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CATSPER4

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Summary

CATSPER4 (cation channel sperm associated 4, HGNC:23220) is a protein-coding gene on chromosome 1p36.11, encoding Cation channel sperm-associated protein 4 (Q7RTX7). Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the….

Predicted to enable voltage-gated calcium channel activity. Predicted to be involved in flagellated sperm motility; sodium ion transport; and sperm capacitation. Predicted to act upstream of or within establishment of localization in cell. Predicted to be located in plasma membrane. Predicted to be part of CatSper complex. Predicted to be active in acrosomal vesicle and sperm principal piece.

Source: NCBI Gene 378807 — RefSeq curated summary.

At a glance

  • GWAS associations: 5
  • Clinical variants (ClinVar): 81 total
  • MANE Select transcript: NM_198137

Identifiers

Gene identifiers

FieldValue
HGNC IDHGNC:23220
Approved symbolCATSPER4
Namecation channel sperm associated 4
Location1p36.11
Locus typegene with protein product
StatusApproved
Ensembl geneENSG00000188782
Ensembl biotypeprotein_coding
OMIM609121
Entrez378807

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 nonsense_mediated_decay

ENST00000338855, ENST00000456354, ENST00000518899

RefSeq mRNA: 1 — MANE Select: NM_198137 NM_198137

CCDS: CCDS30645

Canonical transcript exons

ENST00000456354 — 10 exons

ExonStartEnd
ENSE000000003022619060226190840
ENSE000013659522620083026201041
ENSE000013678782619378726193888
ENSE000013693632619828626198419
ENSE000013776082619768626197783
ENSE000013776302619128726191430
ENSE000013779942619795726198077
ENSE000013886492619988426200058
ENSE000036159802620248926202964
ENSE000036783842620135426201519

Expression profiles

Bgee: expression breadth broad, 14 present calls, max score 79.63.

Top tissues by expression

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

TissueAnatomy IDExpression scoreQuality
left testisUBERON:000453379.63gold quality
right testisUBERON:000453479.33gold quality
testisUBERON:000047378.73gold quality
hindlimb stylopod muscleUBERON:000425259.35gold quality
gastrocnemiusUBERON:000138853.97gold quality
muscle of legUBERON:000138353.40gold quality
skeletal muscle tissueUBERON:000113452.29gold quality
lower esophagus mucosaUBERON:003583452.27gold quality
muscle tissueUBERON:000238544.96silver quality
mucosa of transverse colonUBERON:000499140.38silver quality
right uterine tubeUBERON:000130238.57silver quality
bone marrow cellCL:000209238.47gold quality
right hemisphere of cerebellumUBERON:001489037.34gold quality
colonic epitheliumUBERON:000039737.20gold quality
primary visual cortexUBERON:000243636.96gold quality
ventricular zoneUBERON:000305336.48gold quality
cortical plateUBERON:000534336.47gold quality
ganglionic eminenceUBERON:000402335.49gold quality
olfactory segment of nasal mucosaUBERON:000538635.44silver quality
granulocyteCL:000009435.22gold quality
left lobe of thyroid glandUBERON:000112035.01silver quality
bone marrowUBERON:000237132.92gold quality
body of pancreasUBERON:000115032.70gold quality
prefrontal cortexUBERON:000045132.48gold quality
vermiform appendixUBERON:000115432.31gold quality
metanephros cortexUBERON:001053332.26gold quality
right lungUBERON:000216732.18gold quality
cortex of kidneyUBERON:000122531.94gold quality
pancreasUBERON:000126431.88gold quality
prostate glandUBERON:000236731.14gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

ExperimentMarker?Max mean expression
E-ANND-3no1.97

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

  • Catsper4 has a single channel-forming domain, a pore-loop with the consensus sequence TxDxW, & a coiled-coil protein-protein interaction domain in the C-terminal tail. CatSpers 1,2,3 & 4 may interact directly or indirectly to form a functional tetramer. (PMID:12932298)

Cross-species orthologs

2 orthologs

OrganismSymbolGene ID
mus_musculusCatsper4ENSMUSG00000048003
rattus_norvegicusCatsper4ENSRNOG00000016312

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), SCN3A (ENSG00000153253), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Cation channel sperm-associated protein 4 — Q7RTX7 (reviewed: Q7RTX7)

All UniProt accessions (2): Q7RTX7, J3KNU1

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of the CatSper complex, a sperm-specific voltage-gated calcium channel that plays a central role in calcium-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the oocyte.

Subunit / interactions. Component of the CatSper complex or CatSpermasome composed of the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CATSPERZ, CATSPERT, CATSPERQ, CATSPERH and EFCAB9. HSPA1 may be an additional auxiliary complex member. The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form a heterotetrameric channel. The auxiliary CATSPERB, CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure over the pore which stabilizes the complex through interactions with CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively. CATSPERH interacts with CATSPERB, further stabilizing the complex. CATSPERT interacts at least with CATSPERD and is required for targeting the CatSper complex in the flagellar membrane.

Subcellular location. Cell projection. Cilium. Flagellum membrane.

Tissue specificity. Testis-specific.

Activity regulation. The CatSper calcium channel is indirectly activated by extracellular progesterone and prostaglandins following the sequence: progesterone > PGF1-alpha = PGE1 > PGA1 > PGE2 » PGD2. The CatSper calcium channel is directly inhibited by endocannabinoid 2-arachidonoylglycerol (2AG). Indirect activation by progesterone takes place via the following mechanism: progesterone binds and activates the acylglycerol lipase ABHD2, which in turn mediates hydrolysis of 2AG inhibitor, relieving inhibition of the CatSper channel. The primary effect of progesterone activation is to shift voltage dependence towards more physiological, negative membrane potentials; it is not mediated by metabotropic receptors and second messengers. Sperm capacitation enhances the effect of progesterone by providing additional negative shift. Also activated by the elevation of intracellular pH.

Similarity. Belongs to the cation channel sperm-associated (TC 1.A.1.19) family.

Isoforms (2)

UniProt IDNamesCanonical?
Q7RTX7-11yes
Q7RTX7-22

RefSeq proteins (1): NP_937770* (*=MANE)

Domains & families (InterPro)

IDNameType
IPR005821Ion_trans_domDomain
IPR027359Volt_channel_dom_sfHomologous_superfamily
IPR028744CatSper4Family

Pfam: PF00520

Catalyzed reactions (Rhea), 1 shown:

  • Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (24 total): topological domain 8, transmembrane region 6, sequence variant 4, splice variant 2, chain 1, intramembrane region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

ModelpLDDTFraction very-high
AF-Q7RTX7-F168.290.14

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

IDPathway
R-HSA-1300642Sperm Motility And Taxes

MSigDB gene sets: 62 (showing top): GOCC_SECRETORY_GRANULE, GOBP_MALE_GAMETE_GENERATION, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_SPERM_CAPACITATION, GOBP_ANATOMICAL_STRUCTURE_MATURATION, GOBP_CELL_MATURATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, GOCC_VOLTAGE_GATED_CALCIUM_CHANNEL_COMPLEX, GOCC_SECRETORY_VESICLE

GO Biological Process (12): sodium ion transport (GO:0006814), flagellated sperm motility (GO:0030317), sperm capacitation (GO:0048240), establishment of localization in cell (GO:0051649), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (5): calcium-activated cation channel activity (GO:0005227), voltage-gated calcium channel activity (GO:0005245), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (9): acrosomal vesicle (GO:0001669), plasma membrane (GO:0005886), CatSper complex (GO:0036128), sperm principal piece (GO:0097228), cilium (GO:0005929), membrane (GO:0016020), motile cilium (GO:0031514), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

CategoryPathways
Fertilization1

GO top-level categories

Rollup of top GO terms by namespace:

CategoryTerms
cellular anatomical structure3
metal ion transport2
developmental process involved in reproduction2
transport2
cilium-dependent cell motility1
cilium movement involved in cell motility1
sperm motility1
spermatid development1
cellular process involved in reproduction in multicellular organism1
cell maturation1
establishment of localization1
cellular localization1
male gamete generation1
cellular developmental process1
monoatomic ion transport1
transmembrane transport1
cellular process1
calcium ion transport1
monoatomic cation transmembrane transport1
monoatomic cation transport1
monoatomic ion transmembrane transport1
monoatomic ion-gated channel activity1
ligand-gated monoatomic cation channel activity1
calcium channel activity1
voltage-gated monoatomic cation channel activity1
monoatomic ion transmembrane transporter activity1
channel activity1
monoatomic cation channel activity1
calcium ion transmembrane transporter activity1
binding1
secretory granule1
membrane1
cell periphery1
voltage-gated calcium channel complex1
sperm flagellum1
intraciliary transport particle1
membrane-bounded organelle1
plasma membrane bounded cell projection1
cilium1
transmembrane transporter complex1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein AProtein BPartner UniProtScore
CATSPER4CATSPERBQ9H7T0886
CATSPER4CATSPERDQ86XM0833
CATSPER4EFCAB9A8MZ26806
CATSPER4CATSPER2Q96P56767
CATSPER4CATSPER3Q86XQ3705
CATSPER4CATSPEREQ5SY80648
CATSPER4CATSPERZQ9NTU4617
CATSPER4CATSPER1Q8NEC5592
CATSPER4CATSPERGQ6ZRH7538
CATSPER4SPEM1Q8N4L4507
CATSPER4RBM46Q8TBY0493
CATSPER4KCNU1A8MYU2487
CATSPER4HVCN1Q96D96430
CATSPER4SLC9C1Q4G0N8426
CATSPER4OR5H1A6NKK0402

IntAct

6 interactions, top by confidence:

ABTypeScore
CCL4L1CATSPER4psi-mi:“MI:0915”(physical association)0.560
CATSPER4CCL4L1psi-mi:“MI:0915”(physical association)0.560
CATSPER4POTEFpsi-mi:“MI:0914”(association)0.530

BioGRID (11): CCDC101 (Affinity Capture-MS), SLMAP (Affinity Capture-MS), TRAF4 (Affinity Capture-MS), TRAF4 (Affinity Capture-MS), CCDC101 (Affinity Capture-MS), POTEF (Affinity Capture-MS), SLMAP (Affinity Capture-MS), CCL4L2 (Two-hybrid), CCDC101 (Affinity Capture-MS), TRAF4 (Affinity Capture-MS), POTEF (Affinity Capture-MS)

ESM2 similar proteins: A2ARP9, A2ASI5, B1AWN6, B1AYL1, F1LQQ7, O08562, O46669, O70344, O73925, O88420, O88457, O88944, O97531, P02719, P04775, P08104, P0DMA5, P15389, P15390, P35499, P51787, P59111, P97414, Q01118, Q14524, Q28371, Q28644, Q2XVR7, Q62205, Q62968, Q6AXP6, Q6QIY3, Q7RTX7, Q8K3F6, Q96L42, Q96P56, Q99250, Q9ER60, Q9JJV9, Q9JK45

Diamond homologs: Q7RTX7, Q8BVN3

SIGNOR signaling

1 interactions.

AEffectBMechanism
CATSPER4“form complex”“CatSpermasome complex”binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

ClassificationCount (floor)
Pathogenic0
Likely pathogenic0
Uncertain significance61
Likely benign8
Benign3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2050 predictions. Top by Δscore:

VariantEffectΔscore
1:26190838:GCG:Gdonor_gain1.0000
1:26190838:GCGGT:Gdonor_loss1.0000
1:26190840:GGTA:Gdonor_loss1.0000
1:26190841:G:GGdonor_gain1.0000
1:26190842:T:Gdonor_loss1.0000
1:26191426:ACCAG:Adonor_loss1.0000
1:26191427:CCAG:Cdonor_loss1.0000
1:26191428:CAGGT:Cdonor_loss1.0000
1:26191429:AG:Adonor_loss1.0000
1:26191430:GG:Gdonor_loss1.0000
1:26191431:GTGGG:Gdonor_loss1.0000
1:26191432:T:Adonor_loss1.0000
1:26193785:A:AGacceptor_gain1.0000
1:26193786:G:GGacceptor_gain1.0000
1:26197734:C:CAacceptor_gain1.0000
1:26198074:GCTG:Gdonor_gain1.0000
1:26198076:TGG:Tdonor_loss1.0000
1:26198077:GGT:Gdonor_loss1.0000
1:26198078:G:Cdonor_loss1.0000
1:26198281:GACAG:Gacceptor_loss1.0000
1:26198282:ACAG:Aacceptor_loss1.0000
1:26198283:CAGG:Cacceptor_loss1.0000
1:26198284:A:ATacceptor_loss1.0000
1:26198388:G:GTdonor_gain1.0000
1:26198415:TTCCA:Tdonor_gain1.0000
1:26198416:TCCA:Tdonor_gain1.0000
1:26198417:CCA:Cdonor_gain1.0000
1:26198418:CA:Cdonor_gain1.0000
1:26198420:G:GGdonor_gain1.0000
1:26198420:GTGA:Gdonor_loss1.0000

AlphaMissense

3139 scored. Top likely-pathogenic:

VariantProtein changeam_pathogenicity
1:26198394:T:AW263R0.993
1:26198394:T:CW263R0.993
1:26201026:G:CR395P0.992
1:26201035:T:CL398P0.992
1:26201005:T:CL388P0.989
1:26198337:T:CF244L0.986
1:26198339:C:AF244L0.986
1:26198339:C:GF244L0.986
1:26193859:T:AW144R0.983
1:26193859:T:CW144R0.983
1:26198376:T:CC257R0.983
1:26198396:G:CW263C0.982
1:26198396:G:TW263C0.982
1:26200989:G:CA383P0.981
1:26198338:T:CF244S0.979
1:26198313:T:CF236L0.976
1:26198315:T:AF236L0.976
1:26198315:T:GF236L0.976
1:26198378:C:GC257W0.976
1:26193880:T:CF151L0.972
1:26193882:C:AF151L0.972
1:26193882:C:GF151L0.972
1:26198338:T:GF244C0.972
1:26193883:T:AW152R0.967
1:26193883:T:CW152R0.967
1:26197979:T:CC194R0.967
1:26201371:G:CR406P0.966
1:26199973:T:CL301P0.965
1:26200000:T:CL310P0.964
1:26201003:C:AN387K0.964

dbSNP variants (sampled 300 via entrez): RS1000049738 (1:26201708 G>T), RS1000247849 (1:26196850 G>A,T), RS1000335079 (1:26193215 C>A,G), RS1001057111 (1:26199638 A>G), RS1001393617 (1:26201429 G>A,C,T), RS1001660477 (1:26189963 C>A), RS1002649076 (1:26193890 T>C,G), RS1002652489 (1:26191647 C>T), RS1003245295 (1:26190400 C>G), RS1003251007 (1:26189108 C>T), RS1004201454 (1:26191538 C>A,T), RS1004321033 (1:26197884 C>A), RS1005092433 (1:26193274 G>A), RS1005262568 (1:26190381 C>A,T), RS1005384255 (1:26200581 G>C)

Disease associations

OMIM: gene MIM:609121 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

StudyTraitp-value
GCST000372_1Height6.000000e-08
GCST008476_22Emphysema annual change measurement in smokers (percent low attenuation area)9.000000e-07
GCST90020024_11A body shape index4.000000e-08
GCST90020025_245Waist-to-hip ratio adjusted for BMI1.000000e-09
GCST90020027_1782Waist-hip index4.000000e-09

EFO canonical traits (3, from GWAS)

EFO IDTrait name
EFO:0007626emphysema imaging measurement
EFO:0007789BMI-adjusted waist circumference
EFO:0007788BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — CatSper and Two-Pore channels (TPC)

Most potent curated ligand interactions (9 total), top 9:

LigandActionAffinityParameter
progesteroneFull agonist8.11pEC50
PGE1Full agonist6.3pEC50
PGE2Full agonist6.3pEC50
PGF1αFull agonist6.3pEC50
NNC55-0396Inhibition5.7pIC50
ruthenium redAntagonist5.0pIC50
mibefradilInhibition4.5pIC50
Cd2+Antagonist3.7pIC50
Ni2+Antagonist3.5pIC50

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

ChemicalActions (top 5)PubMed papers
bisphenol Faffects cotreatment, decreases methylation1
bisphenol Adecreases methylation1
ethyl-p-hydroxybenzoatedecreases expression1
bisphenol Sdecreases methylation1
Resveratrolaffects cotreatment, decreases expression1
Arsenic Trioxideincreases expression1
Fulvestrantdecreases methylation, affects cotreatment1
Benzo(a)pyrenedecreases methylation1
Cycloheximideaffects response to substance1
Plant Extractsaffects cotreatment, decreases expression1

Clinical trials (associated diseases)

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

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
v1.1.2
BioBTree
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Sources 76

This page pulls from 76 datasets indexed by BioBTree:

alphafoldalphamissenseantibodybgeebgee_evidencebindingdbbiogrid_interactionbrendabrenda_kineticsccdscellosauruschembl_activitychembl_targetciviccivic_evidenceclingen_dosageclingen_gene_validityclinical_trialsclinvarcollectrictd_gene_interactiondbsnpdepmapdiamond_similarityefoensemblentrezesm2_similarityexonfantom5_genefantom5_promotergenccgenerifgogoparentgtopdbgtopdb_interactiongwasgwas_studyhgnchpointactinterprointogenjasparmeshmimmirdbmondomsigdborphanetorthologparalogpdbpfampharmgkb_clinicalpharmgkb_genepharmgkb_guidelinepharmgkb_variantpubchempubchem_activitypubchem_assaypubmedreactomereactomeparentrefseqrhearnacentralscxa_expressionscxa_gene_experimentsignorspliceaistring_interactiontranscriptufeatureuniprot