:GGAG:Gdonor_gain1.0000
17:74213713:GGAGG:Gdonor_gain1.0000
17:74213714:GAG:Gdonor_gain1.0000
17:74213714:GAGG:Gdonor_gain1.0000
17:74213715:AG:Adonor_gain1.0000
17:74213715:AGG:Adonor_loss1.0000
17:74213716:GG:Gdonor_gain1.0000
17:74213717:G:GGdonor_gain1.0000
17:74213717:GTAA:Gdonor_loss1.0000
17:74222479:TTCCA:Tacceptor_loss1.0000
17:74222480:TCCA:Tacceptor_loss1.0000
17:74222481:CCAG:Cacceptor_loss1.0000
17:74222482:CAGT:Cacceptor_loss1.0000
17:74222483:A:AGacceptor_gain1.0000
17:74222483:AGT:Aacceptor_loss1.0000
17:74222483:AGTC:Aacceptor_gain1.0000
17:74222484:G:GTacceptor_gain1.0000
17:74222484:GTC:Gacceptor_gain1.0000
17:74222484:GTCG:Gacceptor_gain1.0000
17:74222484:GTCGC:Gacceptor_gain1.0000
17:74222653:TGCTG:Tdonor_gain1.0000
17:74222654:GCTG:Gdonor_gain1.0000
17:74222654:GCTGG:Gdonor_gain1.0000
17:74222655:CTG:Cdonor_gain1.0000
17:74222655:CTGG:Cdonor_loss1.0000
17:74222656:TG:Tdonor_gain1.0000
17:74222657:GG:Gdonor_gain1.0000
17:74222657:GGT:Gdonor_loss1.0000
17:74222658:G:GGdonor_gain1.0000

AlphaMissense

3481 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
17:74230918:C:AN111K0.990
17:74230918:C:GN111K0.990
17:74252279:G:CG388R0.987
17:74249017:A:CS271R0.986
17:74249019:T:AS271R0.986
17:74249019:T:GS271R0.986
17:74249027:G:AC274Y0.986
17:74252263:C:GC382W0.985
17:74230904:G:CG107R0.984
17:74249028:T:GC274W0.984
17:74252262:G:AC382Y0.984
17:74213687:T:CF34L0.983
17:74213689:C:AF34L0.983
17:74213689:C:GF34L0.983
17:74249026:T:AC274S0.983
17:74249027:G:CC274S0.983
17:74250342:C:GC367W0.983
17:74249026:T:CC274R0.982
17:74213626:G:CW13C0.981
17:74213626:G:TW13C0.981
17:74230905:G:AG107D0.981
17:74250341:G:AC367Y0.980
17:74252279:G:TG388C0.980
17:74249369:C:GC300W0.979
17:74250340:T:AC367S0.979
17:74250341:G:CC367S0.979
17:74213624:T:AW13R0.978
17:74213624:T:CW13R0.978
17:74250340:T:CC367R0.978
17:74237514:G:TR212M0.977

dbSNP variants (sampled 300 via entrez): RS1000108139 (17:74212251 C>G,T), RS1000199530 (17:74258487 G>A), RS1000223374 (17:74228127 G>A), RS1000235361 (17:74231130 A>C), RS1000239427 (17:74233734 G>A), RS1000258655 (17:74258702 G>A), RS1000346081 (17:74258627 G>A,T), RS1000354671 (17:74243098 C>G,T), RS1000389888 (17:74217391 G>A), RS1000415689 (17:74248314 C>T), RS1000540685 (17:74232817 A>G), RS1000595194 (17:74228421 C>T), RS1000634544 (17:74222879 C>G), RS1000682804 (17:74221771 C>T), RS1000706228 (17:74228624 G>A)

Disease associations

OMIM: gene MIM:608855 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

StudyTraitp-value
GCST003365_2Systolic blood pressure (cigarette smoking interaction)9.000000e-07

EFO canonical traits (1, from GWAS)

EFO IDTrait name
EFO:0006335systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

ChemicalActions (top 5)PubMed papers
Valproic Acidaffects expression, increases expression, increases methylation4
entinostatincreases expression, affects cotreatment2
Benzo(a)pyreneaffects methylation, decreases methylation2
Phenylmercuric Acetatedecreases expression, affects cotreatment2
Aflatoxin B1decreases methylation, increases methylation2
aristolochic acid Iincreases expression1
GSK-J4increases expression1
FR900359affects phosphorylation1
methylmercuric chloridedecreases expression1
triphenyl phosphateaffects expression1
propionaldehydeincreases expression1
bisphenol Adecreases methylation1
beta-lapachoneincreases expression1
benzo(e)pyreneincreases methylation1
S-(1,2-dichlorovinyl)cysteinedecreases reaction, increases expression1
di-n-butylphosphoric acidaffects expression1
CGP 52608affects binding, increases reaction1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamideaffects cotreatment, increases expression, decreases expression1
nutlin 3increases expression, affects cotreatment1
dorsomorphinincreases expression, decreases expression, affects cotreatment1
jinfukangaffects cotreatment, increases expression1
(+)-JQ1 compounddecreases expression1
Sunitinibdecreases expression1
Benztropineincreases expression1
Cisplatinaffects cotreatment, increases expression1
Clozapineincreases expression1
Dactinomycinaffects cotreatment, increases expression1
Doxorubicindecreases expression1
Fluorouracildecreases expression1
Formaldehydeincreases expression1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

CellosaurusNameCategorySex
CVCL_YA85IDG-HEK293T-TTYH2-V5-OETransformed cell lineFemale

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.

No linked Atlas pages yet — the cross-entity mesh grows as the corpus expands.

About this page

Generated deterministically by Sugi Atlas from primary biomedical databases via BioBTree. Every record on this page traces to a primary source.

Generated
Atlas version
v1.1.4
BioBTree
v2.0.2

Sources 75

This page pulls from 75 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot