CARF

Summary

CARF (calcium responsive transcription factor, HGNC:14435) is a protein-coding gene on chromosome 2q33.2, encoding Calcium-responsive transcription factor (Q8N187). Acts as a transcriptional activator that mediates the calcium- and neuron-selective induction of BDNF exon III transcription.

Enables DNA binding activity and DNA-binding transcription activator activity, RNA polymerase II-specific. Involved in cellular response to calcium ion. Predicted to be located in granular component. Predicted to be active in nucleus.

Source: NCBI Gene 79800 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 121 total
• MANE Select transcript: NM_024744

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14435
Approved symbol	CARF
Name	calcium responsive transcription factor
Location	2q33.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ21579, NYD-SP24
Ensembl gene	ENSG00000138380
Ensembl biotype	protein_coding
OMIM	607586
Entrez	79800

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 21 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000320443, ENST00000402905, ENST00000414439, ENST00000414490, ENST00000414857, ENST00000422368, ENST00000427712, ENST00000428585, ENST00000430899, ENST00000431787, ENST00000432024, ENST00000434998, ENST00000438828, ENST00000441569, ENST00000443740, ENST00000444724, ENST00000445120, ENST00000447539, ENST00000457031, ENST00000471271, ENST00000877496, ENST00000877497, ENST00000877498, ENST00000919375, ENST00000943229

RefSeq mRNA: 12 — MANE Select: NM_024744 NM_001104586, NM_001282910, NM_001282911, NM_001282912, NM_001322427, NM_001322428, NM_001322429, NM_001352676, NM_001352677, NM_001352678, NM_001352679, NM_024744

CCDS: CCDS42801, CCDS63091

Canonical transcript exons

ENST00000438828 — 17 exons

Exon	Start	End
ENSE00001526547	202924297	202924415
ENSE00001617071	202971505	202971738
ENSE00001624404	202983506	202988263
ENSE00001638218	202961237	202961426
ENSE00001676928	202974334	202974496
ENSE00001686119	202977269	202977332
ENSE00001730849	202982072	202982441
ENSE00001776252	202912275	202913102
ENSE00001792789	202981555	202981685
ENSE00003470381	202941860	202941980
ENSE00003473669	202942740	202942967
ENSE00003493138	202954005	202954134
ENSE00003502795	202917877	202918043
ENSE00003504358	202966978	202967098
ENSE00003539811	202955674	202955758
ENSE00003588740	202969919	202970062
ENSE00003755550	202952559	202952679

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 86.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6004 / max 108.5483, expressed in 1662 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
24733	7.6004	1662

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	86.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.71	gold quality
ventricular zone	UBERON:0003053	80.21	gold quality
right uterine tube	UBERON:0001302	79.70	gold quality
adrenal tissue	UBERON:0018303	79.57	gold quality
sural nerve	UBERON:0015488	78.37	gold quality
gall bladder	UBERON:0002110	78.16	gold quality
ganglionic eminence	UBERON:0004023	78.10	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.01	gold quality
cortical plate	UBERON:0005343	77.87	gold quality
popliteal artery	UBERON:0002250	77.45	gold quality
tibial artery	UBERON:0007610	77.44	gold quality
islet of Langerhans	UBERON:0000006	77.31	gold quality
rectum	UBERON:0001052	77.20	gold quality
left ovary	UBERON:0002119	77.18	gold quality
tibial nerve	UBERON:0001323	77.11	gold quality
left lobe of thyroid gland	UBERON:0001120	76.90	gold quality
body of uterus	UBERON:0009853	76.86	gold quality
right ovary	UBERON:0002118	76.71	gold quality
corpus callosum	UBERON:0002336	76.68	gold quality
tendon	UBERON:0000043	76.65	gold quality
monocyte	CL:0000576	76.59	gold quality
colonic epithelium	UBERON:0000397	76.54	gold quality
stromal cell of endometrium	CL:0002255	76.43	gold quality
right lobe of thyroid gland	UBERON:0001119	76.40	gold quality
mononuclear cell	CL:0000842	76.35	gold quality
thyroid gland	UBERON:0002046	76.30	gold quality
mucosa of stomach	UBERON:0001199	76.14	gold quality
endothelial cell	CL:0000115	76.04	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

177 targeting CARF, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-548N	99.98	71.94	4170

Literature-anchored findings (GeneRIF, showing 4)

• Cloned as a calcium- and neural-selective transcriptional activator of the gene for Brain-Derived Neurotrophic Factor (BDNF). (PMID:11832226)
• Data demonstrate that CARF is a new target of miR-451 that mediates its tumor suppressor function in normal and stressed biological states. (PMID:29321561)
• Wi-A caused upregulation of CARF (collaborator of ARF) demonstrating an activation of DNA damage oxidative stress response in both cancer and normal cells. In line with this, upregulation of p21WAF1, p16INK4A, and hypophosphorylated pRB and induction of senescence were observed demonstrating that Wi-A-induced senescence is mediated by multiple pathways in which CARF-mediated DNA damage and oxidative stress play a major ro (PMID:29718136)
• Inhibition of MicroRNA-302c on Stemness of Colon Cancer Stem Cells via the CARF/Wnt/beta-Catenin Axis. (PMID:32617772)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	carf	ENSDARG00000019950
mus_musculus	Carf	ENSMUSG00000026017
rattus_norvegicus	Carf	ENSRNOG00000017491

Protein

Protein identifiers

Calcium-responsive transcription factor — Q8N187 (reviewed: Q8N187)

Alternative names: Amyotrophic lateral sclerosis 2 chromosomal region candidate gene 8 protein, Calcium-response factor, Testis development protein NYD-SP24

All UniProt accessions (15): A0A1B0GX63, C9JBK9, C9JCD6, C9JI92, C9JL40, C9JN29, C9JSN4, C9JT99, C9JZ91, C9JZI6, Q8N187, F6SXV3, F8WC01, F8WDH0, F8WDW1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator that mediates the calcium- and neuron-selective induction of BDNF exon III transcription. Binds to the consensus calcium-response element CaRE1 5’-CTATTTCGAG-3’ sequence.

Subcellular location. Nucleus.

Domain organisation. The N-terminus is necessary for DNA-binding. The C-terminus is necessary for transcriptional activation.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N187-1	1	yes
Q8N187-2	2
Q8N187-3	3

RefSeq proteins (12): NP_001098056, NP_001269839, NP_001269840, NP_001269841, NP_001309356, NP_001309357, NP_001309358, NP_001339605, NP_001339606, NP_001339607, NP_001339608, NP_079020* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029309	CaRF	Family

Pfam: PF15299

UniProt features (11 total): sequence conflict 4, splice variant 4, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N187-F1	56.59	0.26

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 182 (showing top): GGGACCA_MIR133A_MIR133B, RNGTGGGC_UNKNOWN, TGCGCANK_UNKNOWN, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GTCTACC_MIR379, GOBP_RESPONSE_TO_METAL_ION, LYF1_01, GOBP_CELLULAR_RESPONSE_TO_CALCIUM_ION, RYTTCCTG_ETS2_B, GATA4_Q3, HOXA4_Q2, GOBP_RESPONSE_TO_CALCIUM_ION, GOCC_NUCLEOLUS, SCGGAAGY_ELK1_02, MGGAAGTG_GABP_B

GO Biological Process (4): regulation of transcription by RNA polymerase II (GO:0006357), cellular response to calcium ion (GO:0071277), regulation of DNA-templated transcription (GO:0006355), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (6): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), DNA-binding transcription factor activity (GO:0003700), protein binding (GO:0005515)

GO Cellular Component (2): granular component (GO:0001652), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
response to calcium ion	1
cellular response to metal ion	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
nucleic acid binding	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
binding	1
nucleolus	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

508 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CARF	BDNF	P23560	637
CARF	MECP2	P51608	505
CARF	TRPC6	Q9Y210	493
CARF	CPA5	Q8WXQ8	478
CARF	NTRK2	Q16620	476
CARF	THADA	Q6YHU6	457
CARF	NBEAL1	Q6ZS30	456
CARF	NTF4	P34130	454
CARF	USF1	P22415	453
CARF	NTF3	P20783	451
CARF	TRPC3	Q13507	430
CARF	HAP1	P54257	429
CARF	MMP7	P09237	424
CARF	SIN3A	Q96ST3	423
CARF	NTRK3	Q16288	421

IntAct

20 interactions, top by confidence:

A	B	Type	Score
CISH	CARF	psi-mi:“MI:0915”(physical association)	0.560
DDX21	CARF	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	CARF	psi-mi:“MI:0915”(physical association)	0.560
CEP55	CARF	psi-mi:“MI:0915”(physical association)	0.560
ZBTB38	CARF	psi-mi:“MI:0915”(physical association)	0.560
CARF	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ECE1	CARF	psi-mi:“MI:0915”(physical association)	0.370
LMO3	CARF	psi-mi:“MI:0915”(physical association)	0.370
purCD	CARF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): CARF (Two-hybrid), CARF (Reconstituted Complex), CARF (Affinity Capture-MS), APP (Reconstituted Complex)

ESM2 similar proteins: A0FIN4, A2VD01, A9ZLX4, D2HNW6, D4A7U2, O88974, O94988, P10914, P14316, P15314, P16236, P17433, P17947, P23570, P23906, P49140, Q00IB7, Q13506, Q13905, Q15047, Q1LY51, Q3B7M3, Q3SZP0, Q3TTA7, Q3UWM4, Q4V7W5, Q5HYC2, Q5RJA1, Q5XJV7, Q61122, Q62722, Q6A098, Q6AI12, Q6BDS1, Q6DFR2, Q6GQL0, Q6PKU1, Q6ZMT4, Q6ZNC4, Q80TJ7

Diamond homologs: D4A7U2, Q58CW6, Q8N187, Q8VHI4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	86
Likely benign	11
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

3313 predictions. Top by Δscore:

Variant	Effect	Δscore
2:202912322:GAGGT:G	donor_gain	1.0000
2:202912324:GGT:G	donor_gain	1.0000
2:202912326:T:G	donor_gain	1.0000
2:202914369:A:AG	acceptor_gain	1.0000
2:202914369:AATTT:A	acceptor_gain	1.0000
2:202914370:A:G	acceptor_gain	1.0000
2:202917871:TTACA:T	acceptor_loss	1.0000
2:202917874:CAGA:C	acceptor_loss	1.0000
2:202917875:A:AG	acceptor_gain	1.0000
2:202917876:G:GG	acceptor_gain	1.0000
2:202917876:GA:G	acceptor_gain	1.0000
2:202917876:GAGA:G	acceptor_gain	1.0000
2:202917876:GAGAA:G	acceptor_gain	1.0000
2:202941858:A:AG	acceptor_gain	1.0000
2:202941859:G:GG	acceptor_gain	1.0000
2:202941859:GCT:G	acceptor_gain	1.0000
2:202942735:A:AG	acceptor_gain	1.0000
2:202942736:A:G	acceptor_gain	1.0000
2:202952547:A:AG	acceptor_gain	1.0000
2:202952548:A:G	acceptor_gain	1.0000
2:202952556:A:AG	acceptor_gain	1.0000
2:202952556:AAGAT:A	acceptor_gain	1.0000
2:202952557:A:G	acceptor_gain	1.0000
2:202954003:A:G	acceptor_gain	1.0000
2:202954004:G:GG	acceptor_gain	1.0000
2:202954004:GAT:G	acceptor_gain	1.0000
2:202955667:A:AG	acceptor_gain	1.0000
2:202955668:T:G	acceptor_gain	1.0000
2:202955672:A:AG	acceptor_gain	1.0000
2:202955673:G:GG	acceptor_gain	1.0000

AlphaMissense

4752 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:202961327:T:A	W245R	1.000
2:202961327:T:C	W245R	1.000
2:202961378:T:A	W262R	1.000
2:202961378:T:C	W262R	1.000
2:202961380:G:C	W262C	1.000
2:202961380:G:T	W262C	1.000
2:202961394:T:A	V267D	1.000
2:202961412:C:A	P273Q	1.000
2:202961414:T:C	F274L	1.000
2:202961416:T:A	F274L	1.000
2:202961416:T:G	F274L	1.000
2:202967001:T:C	C286R	1.000
2:202967088:T:C	C315R	1.000
2:202969931:A:C	K322N	1.000
2:202969931:A:T	K322N	1.000
2:202955732:T:A	W206R	0.999
2:202955732:T:C	W206R	0.999
2:202955734:G:C	W206C	0.999
2:202955734:G:T	W206C	0.999
2:202961252:T:G	Y220D	0.999
2:202961256:G:C	R221P	0.999
2:202961258:G:C	G222R	0.999
2:202961259:G:A	G222D	0.999
2:202961336:C:A	R248S	0.999
2:202961379:G:C	W262S	0.999
2:202961384:T:C	S264P	0.999
2:202961390:T:C	Y266H	0.999
2:202961406:G:T	G271V	0.999
2:202961412:C:G	P273R	0.999
2:202961415:T:C	F274S	0.999

dbSNP variants (sampled 300 via entrez): RS1000080800 (2:202935164 A>T), RS1000177427 (2:202949074 G>A), RS1000188138 (2:202965251 A>T), RS1000194436 (2:202987791 G>A,C), RS1000198006 (2:202964823 A>T), RS1000236425 (2:202918794 C>T), RS1000244206 (2:202949521 T>A,G), RS1000285913 (2:202986102 G>A), RS1000344758 (2:202931808 G>A), RS1000383958 (2:202958097 A>T), RS1000384530 (2:202950943 T>C), RS1000405063 (2:202956500 C>G,T), RS1000457632 (2:202951190 G>A,T), RS1000466455 (2:202942057 G>A), RS1000469635 (2:202972404 C>G,T)

Disease associations

OMIM: gene MIM:607586 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003986_9	Migraine	4.000000e-10
GCST008876_37	Non-lobar intracerebral hemorrhage (MTAG)	1.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010178	non-lobar intracerebral hemorrhage

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	3
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	decreases expression	1
sodium arsenite	affects splicing, decreases expression	1
cobaltous chloride	decreases expression, increases expression	1
butyraldehyde	decreases expression	1
resorcinol	decreases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, increases expression	1
licochalcone B	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression	1
Amphotericin B	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	decreases expression	1

Clinical trials (associated diseases)

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