FHL2

Summary

FHL2 (four and a half LIM domains 2, HGNC:3703) is a protein-coding gene on chromosome 2q12.2, encoding Four and a half LIM domains protein 2 (Q14192). May function as a molecular transmitter linking various signaling pathways to transcriptional regulation.

This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. This protein is thought to have a role in the assembly of extracellular membranes. Also, this gene is down-regulated during transformation of normal myoblasts to rhabdomyosarcoma cells and the encoded protein may function as a link between presenilin-2 and an intracellular signaling pathway. Multiple alternatively spliced variants encoding different isoforms have been identified.

Source: NCBI Gene 2274 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 83 total
• Phenotypes (HPO): 13
• MANE Select transcript: NM_001318895

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3703
Approved symbol	FHL2
Name	four and a half LIM domains 2
Location	2q12.2
Locus type	gene with protein product
Status	Approved
Aliases	SLIM3, DRAL
Ensembl gene	ENSG00000115641
Ensembl biotype	protein_coding
OMIM	602633
Entrez	2274

Gene structure

Transcript identifiers

Ensembl transcripts: 63 — 62 protein_coding, 1 nonsense_mediated_decay

ENST00000322142, ENST00000344213, ENST00000358129, ENST00000393352, ENST00000393353, ENST00000408995, ENST00000409177, ENST00000409807, ENST00000447958, ENST00000452732, ENST00000530340, ENST00000607522, ENST00000876103, ENST00000876104, ENST00000876105, ENST00000876106, ENST00000876107, ENST00000876108, ENST00000876109, ENST00000876110, ENST00000876111, ENST00000876112, ENST00000876113, ENST00000876114, ENST00000876115, ENST00000876116, ENST00000876117, ENST00000876118, ENST00000876119, ENST00000876120, ENST00000876121, ENST00000876122, ENST00000926405, ENST00000971455, ENST00000971456, ENST00000971457, ENST00000971458, ENST00000971459, ENST00000971460, ENST00000971461, ENST00000971462, ENST00000971463, ENST00000971464, ENST00000971465, ENST00000971466, ENST00000971467, ENST00000971468, ENST00000971469, ENST00000971470, ENST00000971471, ENST00000971472, ENST00000971473, ENST00000971474, ENST00000971475, ENST00000971476, ENST00000971477, ENST00000971478, ENST00000971479, ENST00000971480, ENST00000971481, ENST00000971482, ENST00000971483, ENST00000971484

RefSeq mRNA: 11 — MANE Select: NM_001318895 NM_001039492, NM_001318894, NM_001318895, NM_001318896, NM_001318897, NM_001318898, NM_001318899, NM_001374399, NM_001450, NM_201555, NM_201557

CCDS: CCDS2070

Canonical transcript exons

ENST00000530340 — 7 exons

Exon	Start	End
ENSE00001515001	105398842	105399051
ENSE00003473004	105373559	105373733
ENSE00003484131	105367570	105367739
ENSE00003570347	105363285	105363471
ENSE00003595400	105396647	105396697
ENSE00003655994	105360826	105361434
ENSE00003696492	105386361	105386540

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.9480 / max 5260.1936, expressed in 1572 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
30034	37.9135	1531
30033	16.5892	1450
30038	8.1105	91
30032	2.9934	1096
30031	1.3392	484
30035	1.2156	542
30027	0.3408	171
30029	0.2259	116
30030	0.1231	63
30028	0.0889	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.83	gold quality
heart right ventricle	UBERON:0002080	99.76	gold quality
cardiac ventricle	UBERON:0002082	99.60	gold quality
heart left ventricle	UBERON:0002084	99.60	gold quality
apex of heart	UBERON:0002098	99.47	gold quality
left ovary	UBERON:0002119	99.31	gold quality
myocardium	UBERON:0002349	99.20	gold quality
right ovary	UBERON:0002118	99.09	gold quality
heart	UBERON:0000948	98.62	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.41	gold quality
cardiac atrium	UBERON:0002081	98.40	gold quality
right atrium auricular region	UBERON:0006631	98.40	gold quality
stromal cell of endometrium	CL:0002255	98.27	gold quality
urethra	UBERON:0000057	98.22	gold quality
saphenous vein	UBERON:0007318	98.01	gold quality
diaphragm	UBERON:0001103	97.69	gold quality
mucosa of urinary bladder	UBERON:0001259	97.68	gold quality
vena cava	UBERON:0004087	97.57	gold quality
body of tongue	UBERON:0011876	97.53	gold quality
smooth muscle tissue	UBERON:0001135	97.40	gold quality
ovary	UBERON:0000992	97.35	gold quality
gall bladder	UBERON:0002110	97.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.03	gold quality
myometrium	UBERON:0001296	97.01	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.98	gold quality
germinal epithelium of ovary	UBERON:0001304	96.93	gold quality
colonic mucosa	UBERON:0000317	96.85	gold quality
endocervix	UBERON:0000458	96.80	gold quality
mammary duct	UBERON:0001765	96.76	gold quality
cauda epididymis	UBERON:0004360	96.70	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	1741.73
E-GEOD-135922	yes	806.59
E-MTAB-8142	yes	603.25
E-CURD-114	yes	78.93
E-MTAB-6701	yes	78.52
E-HCAD-10	yes	49.26
E-HCAD-6	yes	49.13
E-HCAD-11	yes	47.83
E-GEOD-134144	yes	41.09
E-CURD-112	yes	36.89
E-MTAB-9067	yes	10.65
E-MTAB-6678	yes	6.17
E-MTAB-11268	no	4502.10
E-MTAB-8381	no	1034.75
E-GEOD-124858	no	901.99

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

7 targets.

Target	Regulation
CCND1	Repression
CDKN1A	Activation
CDKN1B	Activation
HAND1	Repression
NFKB1	Unknown
RELA	Unknown
TCF3	Repression

Upstream regulators (CollecTRI, top): AR, ESR1, PAX5, RUNX1, SKI, SP1, SRF, TP53, ZBTB14

miRNA regulators (miRDB)

38 targeting FHL2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4325	99.49	72.20	1342
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-26B-3P	98.71	67.49	1102
HSA-MIR-302F	98.44	69.02	1776

Literature-anchored findings (GeneRIF, showing 40)

• Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). (PMID:11821401)
• TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of NF-kappaB activation. (PMID:12067710)
• evidence of a functional interaction between the promyelocytic leukemia zinc finger protein (PLZF) and DRAL/FHL2 (PMID:12145280)
• FHL2 might enforce beta-catenin transactivation activity in cancer cells (PMID:12466281)
• -FHL2 interaction may be involved in transcriptional regulation and play a significant role in cancer cell growth (PMID:14550570)
• both the recombinant and the natural proteins are post-translationally modified and indicate that such modifications may lead to an abnormal electrophoretic behavior of natural human FHL2 (PMID:14680945)
• FHL2 and FHL3, respectively, are colocalized with alpha(7)beta(1) integrin receptor at the periphery of Z-discs, suggesting a role in mechanical stabilization of muscle cells (PMID:15117962)
• pp125FAK and FHL2 form a protein complex in human ovarian carcinoma. (PMID:15161045)
• The interaction and functional cooperation between FHL2, CITED4, and CTNNB were studied. (PMID:15572674)
• FHL2 inhibits FOXO1 activity in prostate cancer cells by promoting the deacetylation of FOXO1 by SIRT1 (PMID:15692560)
• In conclusion, our findings are consistent with the hypothesis that FHL-2 and ADAM-9 are important modulators of IGFBP-5 actions and are, in part, regulated in a coordinated manner in bone. (PMID:16311053)
• Overall, our findings indicate that FHL2 can also regulate p53 via a direct association with HIPK2. (PMID:16343438)
• FHL2 plays an important role in osteoblast differentiation and bone formation. (PMID:16355270)
• specific expression in tumor tissue points to an important functional role of FHL2 in human breast cancer (PMID:16378916)
• findings show that full-length E4F1 protein but not its E1A-activated & truncated form interacts in vitro & in vivo with FHL2; this E4F1-FHL2 association occurs in the nuclear compartment & inhibits the capacity of E4F1 to block cell proliferation (PMID:16652157)
• the interaction of FHL2 with HPV-16 E7 leads to a promoter-specific impairment of FHL2 function and this may contribute to cell transformation. (PMID:17093190)
• Data suggest that nuclear FHL2 may serve as a novel biomarker predictive for prostate cancer with aggressive biology and point to a role of FHL2 in constitutive activation of AR-mediated growth signals. (PMID:17145880)
• PELP1 functions as a molecular adaptor, coupling FHL2 with nuclear receptors, and PELP1-FHL2 interactions may have a role in prostate cancer progression. (PMID:17192406)
• Suppression of FHL2 induces cell differentiation and inhibits tumorigenesis in gastrointestinal cancers. (PMID:17383428)
• Functional analysis demonstrated that the FHL2 mutation affected the binding to titin/connectin. (PMID:17416352)
• Data indicate that overexpression of the transcriptional cofactor FHL2 contributes to breast cancer development by mediating transcriptional activation of MAPK target genes known to be involved in cancer progression, such as p21. (PMID:17682292)
• These results suggest a novel indirect mechanism of androgen action on FHL2 expression and provide evidence that SRF is an important determinant of AR action in prostate cancer cells. (PMID:17975004)
• Data suggest that IL-1beta is involved in the regulation of various cytoskeletal components in human chondrocytes including the multifunctional protein FHL2, which might be relevant for the pathogenesis of osteoarthritis. (PMID:18224250)
• Role of FHL2 in bundling of focal adhesion structures, in integrin-mediated ERK activation, and subsequently in proper allocation of matrix proteins on the cell surface. (PMID:18356303)
• Overexpression of FHL2 increases the tumorigenicity of glioblastoma cells in nude mice and decreases the mRNA levels of p53. (PMID:18615633)
• FHL2-beta-catenin interaction potentiates beta-catenin nuclear translocation and TCF/LEF transcription, resulting in increased Runx2 and alkaline phosphatase expression, which was inhibited by the Wnt inhibitor DKK1. (PMID:18653765)
• The physiological implication of HERG-FHL2 interaction showed a significant increase in the HERG current amplitude and a faster deactivation of the tail current in human embryonic kidney 293 cells co-expressing HERG and FHL2. (PMID:18680509)
• Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway. (PMID:19139564)
• FHL-2 suppresses VEGF-induced phosphatidylinositol 3-kinase/Akt activation via interaction with sphingosine kinase-1. (PMID:19325137)
• Ectopic FHL2 expression in neuroblastoma cells markedly reduces the transcriptional and cell-cycle promoting functions of Id2. (PMID:19417068)
• Data suggest that in the absence of its ligand Shh the dependence receptor Patched serves as the anchor for a caspase-activating complex that includes DRAL, and caspase-9. (PMID:19465923)
• Aryl hydrocarbon receptor (AhR) modulation of androgen receptor activity is differentially altered by the level of FHL2 and AhR present in the cell. (PMID:19815066)
• In human colorectal carcinoma but not in low-grade dysplasia, we detected up-regulation and enhanced nuclear localization of FHL2, indicating the activation of FHL2 during the development of malignancy (PMID:20442768)
• FHL2 is a potent epithelial-mesenchymal transition (EMT) inducer and might be an important mediator for invasion and/or metastasis of colon cancer. (PMID:20460358)
• In the absence of transgenic FHL2, CCL19-induced bone marrow-derived dendritic cell migratory speed, persistence, and directionality were markedly increased in vitro and in vivo. (PMID:20592280)
• Sp1 up-regulates FHL2 expression in gastrointestinal cancers through transcription regulation. (PMID:20607723)
• cooperative regulation of estrogen signaling by FHL2 and Smad4 in breast cancer cells, and might provide a new regulation mechanism underlying breast cancer development and progression (PMID:20734429)
• Our data suggest a role of FHL2 in odontoblast differentiation and dentin formation both in normal and in carious teeth (PMID:21308406)
• our results indicate FHL2 could exert anti-apoptotic effect independent of tumor growth suppression (PMID:21377781)
• Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in hereditary non-polyposis colorectal cancer. (PMID:21826055)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fhl2b	ENSDARG00000003991
danio_rerio	fhl2a	ENSDARG00000042018
mus_musculus	Fhl2	ENSMUSG00000008136
rattus_norvegicus	Fhl2	ENSRNOG00000016866
caenorhabditis_elegans	lim-9	WBGENE00006407

Paralogs (2): FHL5 (ENSG00000112214), FHL3 (ENSG00000183386)

Protein

Protein identifiers

Four and a half LIM domains protein 2 — Q14192 (reviewed: Q14192)

Alternative names: LIM domain protein DRAL, Skeletal muscle LIM-protein 3

All UniProt accessions (5): C9J3S8, Q14192, F8WDA8, Q6I9R8, U3KQT4

UniProt curated annotations — full annotation on UniProt →

Function. May function as a molecular transmitter linking various signaling pathways to transcriptional regulation. Negatively regulates the transcriptional repressor E4F1 and may function in cell growth. Inhibits the transcriptional activity of FOXO1 and its apoptotic function by enhancing the interaction of FOXO1 with SIRT1 and FOXO1 deacetylation. Negatively regulates the calcineurin/NFAT signaling pathway in cardiomyocytes.

Subunit / interactions. Interacts with ZNF638 and TTN/titin. Interacts with E4F1. Interacts with GRB7. Interacts with SIRT1 and FOXO1. Interacts with CEFIP. Interacts with calcineurin. Interacts with FOXK1.

Subcellular location. Cytoplasm. Nucleus. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed in skeletal muscle and heart.

Domain organisation. The third LIM zinc-binding mediates interaction with E4F1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14192-1	1	yes
Q14192-2	2

RefSeq proteins (11): NP_001034581, NP_001305823, NP_001305824, NP_001305825, NP_001305826, NP_001305827, NP_001305828, NP_001361328, NP_001441, NP_963849, NP_963851 (=MANE)

Domains & families (InterPro)

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

Pfam: PF00412, PF25076

UniProt features (46 total): strand 20, turn 8, helix 5, domain 4, cross-link 3, splice variant 2, chain 1, sequence variant 1, zinc finger region 1, modified residue 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1X4K	SOLUTION NMR
1X4L	SOLUTION NMR
2D8Z	SOLUTION NMR
2MIU	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14192-F1	92.27	0.81

Functional residue map

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

Post-translational modifications (4): 238, 78, 167, 220

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression

MSigDB gene sets: 387 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, MODULE_52, LIANG_HEMATOPOIESIS_STEM_CELL_NUMBER_SMALL_VS_HUGE_UP, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_HEART_TRABECULA_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, ENK_UV_RESPONSE_KERATINOCYTE_UP, chr2q12, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_VENTRICULAR_CARDIAC_MUSCLE_CELL_DIFFERENTIATION, GOBP_OSTEOBLAST_DIFFERENTIATION, NAGASHIMA_NRG1_SIGNALING_UP, GNF2_MYL3

GO Biological Process (9): negative regulation of transcription by RNA polymerase II (GO:0000122), osteoblast differentiation (GO:0001649), response to hormone (GO:0009725), negative regulation of apoptotic process (GO:0043066), atrial cardiac muscle cell development (GO:0055014), ventricular cardiac muscle cell development (GO:0055015), heart trabecula formation (GO:0060347), negative regulation of calcineurin-NFAT signaling cascade (GO:0070885), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (7): transcription corepressor activity (GO:0003714), transcription factor binding (GO:0008134), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), bHLH transcription factor binding (GO:0043425), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), focal adhesion (GO:0005925), Z disc (GO:0030018), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of lipid metabolism by PPARalpha	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	2
cardiac muscle cell development	2
protein binding	2
regulation of transcription by RNA polymerase II	1
ossification	1
cell differentiation	1
response to endogenous stimulus	1
response to chemical	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
atrial cardiac muscle cell differentiation	1
ventricular cardiac muscle cell differentiation	1
cardiac chamber morphogenesis	1
trabecula formation	1
heart trabecula morphogenesis	1
calcineurin-NFAT signaling cascade	1
regulation of calcineurin-NFAT signaling cascade	1
negative regulation of calcineurin-mediated signaling	1
regulation of DNA-templated transcription	1
transcription coregulator activity	1
transition metal ion binding	1
DNA-binding transcription factor binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cell-substrate junction	1
I band	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2188 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FHL2	CTNNB1	P35222	989
FHL2	LEF1	Q9UJU2	988
FHL2	TTN	Q8WZ42	958
FHL2	CARD8	Q9Y2G2	915
FHL2	STXBP2	Q15833	884
FHL2	STX11	O75558	880
FHL2	UNC13D	Q70J99	838
FHL2	PSEN2	P49810	787
FHL2	IGFBP5	P24593	752
FHL2	CAPN3	P20807	713
FHL2	SMAD3	P84022	674
FHL2	OBSCN	Q5VST9	667
FHL2	ELOVL2	Q9NXB9	665
FHL2	ANKRD1	Q15327	659
FHL2	AR	P10275	623

IntAct

660 interactions, top by confidence:

A	B	Type	Score
FHL2	RFX3	psi-mi:“MI:0915”(physical association)	0.900
RFX3	FHL2	psi-mi:“MI:0915”(physical association)	0.900
FHL2	GNG12	psi-mi:“MI:0915”(physical association)	0.830
GNG12	FHL2	psi-mi:“MI:0915”(physical association)	0.830
FHL2	JUP	psi-mi:“MI:0915”(physical association)	0.780
FHL2	CCDC92	psi-mi:“MI:0915”(physical association)	0.780
DCP1A	FHL2	psi-mi:“MI:0915”(physical association)	0.780
RAI2	FHL2	psi-mi:“MI:0915”(physical association)	0.780
FHL2	RAI2	psi-mi:“MI:0915”(physical association)	0.780
CCDC92	FHL2	psi-mi:“MI:0915”(physical association)	0.780
FHL2	DCP1A	psi-mi:“MI:0915”(physical association)	0.780
ZFP64	FHL2	psi-mi:“MI:0915”(physical association)	0.740
FHL2	ZFP64	psi-mi:“MI:0915”(physical association)	0.740
FHL2	BANP	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (582): FHL2 (Two-hybrid), FHL2 (Two-hybrid), FHL2 (Affinity Capture-Western), FOXO1 (Affinity Capture-Western), FOXO1 (Reconstituted Complex), FHL2 (Two-hybrid), FHL2 (Two-hybrid), JUP (Two-hybrid), NRF1 (Two-hybrid), REL (Two-hybrid), RFX3 (Two-hybrid), SP2 (Two-hybrid), ZNF131 (Two-hybrid), BLZF1 (Two-hybrid), ZMYM4 (Two-hybrid)

ESM2 similar proteins: O00151, O04193, O35115, O70400, O70433, O80839, P21291, P29675, P36201, P47875, P50238, P50461, P50462, P50463, P50464, P52943, P52944, P53777, P63254, P63255, P67966, P67967, P97315, Q0VFX8, Q14192, Q16527, Q1ECF5, Q1LZA7, Q24400, Q2KI95, Q3MHY1, Q4KM31, Q4U0T9, Q500W4, Q56K04, Q5E9E1, Q5R7Y1, Q5RCT4, Q5RGJ5, Q5ZLR4

Diamond homologs: A0A1L8F1M4, A0M8R4, A0M8S5, A0M8U6, A1Z6W3, A8WH69, O42565, O43900, P36202, P47226, P50464, P50479, P53667, P53668, P53669, P70271, Q00PK1, Q07DW1, Q07DX3, Q07DY3, Q07DZ4, Q07E27, Q07E40, Q07E51, Q09YI0, Q09YJ2, Q09YK3, Q09YL5, Q09YN8, Q108U9, Q14192, Q174I2, Q17QE2, Q28FG2, Q292U2, Q292U5, Q2IBA3, Q2IBC3, Q2IBH0, Q2LAP6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
RHOA	up-regulates	FHL2	relocalization
FHL2	up-regulates	AR	binding
FHL2	“down-regulates activity”	SPHK1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1115 predictions. Top by Δscore:

Variant	Effect	Δscore
2:105363280:CTCA:C	donor_loss	1.0000
2:105363282:CAC:C	donor_loss	1.0000
2:105363283:A:AC	donor_gain	1.0000
2:105363283:A:T	donor_loss	1.0000
2:105363284:C:CA	donor_loss	1.0000
2:105363284:C:CC	donor_gain	1.0000
2:105363284:CCG:C	donor_gain	1.0000
2:105363315:T:TA	donor_gain	1.0000
2:105363467:ATGGG:A	acceptor_gain	1.0000
2:105363468:TGGG:T	acceptor_gain	1.0000
2:105363469:GGG:G	acceptor_gain	1.0000
2:105363470:GG:G	acceptor_gain	1.0000
2:105363472:C:CC	acceptor_gain	1.0000
2:105367587:A:AC	donor_gain	1.0000
2:105367588:C:CC	donor_gain	1.0000
2:105386356:GGTAC:G	donor_loss	1.0000
2:105386357:GTACC:G	donor_loss	1.0000
2:105386358:TA:T	donor_loss	1.0000
2:105386359:A:T	donor_loss	1.0000
2:105386360:CCT:C	donor_loss	1.0000
2:105386537:CAAC:C	acceptor_gain	1.0000
2:105386539:AC:A	acceptor_gain	1.0000
2:105386539:ACCTA:A	acceptor_loss	1.0000
2:105386540:CC:C	acceptor_gain	1.0000
2:105438395:TTAC:T	donor_loss	1.0000
2:105438396:TACCT:T	donor_loss	1.0000
2:105361432:GTCC:G	acceptor_loss	0.9900
2:105361434:CCTGT:C	acceptor_loss	0.9900
2:105361435:C:CC	acceptor_gain	0.9900
2:105361435:CTGTT:C	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014573 (2:105380865 T>A), RS1000033088 (2:105385053 A>G), RS1000138474 (2:105384356 C>G,T), RS1000144104 (2:105378017 A>C), RS1000168912 (2:105434049 C>T), RS1000196850 (2:105378338 G>A), RS1000285835 (2:105385436 G>A), RS1000302726 (2:105434235 T>C), RS1000327125 (2:105437986 T>C), RS1000345742 (2:105439247 G>A,C), RS1000396754 (2:105418050 A>G), RS1000412217 (2:105363006 A>G,T), RS1000435366 (2:105402537 G>T), RS1000485055 (2:105439534 G>A), RS1000490843 (2:105384027 C>T)

Disease associations

OMIM: gene MIM:602633 | disease phenotypes: MIM:192600

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy	Moderate	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant

Mondo (4): dilated cardiomyopathy (MONDO:0005021), familial hypertrophic cardiomyopathy (MONDO:0024573), cardiomyopathy (MONDO:0004994), (MONDO:0015470)

Orphanet (4): Dilated cardiomyopathy (Orphanet:217604), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Rare cardiomyopathy (Orphanet:167848), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001644	Dilated cardiomyopathy
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST004749_87	Lung cancer in ever smokers	9.000000e-06
GCST006626_15	Pulse pressure	1.000000e-09
GCST007269_45	Pulse pressure	2.000000e-08
GCST008157_67	Body fat mass	5.000000e-06
GCST009524_210	Household income (MTAG)	7.000000e-09
GCST010320_144	PR interval	2.000000e-11
GCST010321_193	PR interval	7.000000e-14
GCST011122_36	Walking pace	3.000000e-09
GCST012307_1	Bipolar disorder x sex interaction	4.000000e-07
GCST90000025_760	Appendicular lean mass	4.000000e-11
GCST90020028_67	Hip circumference adjusted for BMI	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0009695	household income
EFO:0004462	PR interval
EFO:0008343	sex interaction measurement
EFO:0004980	appendicular lean mass
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, increases reaction, affects expression, affects cotreatment, decreases expression (+1 more)	9
sodium arsenite	affects expression, affects methylation, affects splicing, decreases expression, affects cotreatment (+2 more)	5
Valproic Acid	affects expression, decreases methylation, increases expression	5
bisphenol A	affects expression, decreases expression, increases expression, increases methylation	4
Genistein	affects cotreatment, increases expression, decreases expression, increases reaction	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	3
Diethylstilbestrol	decreases expression, increases expression	3
Doxorubicin	increases expression, decreases expression, affects reaction	3
Tetrachlorodibenzodioxin	decreases expression, affects reaction, affects expression, increases expression, affects cotreatment (+2 more)	3
Cyclosporine	increases expression	3
Aflatoxin B1	affects expression, increases expression	3
Raloxifene Hydrochloride	affects expression, affects cotreatment, increases expression, decreases expression	3
Arsenic Trioxide	increases expression	2
Fulvestrant	decreases expression, increases methylation	2
Rotenone	decreases expression, increases expression	2
Tamoxifen	affects expression, affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	increases expression	2
Particulate Matter	decreases expression, increases abundance	2
bisphenol F	increases expression	1
daidzein	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
glycidyl methacrylate	increases expression	1
lead acetate	increases expression	1
methylselenic acid	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
daidzin	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 2 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B0YZ	Abcam U2OS FHL2 KO	Cancer cell line	Female
CVCL_B1S5	Abcam HeLa FHL2 KO	Cancer cell line	Female
CVCL_VE36	WAe009-A-8	Embryonic stem cell	Female
CVCL_VE37	WAe009-A-9	Embryonic stem cell	Female
CVCL_WS23	UCD-Mel-N(Ski+/Fhl2+)	Cancer cell line	Sex unspecified

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00374465	PHASE4	UNKNOWN	Therapy With Verapamil or Carvedilol in Chronic Heart Failure
NCT01293903	PHASE4	COMPLETED	Study of Qiliqiangxin Capsule to Treat Dilated Cardiomyopathy
NCT01557140	PHASE4	COMPLETED	A Randomized Trial of Carvedilol in Chronic Chagas Cardiomyopathy
NCT01917149	PHASE4	COMPLETED	Supramaximal Titrated Inhibition of RAAS in Dilated Cardiomyopathy
NCT02115581	PHASE4	COMPLETED	Coenzyme Q10 Supplementation in Children With Idiopathic Dilated Cardiomyopathy
NCT06236022	PHASE4	RECRUITING	The Effects of Sirolimus in Patients With Dilated Cardiomyopathy Infected With Kaposi Sarcoma-associated Virus
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine