FHL5

Summary

FHL5 (four and a half LIM domains 5, HGNC:17371) is a protein-coding gene on chromosome 6q16.1, encoding Four and a half LIM domains protein 5 (Q5TD97). May be involved in the regulation of spermatogenesis.

The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene. Polymorphisms in this gene may be associated with susceptibility for migraine headaches. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 9457 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_001322466

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17371
Approved symbol	FHL5
Name	four and a half LIM domains 5
Location	6q16.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ33049, ACT, dJ393D12.2
Ensembl gene	ENSG00000112214
Ensembl biotype	protein_coding
OMIM	605126
Entrez	9457

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 11 protein_coding

ENST00000326771, ENST00000450218, ENST00000541107, ENST00000861163, ENST00000861164, ENST00000861165, ENST00000944465, ENST00000944466, ENST00000944467, ENST00000944468, ENST00000944469

RefSeq mRNA: 4 — MANE Select: NM_001322466 NM_001170807, NM_001322466, NM_001322467, NM_020482

CCDS: CCDS5035

Canonical transcript exons

ENST00000450218 — 6 exons

Exon	Start	End
ENSE00000760835	96605902	96606071
ENSE00000760836	96610572	96610758
ENSE00000840214	96603602	96603772
ENSE00002519369	96604750	96604924
ENSE00003916835	96563128	96563355
ENSE00003917615	96615609	96618626

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 98.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.6472 / max 176.6279, expressed in 181 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68941	0.7114	161
68942	0.5113	155
68939	0.1229	3
68943	0.1226	63
68940	0.1002	55
68944	0.0599	37
68945	0.0189	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
popliteal artery	UBERON:0002250	98.93	gold quality
tibial artery	UBERON:0007610	98.93	gold quality
right coronary artery	UBERON:0001625	97.56	gold quality
sperm	CL:0000019	97.13	gold quality
blood vessel layer	UBERON:0004797	96.37	gold quality
left coronary artery	UBERON:0001626	95.26	gold quality
right testis	UBERON:0004534	94.88	gold quality
left testis	UBERON:0004533	94.75	gold quality
coronary artery	UBERON:0001621	94.54	gold quality
male germ cell	CL:0000015	94.48	gold quality
aorta	UBERON:0000947	94.19	gold quality
pericardium	UBERON:0002407	92.71	gold quality
testis	UBERON:0000473	92.11	gold quality
calcaneal tendon	UBERON:0003701	91.49	gold quality
adult organism	UBERON:0007023	91.15	gold quality
descending thoracic aorta	UBERON:0002345	91.13	gold quality
thoracic aorta	UBERON:0001515	88.13	gold quality
saphenous vein	UBERON:0007318	88.05	gold quality
superficial temporal artery	UBERON:0001614	87.91	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.83	gold quality
ascending aorta	UBERON:0001496	87.61	gold quality
endocervix	UBERON:0000458	87.46	gold quality
right lung	UBERON:0002167	86.71	gold quality
omental fat pad	UBERON:0010414	86.32	gold quality
peritoneum	UBERON:0002358	86.28	gold quality
left uterine tube	UBERON:0001303	86.07	gold quality
gall bladder	UBERON:0002110	84.83	gold quality
lower lobe of lung	UBERON:0008949	84.75	gold quality
tibial nerve	UBERON:0001323	84.32	gold quality
adipose tissue of abdominal region	UBERON:0007808	84.07	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	57.61
E-MTAB-6678	yes	11.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting FHL5, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4495	99.82	72.08	3080

Literature-anchored findings (GeneRIF, showing 8)

• No difference was found in the levels of ICER transcripts in thyroid adenomas and surrounding normal tissue (obtained at surgery), independently of the TSH receptor gene status. (PMID:12039695)
• Different haplotypes within the ACT gene may contribute to male factor subfertility. (PMID:16687568)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• Results indicate that SPAG8 acts as a regulator of ACT and plays an important role in CREM-ACT-mediated gene transcription during spermatogenesis. (PMID:20488182)
• Identified CREB activators MAPKAPK3 and FHL5 as mediators of intimal hyperplasia in vein graft samples. (PMID:23127979)
• Common variants in KCNK5 and FHL5 genes contributed to the susceptibility of migraine without aura in Han Chinese population. (PMID:33762637)
• FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells. (PMID:37017084)
• Association of FHL5 and LPA genetic polymorphisms with diabetes mellitus risk: a case-control study. (PMID:37452735)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fhl5	ENSDARG00000014805
mus_musculus	Fhl5	ENSMUSG00000028259
rattus_norvegicus	Fhl5	ENSRNOG00000007680
caenorhabditis_elegans	lim-9	WBGENE00006407

Paralogs (2): FHL2 (ENSG00000115641), FHL3 (ENSG00000183386)

Protein

Protein identifiers

Four and a half LIM domains protein 5 — Q5TD97 (reviewed: Q5TD97)

Alternative names: Activator of cAMP-responsive element modulator in testis

All UniProt accessions (2): Q5TD97, X6RED3

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in the regulation of spermatogenesis. Stimulates CREM transcriptional activity in a phosphorylation-independent manner.

Subunit / interactions. Interacts with CREM (via the third LIM domain). Interacts (via second LIM domain) with SPAG8.

Subcellular location. Nucleus.

Tissue specificity. Testis-specific (at protein level).

RefSeq proteins (4): NP_001164278, NP_001309395, NP_001309396, NP_065228 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001781	Znf_LIM	Domain
IPR042947	FHL5_LIM2	Domain
IPR056807	LIM_FHL1/2/3/5_N	Domain

Pfam: PF00412, PF25076

UniProt features (23 total): strand 5, domain 4, turn 4, sequence variant 4, sequence conflict 3, chain 1, helix 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1X68	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TD97-F1	90.09	0.72

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 64 (showing top): ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, TGGAAA_NFAT_Q4_01, GOCC_I_BAND, MATZUK_SPERMATOZOA, ROVERSI_GLIOMA_COPY_NUMBER_DN, GOMF_TRANSCRIPTION_COACTIVATOR_ACTIVITY, BIOCARTA_CREM_PATHWAY, GOBP_POSITIVE_REGULATION_OF_TRANSCRIPTION_BY_RNA_POLYMERASE_II, GOCC_SUPRAMOLECULAR_COMPLEX, GOMF_TRANSCRIPTION_COREGULATOR_ACTIVITY, RELA_DN.V1_UP, GOCC_SUPRAMOLECULAR_POLYMER, GOMF_TRANSCRIPTION_REGULATOR_ACTIVITY, GSE10094_LCMV_VS_LISTERIA_IND_EFF_CD4_TCELL_DN, MIR3680_3P

GO Biological Process (1): positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (4): transcription coactivator activity (GO:0003713), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (2): nucleus (GO:0005634), Z disc (GO:0030018)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of DNA-templated transcription	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
transcription coregulator activity	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
I band	1
cellular anatomical structure	1

Protein interactions and networks

STRING

922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FHL5	CREM	Q03060	901
FHL5	KIF17	Q9P2E2	704
FHL5	CREBBP	Q92793	498
FHL5	SPATC1	Q76KD6	448
FHL5	SRF	P11831	426
FHL5	CBY2	Q8NA61	408
FHL5	UFL1	O94874	374
FHL5	TSSK6	Q9BXA6	356
FHL5	SOX30	O94993	355
FHL5	TNP2	Q05952	355
FHL5	SHCBP1L	Q9BZQ2	352
FHL5	SUGCT	Q9HAC7	348
FHL5	RFX2	P48378	339
FHL5	PRM1	P04553	337
FHL5	ZNF175	Q9Y473	330

IntAct

298 interactions, top by confidence:

A	B	Type	Score
DNAL4	FHL5	psi-mi:“MI:0915”(physical association)	0.800
ATOSB	FHL5	psi-mi:“MI:0915”(physical association)	0.740
FHL5	SCNM1	psi-mi:“MI:0915”(physical association)	0.740
ZNF131	FHL5	psi-mi:“MI:0915”(physical association)	0.670
	FHL5	psi-mi:“MI:0915”(physical association)	0.560
FHL5		psi-mi:“MI:0915”(physical association)	0.560
CRYBA4	FHL5	psi-mi:“MI:0915”(physical association)	0.560
BANP	FHL5	psi-mi:“MI:0915”(physical association)	0.560
ZNF688	FHL5	psi-mi:“MI:0915”(physical association)	0.560
ANKRD55	FHL5	psi-mi:“MI:0915”(physical association)	0.560
ZNF124	FHL5	psi-mi:“MI:0915”(physical association)	0.560
FHL5	CTSZ	psi-mi:“MI:0915”(physical association)	0.560
FHL5	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
FHL5	SHFL	psi-mi:“MI:0915”(physical association)	0.560
AGXT	FHL5	psi-mi:“MI:0915”(physical association)	0.560
FHL5	DLGAP4	psi-mi:“MI:0915”(physical association)	0.560
FHL5	ZNF587	psi-mi:“MI:0915”(physical association)	0.560
FHL5	NPDC1	psi-mi:“MI:0915”(physical association)	0.560
ZNF23	FHL5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (126): SCNM1 (Affinity Capture-MS), ZNF24 (Affinity Capture-MS), TAX1BP1 (Affinity Capture-MS), ZMYM6 (Affinity Capture-MS), ZMYM1 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), CEP76 (Affinity Capture-MS), ZBTB33 (Affinity Capture-MS), CTU1 (Affinity Capture-MS), ZNF131 (Affinity Capture-MS), DNAL4 (Two-hybrid), FHL5 (PCA), Hoxa1 (Affinity Capture-Western), Fhl4 (Two-hybrid), FHL5 (Two-hybrid)

ESM2 similar proteins: A0M8R4, O04193, O35115, O70433, O80839, P21291, P29675, P47875, P50238, P50461, P50462, P50463, P50464, P53777, P63254, P63255, P67966, P67967, P97315, P97447, Q07DY3, Q07DZ4, Q09YI0, Q13642, Q13643, Q14192, Q16527, Q1ECF5, Q2IBA3, Q2KI95, Q2QLF4, Q2YDK0, Q32LE9, Q3MHY1, Q3ZBI6, Q4R7A4, Q4U0T9, Q500W4, Q56K04, Q5RC52

Diamond homologs: A0A1L8F1M4, A0M8R4, A0M8S5, A0M8U6, A1Z6W3, A8WH69, O43294, O43900, P47226, Q00PK1, Q04650, Q07DW1, Q07DX3, Q07DY3, Q07DZ4, Q07E27, Q07E40, Q07E51, Q09YI0, Q09YJ2, Q09YK3, Q09YL5, Q09YN8, Q108U9, Q174I2, Q17QE2, Q28FG2, Q292U2, Q292U5, Q2IBA3, Q2IBC3, Q2IBH0, Q2LAP6, Q2QL92, Q2QLA1, Q2QLB2, Q2QLC3, Q2QLE3, Q2QLF4, Q2QLG8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
FHL5	“up-regulates activity”	CREM	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	46
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1080 predictions. Top by Δscore:

Variant	Effect	Δscore
6:96604746:AAAG:A	acceptor_gain	0.9900
6:96604921:CCTGG:C	donor_loss	0.9900
6:96604922:CTGGT:C	donor_loss	0.9900
6:96604923:TGGTA:T	donor_loss	0.9900
6:96604925:GTAG:G	donor_loss	0.9900
6:96604926:T:A	donor_loss	0.9900
6:96604745:CAAA:C	acceptor_loss	0.9800
6:96604748:AGG:A	acceptor_loss	0.9800
6:96604749:G:A	acceptor_gain	0.9800
6:96604749:G:GT	acceptor_loss	0.9800
6:96604920:GCCTG:G	donor_gain	0.9800
6:96610756:GTG:G	donor_gain	0.9800
6:96615606:CA:C	acceptor_loss	0.9800
6:96615607:A:C	acceptor_loss	0.9800
6:96615608:G:GT	acceptor_loss	0.9800
6:96603596:TCATA:T	acceptor_loss	0.9700
6:96603597:CATA:C	acceptor_loss	0.9700
6:96603598:ATAGG:A	acceptor_loss	0.9700
6:96603599:TAGG:T	acceptor_loss	0.9700
6:96603600:A:AC	acceptor_loss	0.9700
6:96603600:A:AG	acceptor_gain	0.9700
6:96603601:G:A	acceptor_loss	0.9700
6:96603601:G:GG	acceptor_gain	0.9700
6:96604740:T:A	acceptor_gain	0.9700
6:96604863:G:GT	donor_gain	0.9700
6:96604925:G:GG	donor_gain	0.9700
6:96606068:GAAG:G	donor_gain	0.9700
6:96603586:ACTTT:A	acceptor_loss	0.9600
6:96603769:TAAGG:T	donor_loss	0.9600
6:96603770:AAGGT:A	donor_loss	0.9600

AlphaMissense

1410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:96606056:C:G	C163W	0.989
6:96605955:T:C	C130R	0.988
6:96604831:T:C	F81L	0.987
6:96604833:T:A	F81L	0.987
6:96604833:T:G	F81L	0.987
6:96606055:G:A	C163Y	0.987
6:96606054:T:A	C163S	0.985
6:96606055:G:C	C163S	0.985
6:96604817:T:C	L76S	0.984
6:96605964:T:A	C133S	0.983
6:96605965:G:C	C133S	0.983
6:96605955:T:A	C130S	0.982
6:96605956:G:C	C130S	0.982
6:96605957:T:G	C130W	0.982
6:96610634:T:G	C189W	0.982
6:96605966:C:G	C133W	0.981
6:96606054:T:C	C163R	0.981
6:96606063:T:A	C166S	0.981
6:96606064:G:C	C166S	0.981
6:96605946:T:C	C127R	0.980
6:96610632:T:A	C189S	0.980
6:96610633:G:C	C189S	0.980
6:96604790:T:C	F67S	0.979
6:96605939:T:A	H124Q	0.979
6:96605939:T:G	H124Q	0.979
6:96605956:G:A	C130Y	0.979
6:96606018:T:C	C151R	0.979
6:96610632:T:C	C189R	0.979
6:96604894:T:A	C102S	0.978
6:96604895:G:C	C102S	0.978

dbSNP variants (sampled 300 via entrez): RS1000030124 (6:96598063 T>C), RS1000036928 (6:96562659 G>A,T), RS1000038772 (6:96577475 C>A,G,T), RS1000044067 (6:96591104 G>A,C), RS1000096227 (6:96561445 T>G), RS1000119344 (6:96603037 G>A), RS1000177859 (6:96595241 A>G), RS1000274086 (6:96580986 C>T), RS1000281403 (6:96599447 G>A), RS1000368221 (6:96564706 G>T), RS1000399066 (6:96617901 A>C), RS1000420572 (6:96564897 G>A), RS1000447288 (6:96586702 T>C), RS1000475351 (6:96605801 C>A,T), RS1000606248 (6:96588642 A>G)

Disease associations

OMIM: gene MIM:605126 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001401_2	Coronary heart disease	6.000000e-07
GCST001563_8	Migraine	6.000000e-08
GCST002078_31	Migraine without aura	2.000000e-12
GCST002079_5	Migraine - clinic-based	4.000000e-07
GCST002081_8	Migraine	1.000000e-11
GCST003542_90	Night sleep phenotypes	6.000000e-08
GCST003542_91	Night sleep phenotypes	1.000000e-08
GCST003720_16	Migraine	6.000000e-10
GCST003720_22	Migraine	2.000000e-27
GCST003721_4	Migraine without aura	1.000000e-12
GCST003986_1	Migraine	6.000000e-21
GCST004376_1	Cerebral blood flow	3.000000e-09
GCST005196_130	Coronary artery disease	2.000000e-07
GCST005337_2	Headache	3.000000e-31
GCST007269_251	Pulse pressure	6.000000e-09
GCST009307_17	Spatial memory	7.000000e-06
GCST009391_1142	Metabolite levels	4.000000e-07
GCST011365_70	Myocardial infarction	7.000000e-10
GCST012478_4	Cluster headache	2.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0004874	memory performance
EFO:0010457	Alpha ketoglutarate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, affects cotreatment	1
Fulvestrant	decreases methylation, affects cotreatment	1
Benzo(a)pyrene	decreases methylation	1
Methotrexate	decreases expression	1
Zinc	decreases expression	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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