TRIM63

Summary

TRIM63 (tripartite motif containing 63, HGNC:16007) is a protein-coding gene on chromosome 1p36.11, encoding E3 ubiquitin-protein ligase TRIM63 (Q969Q1). E3 ubiquitin ligase.

This gene encodes a member of the RING zinc finger protein family found in striated muscle and iris. The product of this gene is an E3 ubiquitin ligase that localizes to the Z-line and M-line lattices of myofibrils. This protein plays an important role in the atrophy of skeletal and cardiac muscle and is required for the degradation of myosin heavy chain proteins, myosin light chain, myosin binding protein, and for muscle-type creatine kinase.

Source: NCBI Gene 84676 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 160 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 38
• MANE Select transcript: NM_032588

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16007
Approved symbol	TRIM63
Name	tripartite motif containing 63
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	MURF-1, IRF, SMRZ
Ensembl gene	ENSG00000158022
Ensembl biotype	protein_coding
OMIM	606131
Entrez	84676

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000374272, ENST00000483052

RefSeq mRNA: 1 — MANE Select: NM_032588 NM_032588

CCDS: CCDS273

Canonical transcript exons

ENST00000374272 — 9 exons

Exon	Start	End
ENSE00001036596	26060266	26060361
ENSE00001036610	26057203	26057327
ENSE00001036615	26061166	26061334
ENSE00001036620	26058390	26058623
ENSE00001036623	26057628	26057650
ENSE00001154105	26053893	26053964
ENSE00001462984	26051301	26051883
ENSE00001462989	26067336	26067630
ENSE00003571065	26066268	26066440

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 99.53.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.3816 / max 1790.9033, expressed in 142 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11147	3.3736	141
11148	0.0080	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	99.53	gold quality
tibialis anterior	UBERON:0001385	99.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.94	gold quality
quadriceps femoris	UBERON:0001377	98.89	gold quality
vastus lateralis	UBERON:0001379	98.82	gold quality
deltoid	UBERON:0001476	98.82	gold quality
skeletal muscle tissue	UBERON:0001134	98.79	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.42	gold quality
biceps brachii	UBERON:0001507	98.21	gold quality
left ventricle myocardium	UBERON:0006566	98.18	gold quality
cardiac ventricle	UBERON:0002082	98.06	gold quality
heart left ventricle	UBERON:0002084	98.06	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.97	gold quality
heart right ventricle	UBERON:0002080	97.96	gold quality
apex of heart	UBERON:0002098	97.96	gold quality
myocardium	UBERON:0002349	97.84	gold quality
muscle of leg	UBERON:0001383	97.72	gold quality
body of tongue	UBERON:0011876	97.56	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.41	gold quality
cardiac atrium	UBERON:0002081	97.37	gold quality
right atrium auricular region	UBERON:0006631	97.35	gold quality
muscle tissue	UBERON:0002385	95.08	gold quality
heart	UBERON:0000948	93.18	gold quality
vena cava	UBERON:0004087	91.87	gold quality
tongue	UBERON:0001723	88.87	gold quality
superior surface of tongue	UBERON:0007371	76.21	gold quality
pharyngeal mucosa	UBERON:0000355	74.29	gold quality
cartilage tissue	UBERON:0002418	72.38	gold quality
gall bladder	UBERON:0002110	69.16	gold quality
pigmented layer of retina	UBERON:0001782	68.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	20.63
E-ANND-3	yes	10.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPG, ESR1, FOXO1, FOXO3, FOXO4, FOXO6, HIF1A, IRF1, IRF2, IRF3, IRF4, IRF5, IRF8, MEF2A, MYOG, NFKB, NR1H3, NR3C1, RELA, SMAD3, SP1, SPI1, STAT1, STAT3

miRNA regulators (miRDB)

42 targeting TRIM63, 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-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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-557	99.96	70.01	1640
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-LET-7C-3P	99.95	73.42	2862
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-6882-5P	99.35	71.13	1206

Literature-anchored findings (GeneRIF, showing 40)

• interacts with titin to regulate sarcomeric M-line and thick filament structure and may have nuclear functions via its interaction with glucocorticoid modulatory element binding protein-1. (PMID:11927605)
• MURF2 associates transiently with microtubules, myosin and titin during sarcomere assembly. (PMID:12414993)
• MuRF1 functions as a ubiquitin ligase to catalyze ubiquitylation of troponin I through a RING finger-dependent mechanism (PMID:15601779)
• MuRF1 mRNA expression was significantly increased in quadriceps of patients with COPD; transcriptional regulation of atrogin-1 and MuRF1 may occur via FoxO-1, but independently of AKT (PMID:17478621)
• Expression of mRNA for MuRF-1 increased approximately 3-fold at 10 days without changes in MAFbx or tripeptidyl peptidase II mRNA, but all decreased between 10 and 21 days of muscle disuse. (PMID:17901116)
• MuRF-1 and MAFbx, are differently affected by the exercise as well as by repeated exercise (PMID:17971512)
• Results showed upregulation of MuRf1 and MAFbx in atrophied muscle and support their role as regulatory peptides in various conditions which lead to muscle atrophy. (PMID:17977773)
• MuRF1 expression in skeletal muscle re-directs glycogen synthesis to the liver and stimulates pancreatic insulin secretion, providing a feedback loop that connects skeletal muscle metabolism with the liver and the pancreas during metabolic stress. (PMID:18468620)
• These findings present new insights into the role of the glucocorticoid receptor and FOXO family of transcription factors in the transcriptional regulation of the MuRF1 gene (PMID:18612045)
• Findings aid the future exploration of the cellular function and therapeutic potential of MuRF1. (PMID:18795805)
• This study demenostrated that the muscle RING finger 1 protein, human is reduced in skeletal muscle of chronic spinal cord-injured patients. (PMID:19533653)
• atrogin-1 specifically targets truncated M7t-cMyBP-C, but not WT-cMyBP-C, for proteasomal degradation and that MuRF1 indirectly reduces cMyBP-C levels by regulating the transcription of myosin heavy chain. (PMID:19850579)
• Reduced expression of MuRF1 and MAFbx in the myocardium might permit hypertrophy characteristic of the early post-infarction remodeling phase. (PMID:19859778)
• 11beta-HSD1 controls glucocorticoid-induced protein degradation in human and murine skeletal muscle via regulation of the E3 ubiquitin ligases Atrogin-1 and MuRF-1. (PMID:21304964)
• Data suggest that the inhibition of MuRF1 could be a novel mechanism to prevent or reverse muscle wasting associated with various pathologies. (PMID:21448668)
• MuRF1 regulates cardiomyocyte cell size and energy metabolism to inhibit cardiac hypertrophy and reverse experimental cardiac hypertrophy. (PMID:21686210)
• investigation of factors regulating expression of two ubiquitin ligases (MURF1 and MAFbx) in skeletal muscle (i.e., vastus lateralis): effects of resistance exercise and anabolic dietary supplement (i.e., branched-chain amino acids) (PMID:22127230)
• Regular exercise training leads to a decrease in Rnf28 expression in skeletal muscle in patients with advanced chronic heart failure. (PMID:22445192)
• Data suggest that expression of atrogin-1 and MuRF-1 likely play role in aging-related decrease in muscle mass (i.e., development of sarcopenia); up-regulation of atrogin-1 and MuRF-1 has potential to prevent or reverse sarcopenia. [REVIEW] (PMID:22815045)
• Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy. (PMID:22821932)
• MuRF-1 RNA expression was significantly increased in malnourished cirrhotic patients vs. well-nourished patients. (PMID:23432902)
• relationship was found between IL-6 and MuRF-1 expression after incubation with PGE2 (PMID:23490068)
• MURF-1 protein gene expression is increased in patients with severe burn injury. (PMID:23816995)
• Quadriceps muscle MuRF-1 levels did not differ between patients with COPD (with normal or low fat-free mass index) and controls. MURF1 levels were not associated with quadriceps fiber cross-sectional area or strength in patients. (PMID:23844868)
• In conclusion, atrogin-1, MuRF1, FOXO1/3A, and eIF3-f mRNA, and protein levels, are differentially regulated by exercise contraction mode but not WPH supplementation combined with hypertrophy-inducing training. (PMID:24458747)
• In MuRF1 the COS-box mediates the in vivo targeting of sarcoskeletal structures and points to the pharmacological relevance of the COS domain for treating MuRF1-mediated muscle atrophy. (PMID:24671946)
• Data reveal that Titin protein is a pseudokinase with non-detectable catalytic output but is a high-affinity binding locus for MuRF1. (PMID:24850911)
• These data strongly supported that rare variants in MuRF1 and MuRF2 are associated with higher penetrance and more severe clinical manifestations of hypertrophic cardiomyopathy. (PMID:24865491)
• SMAD3 regulates transcription of MuRF-1 by increasing FoxO3 binding at a conserved FRE-SBE motif within the proximal promoter region, and by increasing FoxO3 protein content and transcriptional activity. (PMID:24920680)
• both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle–REVIEW (PMID:25096180)
• MURF1 expression intended to be increased in the skeletal muscle of patients with malignant disease even before cancer related cachexia weight loss. (PMID:25760630)
• A novel protein aggregate myopathies and cardiomyopathy resulting from combined homozygous MuRF1 null mutation and heterozygous MuRF3 missense mutation. (PMID:25801283)
• Vitamin D3 might have an inhibitory effect on the expression of MAFbx and MuRF1 in skeletal muscle. (PMID:25876656)
• TRIM63 gene expression involved in skin hyperpigmentation. (PMID:25950827)
• Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles (PMID:26048142)
• Skeletal muscle atrophy induced by Angiotensin II involves activation of MuRF1 expression. (PMID:26137861)
• role of the muscle specific E3s MuRF-1 and MAFbx in skeletal muscle wasting during various pathologies, as well as their regulation by modifiable lifestyle factors, were explored (review) (PMID:26738803)
• Altogether, these results suggest a novel function for p63 as a contributor to muscular atrophic processes via the regulation of multiple genes, including the muscle atrophy gene Trim63. (PMID:26919175)
• the involvement of oxidative stress in the atrophy of COPD peripheral muscle cells in vitro, via the FoxO1/MuRF1/atrogin-1 signaling pathway of the ubiquitin/proteasome system (PMID:27526027)
• The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. (PMID:28302626)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Trim63	ENSMUSG00000028834
rattus_norvegicus	Trim63	ENSRNOG00000016543

Paralogs (80): MID2 (ENSG00000080561), TRIM9 (ENSG00000100505), MID1 (ENSG00000101871), MEFV (ENSG00000103313), TRIM35 (ENSG00000104228), TRIM14 (ENSG00000106785), TRIM37 (ENSG00000108395), TRIM2 (ENSG00000109654), TRIM3 (ENSG00000110171), TRIM38 (ENSG00000112343), TRIM62 (ENSG00000116525), TRIM67 (ENSG00000119283), TRIM32 (ENSG00000119401), BSPRY (ENSG00000119411), TRIM25 (ENSG00000121060), TRIM6 (ENSG00000121236), TRIM24 (ENSG00000122779), TRIM51 (ENSG00000124900), TRIM28 (ENSG00000130726), TRIM21 (ENSG00000132109), TRIM5 (ENSG00000132256), TRIM22 (ENSG00000132274), TRIM47 (ENSG00000132481), TRIM45 (ENSG00000134253), TRIM29 (ENSG00000137699), TRIM54 (ENSG00000138100), PML (ENSG00000140464), TRIM65 (ENSG00000141569), TRIM43B (ENSG00000144010), TRIM43 (ENSG00000144015), TRIM7 (ENSG00000146054), TRIM41 (ENSG00000146063), TRIM50 (ENSG00000146755), TRIM4 (ENSG00000146833), TRIM55 (ENSG00000147573), TRIM48 (ENSG00000150244), TRIM36 (ENSG00000152503), TRIM11 (ENSG00000154370), TRIM74 (ENSG00000155428), TRIM42 (ENSG00000155890)

Protein

Protein identifiers

E3 ubiquitin-protein ligase TRIM63 — Q969Q1 (reviewed: Q969Q1)

Alternative names: Iris RING finger protein, Muscle-specific RING finger protein 1, RING finger protein 28, RING-type E3 ubiquitin transferase TRIM63, Striated muscle RING zinc finger protein, Tripartite motif-containing protein 63

All UniProt accessions (1): Q969Q1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin ligase. Mediates the ubiquitination and subsequent proteasomal degradation of CKM, GMEB1 and HIBADH. Regulates the proteasomal degradation of muscle proteins under amino acid starvation, where muscle protein is catabolized to provide other organs with amino acids. Inhibits de novo skeletal muscle protein synthesis under amino acid starvation. Regulates proteasomal degradation of cardiac troponin I/TNNI3 and probably of other sarcomeric-associated proteins. May play a role in striated muscle atrophy and hypertrophy by regulating an anti-hypertrophic PKC-mediated signaling pathway. May regulate the organization of myofibrils through TTN in muscle cells.

Subunit / interactions. Homodimer. Homooligomer and heterooligomer. Interacts with SUMO2, titin/TTN and GMEB1. Interacts with TRIM54 and probably with TRIM55 and TNNI3. Forms a ternary complex with RACK1 and PRKCE. Interacts with CKM.

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

Tissue specificity. Muscle specific. Selectively expressed in heart and skeletal muscle. Also expressed in the iris.

Disease relevance. Cardiomyopathy, familial hypertrophic, 31 (CMH31) [MIM:621270] A form of hypertrophic cardiomyopathy, a heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. CMH31 is an autosomal recessive form characterized by moderate to severe hypertrophy, high incidence of ventricular arrhythmias, extensive fibrosis, and frequent left ventricular dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The RING-type zinc finger mediates interaction with SUMO2 and localization to the nucleus. Also required for the E3 ubiquitin ligase activity. The B box-type zinc finger mediates homodimerization.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q969Q1-1	1	yes
Q969Q1-2	2

RefSeq proteins (1): NP_115977* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000315	Znf_B-box	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017903	COS_domain	Domain
IPR017907	Znf_RING_CS	Conserved_site
IPR027370	Znf-RING_euk	Domain
IPR042667	TRIM63_RING-HC	Domain
IPR050617	E3_ligase_FN3/SPRY	Family

Pfam: PF00643, PF13445

UniProt features (49 total): sequence variant 23, binding site 4, mutagenesis site 4, strand 4, turn 3, zinc finger region 2, region of interest 2, helix 2, chain 1, domain 1, splice variant 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3DDT	X-RAY DIFFRACTION	1.9
4M3L	X-RAY DIFFRACTION	2.1
2D8U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q969Q1-F1	82.88	0.57

Functional residue map

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

Ligand- & substrate-binding residues (4): 145; 151; 122; 125

Mutagenesis-validated functional residues (4):

Position	Phenotype
39	loss of sumo2-binding.
41	loss of sumo2-binding.
44	loss of sumo2-binding.
47	loss of sumo2-binding.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9615017	FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 164 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_SKELETAL_MUSCLE_ADAPTATION, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, FOXO1_01, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS

GO Biological Process (10): muscle contraction (GO:0006936), signal transduction (GO:0007165), negative regulation of cardiac muscle hypertrophy (GO:0010614), skeletal muscle atrophy (GO:0014732), response to electrical stimulus involved in regulation of muscle adaptation (GO:0014878), protein ubiquitination (GO:0016567), innate immune response (GO:0045087), negative regulation of glycolytic process (GO:0045820), response to glucocorticoid (GO:0051384), response to interleukin-1 (GO:0070555)

GO Molecular Function (7): zinc ion binding (GO:0008270), titin binding (GO:0031432), ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), microtubule (GO:0005874), Z disc (GO:0030018), M band (GO:0031430), contractile muscle fiber (GO:0043292)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
FOXO-mediated transcription	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
muscle system process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
negative regulation of muscle hypertrophy	1
striated muscle atrophy	1
skeletal muscle adaptation	1
regulation of muscle adaptation	1
response to electrical stimulus	1
protein modification by small protein conjugation	1
immune response	1
defense response to symbiont	1
glycolytic process	1
regulation of glycolytic process	1
negative regulation of purine nucleotide catabolic process	1
negative regulation of carbohydrate metabolic process	1
negative regulation of ATP metabolic process	1
response to corticosteroid	1
response to cytokine	1
transition metal ion binding	1
cytoskeletal protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
I band	1
A band	1
cytoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

2022 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRIM63	TTN	Q8WZ42	986
TRIM63	FBXO32	Q969P5	958
TRIM63	NBR1	Q14596	902
TRIM63	YIPF1	Q9Y548	875
TRIM63	TCAP	O15273	864
TRIM63	NEB	P20929	850
TRIM63	BBOX1	O75936	775
TRIM63	MSTN	O14793	773
TRIM63	MYBPC3	Q14896	751
TRIM63	MYOG	P15173	694
TRIM63	MYH2	Q9UKX2	679
TRIM63	FOXO3	O43524	676
TRIM63	MYOD1	P15172	668
TRIM63	SQSTM1	Q13501	643
TRIM63	CALM1	P02593	628

IntAct

212 interactions, top by confidence:

A	B	Type	Score
DCAF8	DDB1	psi-mi:“MI:0914”(association)	0.910
EHHADH	TRIM63	psi-mi:“MI:0915”(physical association)	0.560
TRIM63	TTN	psi-mi:“MI:0915”(physical association)	0.550
TTN	TRIM63	psi-mi:“MI:0915”(physical association)	0.550
TRIM63	TCAP	psi-mi:“MI:0915”(physical association)	0.550
TRIM63	DCAF8	psi-mi:“MI:0915”(physical association)	0.540
TRIM63	DCAF8	psi-mi:“MI:0403”(colocalization)	0.540
TRIM63	USP13	psi-mi:“MI:0915”(physical association)	0.510
TRIM63	CCAR1	psi-mi:“MI:0915”(physical association)	0.510
TRIM63	EEF1G	psi-mi:“MI:0915”(physical association)	0.510
TRIM63	GFM1	psi-mi:“MI:0915”(physical association)	0.510
MRPL41	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
MYOZ1	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
CCAR1	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
EEF1G	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
GFM1	TRIM63	psi-mi:“MI:0915”(physical association)	0.510
TRIM63	SQSTM1	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	NEDD8	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	HNRNPLL	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	USP35	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	MYLK2	psi-mi:“MI:0915”(physical association)	0.400
DDB1	TRIM63	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	CAPN3	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	ITGB5	psi-mi:“MI:0915”(physical association)	0.400
TRIM63	DES	psi-mi:“MI:0915”(physical association)	0.370
TNNI3	TRIM63	psi-mi:“MI:0915”(physical association)	0.370
MYBPC3	TRIM63	psi-mi:“MI:0915”(physical association)	0.370
TRIM63	NEBL	psi-mi:“MI:0915”(physical association)	0.370
FLNC	TRIM63	psi-mi:“MI:0915”(physical association)	0.370
FHL2	TRIM63	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (415): DES (Two-hybrid), TRIM63 (Two-hybrid), TCAP (Two-hybrid), ACTA1 (Two-hybrid), MYOT (Two-hybrid), TNNI3 (Two-hybrid), TNNI2 (Two-hybrid), TNNI1 (Two-hybrid), MYBPC3 (Two-hybrid), MYBPC1 (Two-hybrid), TTN (Two-hybrid), NEB (Two-hybrid), NEBL (Two-hybrid), FLNC (Two-hybrid), ANKRD1 (Two-hybrid)

ESM2 similar proteins: A1L4K1, D4A7V9, E9QHE3, F1LW30, H0UZ81, O15344, O70583, O95361, P82457, P82458, P97573, Q14258, Q14596, Q28CB1, Q38HM4, Q3UMR0, Q3V3A7, Q58D15, Q5F479, Q5R760, Q5RC94, Q5REJ9, Q5REW9, Q5RF77, Q5XIH6, Q61510, Q6P549, Q6P6S3, Q6UXZ4, Q7T2L7, Q7TNH6, Q7Z494, Q80VK6, Q80WG7, Q8BZ52, Q8JZL1, Q8K1S2, Q8NFM7, Q91Z63, Q969Q1

Diamond homologs: A0A0G2JXN2, A0JN74, A0JPQ4, A5D7F8, A5D8S5, A6NGJ6, A6NI03, B6VQ60, E1BD59, F6ZQ54, G3X8Y1, O60858, P15533, P86449, Q03601, Q1ACD6, Q1ACD7, Q28E95, Q29RQ5, Q2KHN1, Q2YEM8, Q2YEM9, Q32L60, Q38HM4, Q3TL54, Q3ZEE5, Q503I2, Q505D9, Q5C8T6, Q5C8T8, Q5C8U3, Q5D7H7, Q5D7I2, Q5D7I3, Q5EBN2, Q5M7V1, Q5M929, Q5PQN5, Q5RBR0, Q5RKG6

SIGNOR signaling

18 interactions.

A	Effect	B	Mechanism
FOXO1	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
FOXO3	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
FOXO4	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
FOXO6	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
FOXO	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
Ub:E2	“up-regulates activity”	TRIM63	ubiquitination
TRIM63	“down-regulates quantity”	PPP3CA	ubiquitination
FOXO	“up-regulates activity”	TRIM63	“transcriptional regulation”
NR3C1	“up-regulates quantity by expression”	TRIM63	“transcriptional regulation”
TRIM63	“up-regulates activity”	Muscle_atrophy
TRIM63	“down-regulates quantity by destabilization”	TNNI1	polyubiquitination
UBE2N	“up-regulates activity”	TRIM63	ubiquitination
TRIM63	“down-regulates quantity by destabilization”	PSMD4	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Striated Muscle Contraction	6	19.3×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
sarcomere organization	7	19.6×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	93
Likely benign	28
Benign	20

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
3062228	NM_032588.4(TRIM63):c.277C>T (p.Gln93Ter)	Pathogenic
4057303	NM_032588.4(TRIM63):c.956T>C (p.Leu319Pro)	Pathogenic
4057308	L37V	Pathogenic
985254	NM_032588.4(TRIM63):c.481_482del (p.Ser161fs)	Pathogenic
3895049	NM_032588.4(TRIM63):c.713del (p.Lys238fs)	Likely pathogenic
4540935	NM_032588.4(TRIM63):c.159+1G>A	Likely pathogenic
4820381	NM_032588.4(TRIM63):c.855-1G>A	Likely pathogenic

SpliceAI

917 predictions. Top by Δscore:

Variant	Effect	Δscore
1:26053887:TCTTA:T	donor_loss	1.0000
1:26053888:CTTA:C	donor_loss	1.0000
1:26053889:TTA:T	donor_loss	1.0000
1:26053890:TAC:T	donor_loss	1.0000
1:26053891:A:AC	donor_gain	1.0000
1:26053891:A:C	donor_loss	1.0000
1:26053892:C:CC	donor_gain	1.0000
1:26053892:CCTT:C	donor_gain	1.0000
1:26053960:CTCAT:C	acceptor_gain	1.0000
1:26053961:TCAT:T	acceptor_gain	1.0000
1:26053961:TCATC:T	acceptor_gain	1.0000
1:26053962:CAT:C	acceptor_gain	1.0000
1:26053962:CATC:C	acceptor_gain	1.0000
1:26053963:AT:A	acceptor_gain	1.0000
1:26053964:TCTG:T	acceptor_loss	1.0000
1:26053965:C:CC	acceptor_gain	1.0000
1:26053965:C:CG	acceptor_loss	1.0000
1:26053966:T:C	acceptor_loss	1.0000
1:26053967:G:C	acceptor_gain	1.0000
1:26053971:C:CT	acceptor_gain	1.0000
1:26057195:T:TA	donor_gain	1.0000
1:26057197:CTTTA:C	donor_loss	1.0000
1:26057198:TTTA:T	donor_loss	1.0000
1:26057200:TAC:T	donor_loss	1.0000
1:26057201:ACCT:A	donor_loss	1.0000
1:26057202:CCT:C	donor_loss	1.0000
1:26057323:CAATG:C	acceptor_gain	1.0000
1:26057325:ATG:A	acceptor_gain	1.0000
1:26057325:ATGCT:A	acceptor_loss	1.0000
1:26057326:TG:T	acceptor_gain	1.0000

AlphaMissense

2368 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:26066315:G:C	N95K	1.000
1:26066315:G:T	N95K	1.000
1:26066319:C:A	R94M	1.000
1:26066377:A:G	C75R	1.000
1:26067365:A:G	C44R	1.000
1:26067369:G:C	N42K	1.000
1:26067369:G:T	N42K	1.000
1:26067380:A:G	C39R	1.000
1:26067426:G:C	C23W	1.000
1:26067428:A:G	C23R	1.000
1:26067433:A:G	L21P	1.000
1:26061233:C:G	C145S	0.999
1:26061234:A:G	C145R	0.999
1:26061234:A:T	C145S	0.999
1:26061241:G:C	C142W	0.999
1:26061242:C:T	C142Y	0.999
1:26061243:A:G	C142R	0.999
1:26061265:A:C	C134W	0.999
1:26061267:A:G	C134R	0.999
1:26061302:C:G	C122S	0.999
1:26061303:A:G	C122R	0.999
1:26061303:A:T	C122S	0.999
1:26066304:T:A	E99V	0.999
1:26066316:T:A	N95I	0.999
1:26066317:T:C	N95D	0.999
1:26066318:C:A	R94S	0.999
1:26066318:C:G	R94S	0.999
1:26066319:C:G	R94T	0.999
1:26066366:G:C	C78W	0.999
1:26066367:C:T	C78Y	0.999

dbSNP variants (sampled 300 via entrez): RS1000742924 (1:26055535 A>G), RS1001034567 (1:26066572 C>G), RS1001034858 (1:26050852 G>A), RS1001714510 (1:26066758 C>T), RS1002038784 (1:26065422 A>C,G), RS1002046592 (1:26065726 C>A), RS1002197233 (1:26065639 A>G), RS1002338970 (1:26053651 C>G,T), RS1002476028 (1:26053960 C>T), RS1002709367 (1:26062980 C>G,T), RS1002868349 (1:26063205 A>G), RS1002933656 (1:26057147 C>G,T), RS1002972307 (1:26054093 C>T), RS1003035256 (1:26068212 C>T), RS1003142309 (1:26051263 C>G,T)

Disease associations

OMIM: gene MIM:606131 | disease phenotypes: MIM:192600, MIM:621270

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Moderate	AR
hypertrophic cardiomyopathy	Disputed	AD

Mondo (4): hypertrophic cardiomyopathy (MONDO:0005045), familial hypertrophic cardiomyopathy (MONDO:0024573), cardiomyopathy, familial hypertrophic, 31 (MONDO:0979573), idiopathic cardiomyopathy (MONDO:0005110)

Orphanet (3): Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000822	Hypertension
HP:0001265	Hyporeflexia
HP:0001279	Syncope
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001670	Asymmetric septal hypertrophy
HP:0001681	Angina pectoris
HP:0001685	Myocardial fibrosis
HP:0001712	Left ventricular hypertrophy
HP:0001723	Restrictive cardiomyopathy
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002326	Transient ischemic attack
HP:0002375	Hypokinesia
HP:0002515	Waddling gait
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003306	Spinal rigidity
HP:0003458	EMG: myopathic abnormalities
HP:0003551	Difficulty climbing stairs
HP:0003557	Increased variability in muscle fiber diameter
HP:0003596	Middle age onset
HP:0003621	Juvenile onset
HP:0003687	Centrally nucleated skeletal muscle fibers
HP:0003701	Proximal muscle weakness
HP:0004749	Atrial flutter
HP:0005110	Atrial fibrillation

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST010796_4304	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-12
GCST010796_4305	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-13
GCST010796_4306	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-13
GCST010796_4307	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-13
GCST010796_4308	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-14
GCST010796_4309	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-13
GCST010796_4310	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-12
GCST010796_4311	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-10
GCST010796_4312	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
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

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	2
Particulate Matter	decreases expression, increases expression	2
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation	1
2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	increases expression, affects cotreatment	1
Doxorubicin	increases expression	1
Estradiol	decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Triclosan	decreases expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy