CSRP3

Summary

CSRP3 (cysteine and glycine rich protein 3, HGNC:2472) is a protein-coding gene on chromosome 11p15.1, encoding Cysteine and glycine-rich protein 3 (P50461). Positive regulator of myogenesis.

This gene encodes a member of the CSRP family of LIM domain proteins, which may be involved in regulatory processes important for development and cellular differentiation. The LIM/double zinc-finger motif found in this protein is found in a group of proteins with critical functions in gene regulation, cell growth, and somatic differentiation. Mutations in this gene are thought to cause heritable forms of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) in humans. Alternatively spliced transcript variants with different 5’ UTR, but encoding the same protein, have been found for this gene.

Source: NCBI Gene 8048 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypertrophic cardiomyopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 511 total — 24 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 25
• MANE Select transcript: NM_003476

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2472
Approved symbol	CSRP3
Name	cysteine and glycine rich protein 3
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	CLP, MLP, CMD1M
Ensembl gene	ENSG00000129170
Ensembl biotype	protein_coding
OMIM	600824
Entrez	8048

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 18 protein_coding

ENST00000265968, ENST00000533783, ENST00000647990, ENST00000648719, ENST00000649235, ENST00000649842, ENST00000862857, ENST00000862858, ENST00000862859, ENST00000862860, ENST00000862861, ENST00000951069, ENST00000951070, ENST00000951071, ENST00000951072, ENST00000951073, ENST00000951074, ENST00000951075

RefSeq mRNA: 2 — MANE Select: NM_003476 NM_001369404, NM_003476

CCDS: CCDS7848, CCDS91449

Canonical transcript exons

ENST00000265968 — 6 exons

Exon	Start	End
ENSE00000707240	19186216	19186348
ENSE00000707241	19188136	19188304
ENSE00000997759	19192337	19192476
ENSE00001746098	19184952	19185045
ENSE00003834859	19201954	19201983
ENSE00003891764	19182030	19182746

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 99.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.5223 / max 841.6679, expressed in 72 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118984	3.4820	71
206223	0.0403	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.94	gold quality
heart right ventricle	UBERON:0002080	99.93	gold quality
left ventricle myocardium	UBERON:0006566	99.88	gold quality
biceps brachii	UBERON:0001507	99.81	gold quality
apex of heart	UBERON:0002098	99.81	gold quality
myocardium	UBERON:0002349	99.79	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.76	gold quality
diaphragm	UBERON:0001103	99.70	gold quality
gluteal muscle	UBERON:0002000	99.69	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.63	gold quality
cardiac atrium	UBERON:0002081	99.62	gold quality
right atrium auricular region	UBERON:0006631	99.61	gold quality
vastus lateralis	UBERON:0001379	99.60	gold quality
quadriceps femoris	UBERON:0001377	99.57	gold quality
triceps brachii	UBERON:0001509	99.55	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.55	gold quality
skeletal muscle tissue	UBERON:0001134	99.47	gold quality
body of tongue	UBERON:0011876	99.45	gold quality
cardiac ventricle	UBERON:0002082	99.41	gold quality
heart left ventricle	UBERON:0002084	99.39	gold quality
vena cava	UBERON:0004087	99.31	gold quality
deltoid	UBERON:0001476	99.16	gold quality
tibialis anterior	UBERON:0001385	98.97	gold quality
gastrocnemius	UBERON:0001388	95.94	gold quality
muscle organ	UBERON:0001630	95.82	gold quality
skeletal muscle organ	UBERON:0014892	95.81	gold quality
heart	UBERON:0000948	94.61	gold quality
muscle tissue	UBERON:0002385	94.50	gold quality
muscle of leg	UBERON:0001383	94.35	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MEF2C

miRNA regulators (miRDB)

31 targeting CSRP3, 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-4682	100.00	68.89	1258
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-1197	99.70	67.75	1027
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-12126	98.09	64.82	637
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-890	97.47	68.67	982
HSA-MIR-3200-5P	97.34	65.97	826
HSA-MIR-4689	96.97	65.79	1209

Literature-anchored findings (GeneRIF, showing 21)

• CSRP3 is involved in cardiac mechanosensory processes, is localized to the sarcomeric Z-disc and human mutations cause cardiomyopathy(DCM)and heart failure. (PMID:12507422)
• Mutations in the CRP3/MLP gene can cause hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). (PMID:12642359)
• CSRP3, MUSTN1, SIX1, and FBXO32 expression changes in response to lengthening and shortening contractions in human muscle (PMID:17519359)
• A myocardial actin-binding protein that increases actin cytoskeleton stability by promoting bundling of actin filaments. (PMID:18331358)
• These findings suggest that hhLIM is a typical LIM family member with powerful transcription activation. (PMID:18393774)
• Study used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by hypertrophic cardiomyopathy. (PMID:18505755)
• CSRP3 mutation was found involved in hypertrophic cardiomyopathy. (PMID:19035361)
• The structure of both LIM domains of human MLP by nuclear magnetic resonance spectroscopy. (PMID:19230835)
• CRP3/MLP is primarily expressed in arterial smooth muscle cells and that stretch is the main stimulus for CRP3/MLP induction in veins exposed to arterial haemodynamic conditions. (PMID:19351738)
• Complete chemical shift assignment was achieved for the first LIM domain and for most of the second domain, the N-terminal and C-terminal linker and part of the intervening linker. (PMID:19636821)
• MLP binds directly to CFL2 in human cardiac and skeletal muscles. (PMID:19752190)
• The CSRP3-W4R mutation causes cardiomyopathy and heart failure in patients and engineered knock-in animals. (PMID:20044516)
• KLF5 reverses hhLIM function from anti-proliferation to pro-proliferation through its interaction with hhLIM on the cyclin E promoter. (PMID:22584587)
• study reports the discovery of an alternative splice variant of muscle lim protein encoded by the CSRP3 gene, designated as MLP-b, showing distinct expression in neuromuscular disease and direct roles in actin dynamics and muscle differentiation (PMID:24860983)
• MLP contributes to the maintenance of cardiomyocyte cytoarchitecture by a mechanism involving its self-association and actin filament cross-linking. (PMID:24934443)
• Previous results along with the newly identified homozygous CSRP3 truncating variants in two unrelated hypertrophic cardiomyopathy (HCM) patients suggest that the association of CSRP3 as a validated HCM-causing gene require additional studies and those CSRP3 variants could result in HCM with an autosomal recessive inheritance rather than with an autosomal dominant transmission as usually reported on HCM. (PMID:30012424)
• MLP-deficient human embryonic stem cell derived cardiomyocytes recapitulate the pathogenesis of hypertrophic cardiomyopathy. (PMID:31406109)
• Identification of a variant hotspot in MYBPC3 and of a novel CSRP3 autosomal recessive alteration in a cohort of Polish patients with hypertrophic cardiomyopathy. (PMID:31919335)
• The p.(Cys150Tyr) variant in CSRP3 is associated with late-onset hypertrophic cardiomyopathy in heterozygous individuals. (PMID:33035702)
• LIM domain-wide comprehensive virtual mutagenesis provides structural rationale for cardiomyopathy mutations in CSRP3. (PMID:35241752)
• Identification and in silico characterization of CSRP3 synonymous variants in dilated cardiomyopathy. (PMID:36877346)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	csrp3	ENSDARG00000101706
mus_musculus	Csrp3	ENSMUSG00000030470
rattus_norvegicus	Csrp3	ENSRNOG00000014327
drosophila_melanogaster	Mlp84B	FBGN0014863
drosophila_melanogaster	Mlp60A	FBGN0259209
caenorhabditis_elegans		WBGENE00003375

Paralogs (2): CSRP1 (ENSG00000159176), CSRP2 (ENSG00000175183)

Protein

Protein identifiers

Cysteine and glycine-rich protein 3 — P50461 (reviewed: P50461)

Alternative names: Cardiac LIM protein, Cysteine-rich protein 3, LIM domain protein, cardiac, Muscle LIM protein

All UniProt accessions (5): P50461, A0A3B3IRI5, A0A3B3ISZ2, A0A3B3IT61, A2TDB8

UniProt curated annotations — full annotation on UniProt →

Function. Positive regulator of myogenesis. Acts as a cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis. Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein that promotes the assembly of interacting proteins at Z-line structures. It is essential for calcineurin anchorage to the Z line. Required for stress-induced calcineurin-NFAT activation. The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly: Shown to enhance CFL2-mediated F-actin depolymerization dependent on the CSRP3:CFL2 molecular ratio, and also shown to reduce the ability of CLF1 and CFL2 to enhance actin depolymerization. Proposed to contribute to the maintenance of muscle cell integrity through an actin-based mechanism. Can directly bind to actin filaments, cross-link actin filaments into bundles without polarity selectivity and protect them from dilution- and cofilin-mediated depolymerization; the function seems to involve its self-association. In vitro can inhibit PKC/PRKCA activity. Proposed to be involved in cardiac stress signaling by down-regulating excessive PKC/PRKCA signaling. May play a role in early sarcomere organization. Overexpression in myotubes negatively regulates myotube differentiation. By association with isoform 1 and thus changing the CSRP3 isoform 1:CFL2 stoichiometry is proposed to down-regulate CFL2-mediated F-actin depolymerization.

Subunit / interactions. Self-associates. Oligomeric in the cytoplasm and monomeric in the nucleus. Homooligomers preferentially form along the actin cytoskeleton. Isoform 2 interacts with isoform 1. Isoform 1 but not isoform 2 interacts with MYOD1 and MYOG. Isoform 1 interacts with TCAP, ACTN2 and NRAP. Isoform 2 interacts with TCAP and alpha-actinin. Interacts with LDHD. Interacts (via N-terminus)with GLRX3 (via C-terminus) and PPP3CA; GLRX3 and calcineurin compete for interaction with CSRP3. Interacts with MYF6. Interacts with CFL2; the stoichiometry influences F-actin depolymerization and possibly two molecules of CFL2 can interact with one molecule of CSRP3 resulting in the highest functional impact; the interaction is stronger with phosphorylated CFL2.

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

Tissue specificity. Cardiac and slow-twitch skeletal muscles. Isoform 2 is expressed in striated muscle. Isoform 2 is specifically expressed at higher levels in patients with neuromuscular diseases, such as limb-girdle muscular dystrophy 2A (LGMD2A), Duchenne muscular dystrophy (DMD) and dermatomyositis.

Post-translational modifications. Phosphorylated by PKC/PRKCA.

Disease relevance. Cardiomyopathy, dilated, 1M (CMD1M) [MIM:607482] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, familial hypertrophic, 12 (CMH12) [MIM:612124] A hereditary 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. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. LIM zinc-binding domain 1 is required for self-association. LIM zinc-binding domain 1 and LIM zinc-binding domain 2 both are required for optimal actin-bundling activity. LIM zinc-binding domain 1 mediates binding to MYOD1. LIM zinc-binding domain 2 mediates binding to SPTB.

Isoforms (2)

UniProt ID	Names	Canonical?
P50461-1	1, MLP-a	yes
P50461-2	2, MLP-b

RefSeq proteins (2): NP_001356333, NP_003467* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001781	Znf_LIM	Domain

Pfam: PF00412

UniProt features (37 total): strand 11, turn 6, sequence variant 5, helix 3, domain 2, region of interest 2, modified residue 2, splice variant 2, chain 1, mutagenesis site 1, sequence conflict 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2O10	SOLUTION NMR
2O13	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50461-F1	73.91	0.13

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 (2): 95, 153

Mutagenesis-validated functional residues (1):

Position	Phenotype
69	increases pkc/prkca activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 244 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_INFLAMMATORY_RESPONSE, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, MEF2_02, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MODULE_329, GOBP_SARCOMERE_ORGANIZATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GNF2_MYL3

GO Biological Process (26): regulation of the force of heart contraction (GO:0002026), cardiac muscle hypertrophy (GO:0003300), intracellular calcium ion homeostasis (GO:0006874), inflammatory response (GO:0006954), skeletal muscle tissue development (GO:0007519), insulin receptor signaling pathway (GO:0008286), T-tubule organization (GO:0033292), detection of muscle stretch (GO:0035995), glucose homeostasis (GO:0042593), sarcomere organization (GO:0045214), negative regulation of myoblast differentiation (GO:0045662), positive regulation of myoblast differentiation (GO:0045663), positive regulation of transcription by RNA polymerase II (GO:0045944), muscle cell cellular homeostasis (GO:0046716), cardiac muscle tissue development (GO:0048738), cardiac myofibril assembly (GO:0055003), cardiac muscle contraction (GO:0060048), muscle tissue development (GO:0060537), establishment of protein localization to organelle (GO:0072594), phospholipase C/protein kinase C signal transduction (GO:0141212), regulation of protein localization to plasma membrane (GO:1903076), negative regulation of actin filament severing (GO:1903919), positive regulation of actin filament severing (GO:1903920), heart development (GO:0007507), muscle organ development (GO:0007517), cell differentiation (GO:0030154)

GO Molecular Function (7): actin binding (GO:0003779), structural constituent of muscle (GO:0008307), telethonin binding (GO:0031433), identical protein binding (GO:0042802), actinin binding (GO:0042805), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), Z disc (GO:0030018), sarcomere (GO:0030017)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeletal protein binding	3
striated muscle tissue development	2
myofibril assembly	2
myoblast differentiation	2
regulation of myoblast differentiation	2
regulation of heart contraction	1
regulation of biological quality	1
striated muscle hypertrophy	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
defense response	1
skeletal muscle organ development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
plasma membrane organization	1
muscle cell development	1
membrane organization	1
response to muscle stretch	1
detection of mechanical stimulus	1
carbohydrate homeostasis	1
actomyosin structure organization	1
negative regulation of cell differentiation	1
positive regulation of cell differentiation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cellular homeostasis	1
heart development	1
cardiac muscle cell development	1
striated muscle contraction	1
heart contraction	1
tissue development	1
establishment of protein localization	1
intracellular signaling cassette	1
structural molecule activity	1
protein binding	1
cation binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSRP3	TCAP	O15273	996
CSRP3	TTN	Q8WZ42	991
CSRP3	MYBPC3	Q14896	934
CSRP3	ACTN2	P35609	874
CSRP3	MYL3	P08590	853
CSRP3	GLRX3	O76003	848
CSRP3	TNNI3	P19429	845
CSRP3	MYH7	P12883	831
CSRP3	ACTC1	P04270	829
CSRP3	TNNT2	P45379	825
CSRP3	TPM1	P09493	821
CSRP3	MYL2	P10916	792
CSRP3	LDB3	O75112	779
CSRP3	RBM20	Q5T481	777
CSRP3	PRKAG2	Q9UGJ0	776

IntAct

25 interactions, top by confidence:

A	B	Type	Score
ACTN2	CSRP3	psi-mi:“MI:0407”(direct interaction)	0.690
ACTN2	CSRP3	psi-mi:“MI:0914”(association)	0.690
CSRP3	ACTN2	psi-mi:“MI:0915”(physical association)	0.690
CSRP3	TCAP	psi-mi:“MI:0915”(physical association)	0.630
CSRP3	TCAP	psi-mi:“MI:0914”(association)	0.630
HTT	CSRP3	psi-mi:“MI:0915”(physical association)	0.560
CSRP3	NRAP	psi-mi:“MI:0407”(direct interaction)	0.440
SDC4	CSRP3	psi-mi:“MI:0407”(direct interaction)	0.440
CSRP3	CSRP3	psi-mi:“MI:0407”(direct interaction)	0.440
CSRP3	MYOD1	psi-mi:“MI:0407”(direct interaction)	0.440
MYOG	CSRP3	psi-mi:“MI:0407”(direct interaction)	0.440
CSRP3	CFL2	psi-mi:“MI:0407”(direct interaction)	0.440
CFL2	CSRP3	psi-mi:“MI:0407”(direct interaction)	0.440
CSRP3	XPNPEP1	psi-mi:“MI:0915”(physical association)	0.400
CSRP3	RIN3	psi-mi:“MI:0915”(physical association)	0.370
MRPL11	CSRP3	psi-mi:“MI:0914”(association)	0.350
CSRP3	NME2	psi-mi:“MI:0914”(association)	0.350
FHL1	CSRP3	psi-mi:“MI:0915”(physical association)	0.000
LIMS1	CSRP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): CSRP3 (Two-hybrid), KLF5 (Affinity Capture-Western), LDHD (Reconstituted Complex), CSRP3 (Two-hybrid), CSRP3 (Two-hybrid), CSRP3 (Affinity Capture-MS), MYOD1 (Phenotypic Enhancement), MYOD1 (Reconstituted Complex), MYF6 (Reconstituted Complex), MYOG (Reconstituted Complex), CSRP3 (Affinity Capture-Western), MYOD1 (Two-hybrid), CSRP3 (Affinity Capture-MS), XPNPEP1 (Affinity Capture-MS), NME2 (Affinity Capture-MS)

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: B0KYV5, D4A1F2, E7F9T0, F1LR10, F1MF74, F1MH07, F1QH17, F1QWK4, F1RA39, F6QZ15, G3MWR8, O04193, O60952, O80839, O94851, P29675, P34416, P50461, P50462, P50463, Q0E908, Q1ECF5, Q1LZA7, Q4KM31, Q4U0T9, Q4U4S6, Q500W4, Q7F9R9, Q7RTP6, Q8BGB5, Q8BML1, Q8CJ19, Q8I7C3, Q94JX5, Q9BT23, Q9ERG0, Q9M047, Q9UHB6, G5EF51, O77506

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
CSRP3	“up-regulates activity”	MYF6	binding
CSRP3	“up-regulates activity”	MYOG	binding
CSRP3	“up-regulates activity”	MYOD1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	11
Uncertain significance	278
Likely benign	132
Benign	19

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1008253	NM_003476.5(CSRP3):c.377C>G (p.Ser126Ter)	Pathogenic
1009234	NM_003476.5(CSRP3):c.49_55del (p.Val17fs)	Pathogenic
1011003	NM_003476.5(CSRP3):c.72del (p.Gln24fs)	Pathogenic
1324182	NM_003476.5(CSRP3):c.50_51insGCAGATTTCTT (p.Tyr18fs)	Pathogenic
1418855	NM_003476.5(CSRP3):c.82_85del (p.Arg28fs)	Pathogenic
1470431	NM_003476.5(CSRP3):c.165del (p.Ile56fs)	Pathogenic
216572	NM_003476.5(CSRP3):c.337A>T (p.Lys113Ter)	Pathogenic
279792	NM_003476.5(CSRP3):c.122_123dup (p.Lys42fs)	Pathogenic
2932324	NM_003476.5(CSRP3):c.186T>G (p.Tyr62Ter)	Pathogenic
2951005	NM_003476.5(CSRP3):c.279del (p.Gln93fs)	Pathogenic
3244681	NC_000011.9:g.(?18418390)(19213995_?)del	Pathogenic
3752686	NM_003476.5(CSRP3):c.444dup (p.Ile149fs)	Pathogenic
3755823	NM_003476.5(CSRP3):c.304del (p.Val102fs)	Pathogenic
3759643	NM_003476.5(CSRP3):c.54C>A (p.Tyr18Ter)	Pathogenic
3764079	NM_003476.5(CSRP3):c.27del (p.Lys9fs)	Pathogenic
4784477	NM_003476.5(CSRP3):c.161C>A (p.Ser54Ter)	Pathogenic
4786672	NM_003476.5(CSRP3):c.298del (p.Arg100fs)	Pathogenic
543041	NM_003476.5(CSRP3):c.55del (p.His19fs)	Pathogenic
543042	NM_003476.5(CSRP3):c.373A>T (p.Lys125Ter)	Pathogenic
585278	NM_003476.5(CSRP3):c.420G>C (p.Trp140Cys)	Pathogenic
58856	GRCh38/hg38 11p15.1(chr11:17905089-19674505)x1	Pathogenic
655718	NM_003476.5(CSRP3):c.52del (p.Tyr18fs)	Pathogenic
8777	NM_003476.5(CSRP3):c.172T>G (p.Cys58Gly)	Pathogenic
8779	NM_003476.5(CSRP3):c.160_164delinsAGGGG (p.Ser54_Glu55delinsArgGly)	Pathogenic
1324183	NM_003476.5(CSRP3):c.2T>C (p.Met1Thr)	Likely pathogenic
1704413	NM_003476.5(CSRP3):c.282-1G>A	Likely pathogenic
2941886	NM_003476.5(CSRP3):c.281+2T>C	Likely pathogenic
2947685	NM_003476.5(CSRP3):c.414+1G>A	Likely pathogenic
3763020	NM_003476.5(CSRP3):c.414+1G>C	Likely pathogenic
4791293	NM_003476.5(CSRP3):c.281+1G>C	Likely pathogenic

SpliceAI

733 predictions. Top by Δscore:

Variant	Effect	Δscore
11:19185041:CAAGG:C	acceptor_gain	1.0000
11:19185044:GG:G	acceptor_gain	1.0000
11:19185045:GCTG:G	acceptor_loss	1.0000
11:19185046:C:CC	acceptor_gain	1.0000
11:19185046:CTGAG:C	acceptor_loss	1.0000
11:19185047:T:G	acceptor_loss	1.0000
11:19186258:G:A	donor_gain	1.0000
11:19188134:A:AC	donor_gain	1.0000
11:19188135:C:CC	donor_gain	1.0000
11:19182747:C:CC	acceptor_gain	0.9900
11:19185042:AAGG:A	acceptor_gain	0.9900
11:19185043:AGG:A	acceptor_gain	0.9900
11:19185054:C:CT	acceptor_gain	0.9900
11:19186212:TTACC:T	donor_loss	0.9900
11:19186213:TACC:T	donor_loss	0.9900
11:19186214:A:AG	donor_loss	0.9900
11:19186215:C:CA	donor_loss	0.9900
11:19186217:TTGCC:T	donor_gain	0.9900
11:19186347:ACC:A	acceptor_loss	0.9900
11:19186348:CCT:C	acceptor_loss	0.9900
11:19186349:CTGTT:C	acceptor_loss	0.9900
11:19186350:T:G	acceptor_loss	0.9900
11:19188135:CTG:C	donor_gain	0.9900
11:19188305:C:CC	acceptor_gain	0.9900
11:19201949:CTCA:C	donor_loss	0.9900
11:19201951:CA:C	donor_loss	0.9900
11:19201952:A:T	donor_loss	0.9900
11:19201952:ACCTG:A	donor_gain	0.9900
11:19201953:CC:C	donor_loss	0.9900
11:19201953:CCTGC:C	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000048794 (11:19190770 A>G), RS1000138177 (11:19182492 A>G), RS1000375710 (11:19203004 T>C), RS1000387911 (11:19197501 C>A,T), RS1000474470 (11:19191838 C>T), RS1000685232 (11:19202778 A>G), RS1000848731 (11:19192685 G>A), RS1000878781 (11:19193525 T>C), RS1001018017 (11:19183542 C>T), RS1001196999 (11:19202690 T>C), RS1001365068 (11:19193063 T>C,G), RS1001389058 (11:19198621 A>T), RS1001540874 (11:19183123 A>G), RS1001629817 (11:19202435 C>T), RS1001857042 (11:19200187 C>A)

Disease associations

OMIM: gene MIM:600824 | disease phenotypes: MIM:607482, MIM:612124, MIM:192600, MIM:259050, MIM:616187

GenCC curated gene-disease

Disease	Classification	Inheritance
hypertrophic cardiomyopathy 12	Strong	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
dilated cardiomyopathy 1M	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Definitive	SD
dilated cardiomyopathy 1M	Limited	AD

Mondo (10): dilated cardiomyopathy 1M (MONDO:0011840), hypertrophic cardiomyopathy 12 (MONDO:0012804), cardiomyopathy (MONDO:0004994), hypertrophic cardiomyopathy (MONDO:0005045), familial hypertrophic cardiomyopathy (MONDO:0024573), hypertrophic cardiomyopathy 1 (MONDO:0008647), dilated cardiomyopathy (MONDO:0005021), Primrose syndrome (MONDO:0009798), progressive myoclonic epilepsy type 7 (MONDO:0014521), (MONDO:0015470)

Orphanet (8): Familial isolated dilated cardiomyopathy (Orphanet:154), Rare cardiomyopathy (Orphanet:167848), Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Intellectual disability-cataracts-calcified pinnae-myopathy syndrome (Orphanet:3042), Progressive myoclonic epilepsy type 7 (Orphanet:435438), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001706	Endocardial fibroelastosis
HP:0001727	Thromboembolic stroke
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0003581	Adult onset
HP:0004756	Ventricular tachycardia
HP:0004757	Paroxysmal atrial fibrillation
HP:0005144	Ventricular septal hypertrophy
HP:0006670	Impaired myocardial contractility
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012664	Reduced left ventricular ejection fraction
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0033755	Increased left ventricular end-diastolic volume
HP:0034386	Reduced left ventricular endsystolic diameter
HP:0100578	Lipoatrophy

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004601_154	Red blood cell count	8.000000e-16
GCST004602_193	Mean corpuscular volume	9.000000e-20
GCST004630_247	Mean corpuscular hemoglobin	6.000000e-14
GCST004863_14	Mosquito bite size	7.000000e-06
GCST90002390_508	Mean corpuscular hemoglobin	1.000000e-38
GCST90002392_564	Mean corpuscular volume	5.000000e-12
GCST90002392_565	Mean corpuscular volume	2.000000e-24
GCST90002397_519	Mean spheric corpuscular volume	3.000000e-24
GCST90002403_196	Red blood cell count	1.000000e-28

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0008378	mosquito bite reaction size measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
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
C564390	Cardiomyopathy, Dilated, 1M (supp.)
C536420	Primrose syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs983332	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs983332	CSRP3	3	2.75	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	increases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
perfluorohexanesulfonic acid	increases expression	1
incobotulinumtoxinA	decreases expression	1
Temozolomide	affects response to substance	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carmustine	affects response to substance	1
Doxorubicin	increases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, affects response to substance	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Triclosan	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	decreases expression	1
Okadaic Acid	increases expression	1

Cellosaurus cell lines

2 cell lines: 1 embryonic stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1YG	WAe009-A-41	Embryonic stem cell	Female
CVCL_E1UM	HAP1 CSRP3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

300 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
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
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	PHASE2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	PHASE2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy