FXYD4

Summary

FXYD4 (FXYD domain containing ion transport regulator 4, HGNC:4028) is a protein-coding gene on chromosome 10q11.21, encoding FXYD domain-containing ion transport regulator 4 (P59646). Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane.

This gene encodes a member of a family of small membrane proteins that share a 35-amino acid signature sequence domain, beginning with the sequence PFXYD and containing 7 invariant and 6 highly conserved amino acids. The approved human gene nomenclature for the family is FXYD-domain containing ion transport regulator. FXYD4, originally named CHIF for channel-inducing factor, has been shown to modulate the properties of the Na,K-ATPase, as has FXYD2, also known as the gamma subunit of the Na,K-ATPase, and FXYD7. Transmembrane topology has been established for FXYD4 and two family members (FXYD1 and FXYD2), with the N-terminus extracellular and the C-terminus on the cytoplasmic side of the membrane. Alternatively spliced transcript variants encoding the same protein have been found.

Source: NCBI Gene 53828 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 31 total — 1 likely-pathogenic
• MANE Select transcript: NM_173160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4028
Approved symbol	FXYD4
Name	FXYD domain containing ion transport regulator 4
Location	10q11.21
Locus type	gene with protein product
Status	Approved
Aliases	CHIF
Ensembl gene	ENSG00000150201
Ensembl biotype	protein_coding
OMIM	616926
Entrez	53828

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000476166, ENST00000479189, ENST00000480834, ENST00000616495, ENST00000863530, ENST00000863531, ENST00000863532, ENST00000863533, ENST00000863534

RefSeq mRNA: 2 — MANE Select: NM_173160 NM_001184963, NM_173160

CCDS: CCDS7203

Canonical transcript exons

ENST00000476166 — 9 exons

Exon	Start	End
ENSE00001463547	43372727	43372772
ENSE00001463550	43371636	43371697
ENSE00003452102	43373515	43373783
ENSE00003483036	43375695	43375734
ENSE00003571199	43374613	43374639
ENSE00003636709	43376032	43376069
ENSE00003639710	43375499	43375573
ENSE00003640435	43374470	43374502
ENSE00003737848	43376147	43376335

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 97.85.

FANTOM5 (CAGE): breadth broad, TPM avg 2.1267 / max 637.1490, expressed in 195 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
104751	2.1267	195

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
metanephros cortex	UBERON:0010533	97.85	gold quality
renal medulla	UBERON:0000362	97.05	gold quality
adult mammalian kidney	UBERON:0000082	95.15	gold quality
kidney epithelium	UBERON:0004819	94.51	gold quality
kidney	UBERON:0002113	85.37	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.87	silver quality
adult organism	UBERON:0007023	81.35	gold quality
metanephros	UBERON:0000081	77.18	gold quality
cortex of kidney	UBERON:0001225	75.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	73.40	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	68.42	gold quality
body of stomach	UBERON:0001161	67.34	gold quality
ileal mucosa	UBERON:0000331	66.45	silver quality
upper lobe of left lung	UBERON:0008952	65.94	gold quality
spinal cord	UBERON:0002240	65.90	gold quality
left testis	UBERON:0004533	64.17	gold quality
right testis	UBERON:0004534	63.82	gold quality
upper lobe of lung	UBERON:0008948	63.71	gold quality
putamen	UBERON:0001874	63.59	gold quality
stomach	UBERON:0000945	63.21	gold quality
substantia nigra	UBERON:0002038	63.20	gold quality
right lung	UBERON:0002167	61.56	gold quality
amygdala	UBERON:0001876	61.55	gold quality
testis	UBERON:0000473	61.50	gold quality
midbrain	UBERON:0001891	60.52	gold quality
gastrocnemius	UBERON:0001388	59.81	gold quality
muscle of leg	UBERON:0001383	59.76	gold quality
tibialis anterior	UBERON:0001385	59.39	silver quality
Brodmann (1909) area 9	UBERON:0013540	58.51	gold quality
Ammon’s horn	UBERON:0001954	57.00	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	266.92
E-ANND-3	no	2.12

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting FXYD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-6791-3P	97.45	64.31	1123
HSA-MIR-6829-3P	97.45	64.31	1137
HSA-MIR-383-5P	96.86	67.55	820
HSA-MIR-6762-5P	96.55	64.62	972
HSA-MIR-6845-5P	96.55	64.65	969

Literature-anchored findings (GeneRIF, showing 2)

• CHIF can act as tissue-specific modulators of Na-K-ATPase (PMID:12217851)
• molecular cloning, protein expression, sequencing and NMR structure determination (PMID:12535606)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fxyd4	ENSMUSG00000004988
rattus_norvegicus	Fxyd4	ENSRNOG00000014578

Paralogs (6): FXYD5 (ENSG00000089327), FXYD3 (ENSG00000089356), FXYD6 (ENSG00000137726), FXYD2 (ENSG00000137731), FXYD7 (ENSG00000221946), FXYD1 (ENSG00000266964)

Protein

Protein identifiers

FXYD domain-containing ion transport regulator 4 — P59646 (reviewed: P59646)

All UniProt accessions (1): P59646

UniProt curated annotations — full annotation on UniProt →

Function. Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. Increases the apparent affinity of the transporter for Na(+) and increases NKA activity.

Subunit / interactions. Regulatory subunit of the sodium/potassium-transporting ATPase which is composed of a catalytic alpha subunit, a non-catalytic beta subunit and a regulatory subunit. The regulatory subunit, a member of the FXYD protein family, modulates the enzymatic activity in a tissue- and isoform-specific way by changing affinities of the Na+/K+-ATPase toward Na(+), K(+) or ATP.

Subcellular location. Cell membrane. Basolateral cell membrane.

Similarity. Belongs to the FXYD family.

RefSeq proteins (2): NP_001171892, NP_775183* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000272	Ion-transport_regulator_FXYD	Family
IPR047283	FXYD4	Family
IPR047297	FXYD_motif	Conserved_site

Pfam: PF02038

UniProt features (6 total): topological domain 2, signal peptide 1, chain 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P59646-F1	70.08	0.10

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5578775	Ion homeostasis
R-HSA-936837	Ion transport by P-type ATPases
R-HSA-9679191	Potential therapeutics for SARS

MSigDB gene sets: 94 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_TRANSMEMBRANE_ELECTROCHEMICAL_GRADIENT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_POTASSIUM_ION_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT, MARTINEZ_RB1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_INTRACELLULAR_POTASSIUM_ION_HOMEOSTASIS, GOBP_INTRACELLULAR_SODIUM_ION_HOMEOSTASIS, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_HOMEOSTASIS

GO Biological Process (6): sodium ion transport (GO:0006814), potassium ion transmembrane transport (GO:0071805), positive regulation of sodium ion export across plasma membrane (GO:1903278), monoatomic ion transport (GO:0006811), potassium ion transport (GO:0006813), regulation of monoatomic ion transport (GO:0043269)

GO Molecular Function (3): sodium channel regulator activity (GO:0017080), ATPase binding (GO:0051117), ion channel regulator activity (GO:0099106)

GO Cellular Component (4): plasma membrane (GO:0005886), sodium:potassium-exchanging ATPase complex (GO:0005890), basolateral plasma membrane (GO:0016323), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cardiac conduction	1
Ion channel transport	1
SARS-CoV Infections	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	2
potassium ion transport	1
monoatomic cation transmembrane transport	1
sodium ion export across plasma membrane	1
positive regulation of sodium ion transmembrane transport	1
regulation of sodium ion export across plasma membrane	1
transport	1
monoatomic ion transport	1
regulation of transport	1
sodium channel activity	1
ion channel regulator activity	1
enzyme binding	1
monoatomic ion channel activity	1
channel regulator activity	1
membrane	1
cell periphery	1
cation-transporting ATPase complex	1
plasma membrane protein complex	1
basal plasma membrane	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

490 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FXYD4	GJD4	Q96KN9	961
FXYD4	FXYD7	P58549	829
FXYD4	FXYD2	P54710	777
FXYD4	FXYD5	Q96DB9	720
FXYD4	A0A087WZ82	A0A087WZ82	598
FXYD4	SPINK14	Q6IE38	594
FXYD4	SPINK9	Q5DT21	571
FXYD4	COXFA4L2	Q9NRX3	553
FXYD4	SPINK7	P58062	552
FXYD4	OR1E1	P30953	545
FXYD4	ATP6V1C2	Q8NEY4	536
FXYD4	FXYD1	O00168	529
FXYD4	PILRA	Q9UKJ1	467
FXYD4	SPATA18	Q8TC71	447
FXYD4	UNC45B	Q8IWX7	444

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ATP1A1	ATP1B1	psi-mi:“MI:0915”(physical association)	0.910

ESM2 similar proteins: A4F4L0, O00453, O14669, O43914, O54885, P04234, P04235, P07766, P0CAN6, P18438, P19377, P20963, P24161, P29328, P29329, P59646, Q13113, Q28072, Q28073, Q2KIP5, Q3TYX2, Q5R1Q1, Q5RA41, Q63113, Q64159, Q6AYD4, Q6ITQ4, Q6X9T7, Q764N2, Q8K1T1, Q8MII8, Q8N386, Q8NET5, Q8R182, Q8WNQ8, Q923S2, Q925F2, Q95J79, Q95LI5, Q95LI8

Diamond homologs: G1TZA0, I3LMB3, O00168, O08589, O13001, O97797, P54710, P56513, P58549, P58550, P59645, P59646, P59647, P59648, P59649, Q04645, Q04646, Q04679, Q04680, Q14802, Q3MHZ5, Q3SZX0, Q3ZBJ3, Q4R566, Q5RB29, Q61835, Q63113, Q91XV6, Q96DB9, Q9D164, Q9D2W0, Q9H0Q3, Q9Z239, W5P3P0, P97808, C0HJJ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
393538	GRCh37/hg19 10q11.21(chr10:43796180-44037408)x3	Likely pathogenic

SpliceAI

1141 predictions. Top by Δscore:

Variant	Effect	Δscore
10:43372769:GTTG:G	donor_gain	1.0000
10:43374466:ACAG:A	acceptor_gain	1.0000
10:43374467:C:G	acceptor_gain	1.0000
10:43374467:CAGGC:C	acceptor_loss	1.0000
10:43374468:A:AG	acceptor_gain	1.0000
10:43374468:A:AT	acceptor_loss	1.0000
10:43374469:G:GG	acceptor_gain	1.0000
10:43374469:GGC:G	acceptor_gain	1.0000
10:43375572:GA:G	donor_gain	1.0000
10:43375574:G:GG	donor_gain	1.0000
10:43375690:CCCAG:C	acceptor_loss	1.0000
10:43375691:CCAG:C	acceptor_loss	1.0000
10:43375693:A:AG	acceptor_gain	1.0000
10:43375693:AGGT:A	acceptor_gain	1.0000
10:43375694:G:GG	acceptor_gain	1.0000
10:43375694:G:GT	acceptor_loss	1.0000
10:43375694:GGT:G	acceptor_gain	1.0000
10:43375694:GGTG:G	acceptor_gain	1.0000
10:43376030:A:AG	acceptor_gain	1.0000
10:43376031:G:GG	acceptor_gain	1.0000
10:43372721:TTACA:T	acceptor_loss	0.9900
10:43372722:TACA:T	acceptor_loss	0.9900
10:43372724:CA:C	acceptor_loss	0.9900
10:43372725:A:AC	acceptor_loss	0.9900
10:43372772:GGT:G	donor_loss	0.9900
10:43372773:G:GG	donor_gain	0.9900
10:43372774:T:A	donor_loss	0.9900
10:43372775:AAGTT:A	donor_loss	0.9900
10:43374464:A:AG	acceptor_gain	0.9900
10:43374465:C:G	acceptor_gain	0.9900

AlphaMissense

570 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:43375531:T:C	C44R	0.952
10:43375537:G:A	G46R	0.944
10:43375537:G:C	G46R	0.944
10:43375555:G:A	G52R	0.941
10:43375555:G:C	G52R	0.941
10:43375503:G:C	W34C	0.937
10:43375503:G:T	W34C	0.937
10:43374630:T:C	F30L	0.934
10:43374632:C:A	F30L	0.934
10:43374632:C:G	F30L	0.934
10:43375553:C:A	A51D	0.924
10:43375547:C:A	A49D	0.921
10:43375556:G:A	G52E	0.921
10:43375538:G:A	G46E	0.912
10:43375541:T:G	L47R	0.900
10:43375544:T:G	L48R	0.897
10:43375541:T:A	L47H	0.890
10:43375523:G:A	G41E	0.873
10:43375526:T:C	L42P	0.864
10:43375522:G:A	G41R	0.855
10:43375522:G:C	G41R	0.855
10:43375535:G:A	G45E	0.854
10:43375544:T:A	L48Q	0.847
10:43375534:G:A	G45R	0.842
10:43375534:G:C	G45R	0.842
10:43375511:T:C	L37P	0.840
10:43374631:T:G	F30C	0.839
10:43375559:T:A	I53N	0.832
10:43375550:T:A	I50N	0.824
10:43375555:G:T	G52W	0.821

dbSNP variants (sampled 300 via entrez): RS1000146563 (10:43370236 A>T), RS1000213898 (10:43371609 A>G), RS1000248334 (10:43370545 G>A), RS1000299501 (10:43376317 C>T), RS1000642000 (10:43375009 G>A), RS1002209672 (10:43374528 C>A,T), RS1002877392 (10:43371519 G>A,C), RS1003114558 (10:43371172 T>C), RS1003211039 (10:43373058 G>A), RS1003867084 (10:43372905 A>G), RS1004441547 (10:43376590 T>C), RS1004578202 (10:43373080 G>A,T), RS1004774125 (10:43375442 TG>T), RS1006512278 (10:43371576 C>G,T), RS1006565246 (10:43375316 C>T)

Disease associations

OMIM: gene MIM:616926 | disease phenotypes: MIM:192350

GenCC curated gene-disease

Mondo (1): VACTERL/vater association (MONDO:0008642)

Orphanet (1): VACTERL/VATER association (Orphanet:887)

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002336_5	Telomere length	7.000000e-06
GCST005986_13	Blood urea nitrogen levels	2.000000e-10
GCST006979_575	Heel bone mineral density	1.000000e-09
GCST009391_306	Metabolite levels	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0010429	triacylglycerol 56:2 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Methotrexate	increases expression	1
Progesterone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03799705	Not specified	COMPLETED	Genetic Variants in Nicotinamide Adenine Dinucleotide (NAD) Synthesis Pathway