LDB3

Summary

LDB3 (LIM domain binding 3, HGNC:15710) is a protein-coding gene on chromosome 10q23.2, encoding LIM domain-binding protein 3 (O75112). May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.

This gene encodes a PDZ domain-containing protein. PDZ motifs are modular protein-protein interaction domains consisting of 80-120 amino acid residues. PDZ domain-containing proteins interact with each other in cytoskeletal assembly or with other proteins involved in targeting and clustering of membrane proteins. The protein encoded by this gene interacts with alpha-actinin-2 through its N-terminal PDZ domain and with protein kinase C via its C-terminal LIM domains. The LIM domain is a cysteine-rich motif defined by 50-60 amino acids containing two zinc-binding modules. This protein also interacts with all three members of the myozenin family. Mutations in this gene have been associated with myofibrillar myopathy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding different isoforms have been identified; all isoforms have N-terminal PDZ domains while only longer isoforms (1, 2 and 5) have C-terminal LIM domains.

Source: NCBI Gene 11155 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy, dilated, 2l (Strong, ClinGen) — +6 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 1,541 total — 29 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 83
• MANE Select transcript: NM_007078

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15710
Approved symbol	LDB3
Name	LIM domain binding 3
Location	10q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PDLIM6, KIAA0613, ZASP
Ensembl gene	ENSG00000122367
Ensembl biotype	protein_coding
OMIM	605906
Entrez	11155

Gene structure

Transcript identifiers

Ensembl transcripts: 67 — 60 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000263066, ENST00000361373, ENST00000372056, ENST00000372066, ENST00000429277, ENST00000477489, ENST00000542786, ENST00000623007, ENST00000623056, ENST00000686051, ENST00000686176, ENST00000687154, ENST00000687598, ENST00000687856, ENST00000688001, ENST00000688678, ENST00000688785, ENST00000689296, ENST00000689740, ENST00000691462, ENST00000691495, ENST00000693680, ENST00000871438, ENST00000871439, ENST00000871440, ENST00000871441, ENST00000871442, ENST00000871443, ENST00000871444, ENST00000871445, ENST00000871446, ENST00000871447, ENST00000871448, ENST00000871449, ENST00000871450, ENST00000871451, ENST00000871452, ENST00000871453, ENST00000871454, ENST00000871455, ENST00000871456, ENST00000871457, ENST00000871458, ENST00000871459, ENST00000871460, ENST00000871461, ENST00000871462, ENST00000871463, ENST00000871464, ENST00000871465, ENST00000871466, ENST00000871467, ENST00000945666, ENST00000945667, ENST00000945668, ENST00000945669, ENST00000945670, ENST00000945671, ENST00000945672, ENST00000945673, ENST00000945674, ENST00000945675, ENST00000945676, ENST00000945677, ENST00000945678, ENST00000945679, ENST00000945680

RefSeq mRNA: 12 — MANE Select: NM_007078 NM_001080114, NM_001080115, NM_001080116, NM_001171610, NM_001171611, NM_001368063, NM_001368064, NM_001368065, NM_001368066, NM_001368067, NM_001368068, NM_007078

CCDS: CCDS41544, CCDS41545, CCDS44450, CCDS53549, CCDS53550, CCDS7377, CCDS91289, CCDS91290

Canonical transcript exons

ENST00000361373 — 14 exons

Exon	Start	End
ENSE00000830532	86679367	86679518
ENSE00001210275	86709905	86710050
ENSE00001210293	86706531	86706719
ENSE00001210296	86681436	86681803
ENSE00001210447	86668669	86668784
ENSE00001323572	86680082	86680157
ENSE00002251872	86732887	86736072
ENSE00002306452	86668511	86668570
ENSE00003265335	86717964	86718144
ENSE00003299484	86716327	86716771
ENSE00003344834	86718727	86718847
ENSE00003390845	86726137	86726252
ENSE00003628120	86691896	86692065
ENSE00003661984	86692535	86692571

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 99.80.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5486 / max 14.4944, expressed in 316 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105970	25.5870	413
105968	5.5007	222
105969	0.8695	42
85214	0.5486	316
105972	0.5139	73
105974	0.3596	52
105971	0.1083	29
105973	0.0873	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.80	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.78	gold quality
apex of heart	UBERON:0002098	99.77	gold quality
body of tongue	UBERON:0011876	99.74	gold quality
biceps brachii	UBERON:0001507	99.71	gold quality
vastus lateralis	UBERON:0001379	99.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.67	gold quality
cardiac ventricle	UBERON:0002082	99.61	gold quality
heart left ventricle	UBERON:0002084	99.61	gold quality
quadriceps femoris	UBERON:0001377	99.57	gold quality
vena cava	UBERON:0004087	99.54	gold quality
left ventricle myocardium	UBERON:0006566	99.53	gold quality
cardiac atrium	UBERON:0002081	99.52	gold quality
right atrium auricular region	UBERON:0006631	99.51	gold quality
diaphragm	UBERON:0001103	99.45	gold quality
gluteal muscle	UBERON:0002000	99.43	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.43	gold quality
gastrocnemius	UBERON:0001388	99.41	gold quality
heart right ventricle	UBERON:0002080	99.39	gold quality
skeletal muscle tissue	UBERON:0001134	99.37	gold quality
myocardium	UBERON:0002349	99.33	gold quality
triceps brachii	UBERON:0001509	99.30	gold quality
muscle organ	UBERON:0001630	98.71	gold quality
blood vessel layer	UBERON:0004797	98.71	gold quality
skeletal muscle organ	UBERON:0014892	98.71	gold quality
deltoid	UBERON:0001476	98.68	gold quality
heart	UBERON:0000948	98.53	gold quality
muscle tissue	UBERON:0002385	98.46	gold quality
muscle of leg	UBERON:0001383	98.39	gold quality
inferior vagus X ganglion	UBERON:0005363	98.24	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4532.47
E-HCAD-25	yes	49.09
E-MTAB-11268	no	3195.31
E-MTAB-6142	no	0.52
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

118 targeting LDB3, 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-4668-3P	100.00	68.74	2635
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-95-5P	99.89	72.17	3973

Literature-anchored findings (GeneRIF, showing 19)

• the D626N mutation of Cypher/ZASP increases the affinity of the LIM domain for protein kinase C, which may be related to pathogenesis of dilated cardiomyopathy (PMID:14660611)
• ZASP/Cypher internal fragments containing either ZM exon 4 or 6 co-localized with alpha-actinin in cultured myoblasts and nonmuscle cells. (PMID:16476425)
• Tafazzins are essential during fetal and early post-natal life. (PMID:17394203)
• ZASP/Cypher anchors PGM1 to Z-disc under conditions of stress. The impaired binding of PGM1 to ZASP/Cypher might be involved in the pathogenesis of dilated cardiomyopathy. (PMID:19377068)
• TNNT3 and LDB3 showed abnormal splicing and appeared more pronounced in myotonic dystrophies type 2 relative to myotonic dystrophies type 1. (PMID:20066428)
• This results of this indicted that One patient harbored the missense mutation c.1719G>A (p.V566M) in the ZASP gene. (PMID:22349865)
• ZASP1 can form protein complex with telethonin/T-Cap and Na(v)1.5. The left ventricular noncompaction-specific ZASP1 mutation can cause loss of function of Na(v)1.5, without significant alteration of the cytoskeletal protein complex. (PMID:22929165)
• Z-band alternatively spliced PDZ motif protein (ZASP) is the major O-linked beta-N-acetylglucosamine-substituted protein in human heart myofibrils (PMID:23271734)
• results show that MFM-associated ZASP mutations in the actin-binding domain have deleterious effects on the core structure of the Z-discs in skeletal muscle. (PMID:24668811)
• Study identified abnormal inclusion of LDB3 exon 11 specific to myotonic dystrophy type at the RNA and protein level; inclusion changed the affinity of LDB3 for PKC, indicating that exon 11 may contribute to the activation of PKC in DM1 (PMID:24878509)
• this is the first family with Arrhythmogenic right ventricular cardiomyopathy where a mutation in LDB3 is associated with Arrhythmogenic right ventricular cardiomyopathy (PMID:25041374)
• p.(D117N) variant in Cypher/ZASP is not a causative mutation for dilated cardiomyopathy and ventricular arrhythmias. (PMID:26419279)
• A novel heterozygous missense mutation (p.N155H) in a highly conserved PDZ-like motif of ZASP was identified. The results indicate that typical ZASP-MFM presenting with late-onset distal myopathy is commonly associated with mutations in PDZ-like motif of ZASP. (PMID:27546599)
• The molecular basis for high-affinity binding of ZASP to G-Actin has been described. (PMID:28349680)
• Alterations of protein expression of phospholamban, ZASP and plakoglobin in human atria in subgroups of seniors. (PMID:30948763)
• The rs4468255 of LIM domain binding 3 (LDB3) is significantly correlated with idiopathic dilated cardiomyopathy of Chinese Han population (PMID:31379146)
• Protein aggregates and autophagy involvement in a family with a mutation in Z-band alternatively spliced PDZ-motif protein. (PMID:33308939)
• Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy. (PMID:36253531)
• Association between ZASP/LDB3 Pro26Ser and Inclusion Body Myopathy. (PMID:38928252)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ldb3b	ENSDARG00000099974
mus_musculus	Ldb3	ENSMUSG00000021798
rattus_norvegicus	Ldb3	ENSRNOG00000059166

Paralogs (7): PDLIM1 (ENSG00000107438), PDLIM2 (ENSG00000120913), PDLIM4 (ENSG00000131435), PDLIM3 (ENSG00000154553), PDLIM5 (ENSG00000163110), PDLIM7 (ENSG00000196923), PRICKLE4 (ENSG00000278224)

Protein

Protein identifiers

LIM domain-binding protein 3 — O75112 (reviewed: O75112)

Alternative names: Protein cypher, Z-band alternatively spliced PDZ-motif protein

All UniProt accessions (10): A0A096LPD7, A0A0C4DGG7, A0A0S2Z501, A0A0S2Z521, A0A0S2Z530, A0A8I5KV04, A0A8I5KX76, A0A8I5QJN0, O75112, V5T7C5

UniProt curated annotations — full annotation on UniProt →

Function. May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.

Subunit / interactions. Interacts via its LIM domains with various PKC isoforms. Interacts via its PDZ domain with the ACTN2 C-terminal region. Interacts with MYOZ1, MYOZ2 and MYOZ3.

Subcellular location. Cytoplasm. Perinuclear region. Cell projection. Pseudopodium. Cytoskeleton. Myofibril. Sarcomere. Z line.

Tissue specificity. Expressed primarily in skeletal muscle and to a lesser extent in heart. Also detected in brain and placenta.

Disease relevance. Cardiomyopathy, dilated, 1C, with or without left ventricular non-compaction (CMD1C) [MIM:601493] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. Cardiomyopathy dilated type 1C is associated with left ventricular non-compaction in some patients. Left ventricular non-compaction is characterized by numerous prominent trabeculations and deep intertrabecular recesses in hypertrophied and hypokinetic segments of the left ventricle. The disease is caused by variants affecting the gene represented in this entry. Left ventricular non-compaction 3 (LVNC3) [MIM:601493] A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. LVNC3 is an autosomal dominant condition. The disease is caused by variants affecting the gene represented in this entry. Myopathy, myofibrillar, 4 (MFM4) [MIM:609452] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM4 is characterized by distal and proximal muscle weakness with signs of cardiomyopathy and neuropathy. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, familial hypertrophic, 24 (CMH24) [MIM:601493] 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 may be caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 2L (CMD2L) [MIM:621237] A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2L is an autosomal recessive, severe form characterized by neonatal or infantile onset. Some patients show additional skeletal muscle involvement. Death in infancy or early childhood may occur. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (7)

UniProt ID	Names	Canonical?
O75112-1	1	yes
O75112-2	2
O75112-3	3
O75112-4	4
O75112-5	5
O75112-6	6
O75112-7	7

RefSeq proteins (12): NP_001073583, NP_001073584, NP_001073585, NP_001165081, NP_001165082, NP_001354992, NP_001354993, NP_001354994, NP_001354995, NP_001354996, NP_001354997, NP_009009* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001781	Znf_LIM	Domain
IPR006643	Zasp-like_motif	Domain
IPR031847	PDLI1-4/Zasp-like_mid	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR050604	PDZ-LIM_domain	Family

Pfam: PF00412, PF00595, PF15936

UniProt features (60 total): sequence variant 22, modified residue 8, splice variant 6, strand 6, compositionally biased region 5, domain 4, helix 3, region of interest 3, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4YDP	X-RAY DIFFRACTION	1.4
1RGW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75112-F1	61.98	0.22

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 (8): 44, 121, 123, 217, 219, 223, 516, 533

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 272 (showing top): MORF_ITGA2, MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, MAZ_Q6, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, TGACCTY_ERR1_Q2, MODULE_453, GOBP_SARCOMERE_ORGANIZATION, CAGCTG_AP4_Q5, MORF_RAD51L3, SRF_C

GO Biological Process (4): heart development (GO:0007507), actin cytoskeleton organization (GO:0030036), sarcomere organization (GO:0045214), muscle structure development (GO:0061061)

GO Molecular Function (7): actin binding (GO:0003779), protein kinase C binding (GO:0005080), cytoskeletal protein binding (GO:0008092), metal ion binding (GO:0046872), muscle alpha-actinin binding (GO:0051371), protein binding (GO:0005515), enzyme binding (GO:0019899)

GO Cellular Component (9): stress fiber (GO:0001725), cytoskeleton (GO:0005856), adherens junction (GO:0005912), Z disc (GO:0030018), pseudopodium (GO:0031143), filamentous actin (GO:0031941), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
animal organ development	1
circulatory system development	1
cytoskeleton organization	1
actin filament-based process	1
myofibril assembly	1
actomyosin structure organization	1
anatomical structure development	1
cytoskeletal protein binding	1
protein kinase binding	1
cation binding	1
alpha-actinin binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
intracellular membraneless organelle	1
cell-cell junction	1
I band	1
plasma membrane bounded cell projection	1
actin filament	1
protein-containing complex	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LDB3	ACTN2	P35609	947
LDB3	MYOT	Q9UBF9	946
LDB3	FLNC	Q14315	916
LDB3	MYOZ1	Q9NP98	899
LDB3	MYOZ2	Q9NPC6	893
LDB3	MYOZ3	Q8TDC0	871
LDB3	TCAP	O15273	868
LDB3	TNNT2	P45379	857
LDB3	BAG3	O95817	824
LDB3	TAFAZZIN	Q16635	819
LDB3	RBM20	Q5T481	813
LDB3	MYH7	P12883	805
LDB3	MBNL1	Q9NR56	801
LDB3	MYBPC3	Q14896	791
LDB3	CSRP3	P50461	779
LDB3	TTN	Q8WZ42	779

IntAct

415 interactions, top by confidence:

A	B	Type	Score
SRC	LDB3	psi-mi:“MI:0407”(direct interaction)	0.620
MYOZ2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
MYOT	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
MYOZ3	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
PALLD	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
MYPN	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
LDB3	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.440
MYOZ1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
ACTN2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
YAP1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
RCN2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNB1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
TJP3	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
CREBBP	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
E6	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
Tax	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
E	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
NET1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
PTEN	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
RPS6KA1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
GP1	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
ABRAXAS2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
ACE2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
ACVR2A	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440
ADRB2	LDB3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (22): HSPA1A (Affinity Capture-MS), RHOA (Affinity Capture-MS), NPC2 (Affinity Capture-MS), LDB3 (Co-fractionation), HSPA1A (Affinity Capture-MS), NPC2 (Affinity Capture-MS), RHOA (Affinity Capture-MS), TFCP2 (Two-hybrid), ANKRD2 (Affinity Capture-Western), LDB3 (Affinity Capture-Western), LDB3 (Far Western), ACTN1 (Affinity Capture-Western), TP53 (Affinity Capture-Western), LDB3 (Affinity Capture-Western), LDB3 (Far Western)

ESM2 similar proteins: A5D7K1, A5H447, B5DEH0, D3ZEN0, D3ZIE4, D3ZQL6, E1B7L7, E1BBG2, G5E5X0, O15117, O35601, O75112, P49023, Q03173, Q04584, Q0VA45, Q15942, Q3TN34, Q3ULZ2, Q4G0F8, Q5F464, Q5HYK7, Q5R7I1, Q5T0Z8, Q5XI07, Q62523, Q64GL0, Q68CZ2, Q6NZJ6, Q6ZU65, Q80WC1, Q80XI3, Q8BFW7, Q8BGT6, Q8CC35, Q8CI51, Q8IY33, Q8N3F8, Q8VI36, Q8WX93

Diamond homologs: A1ZA47, A2ALU4, A5H447, D4A702, E1BKA3, O00151, O14639, O43294, O60711, O70209, O70400, O75112, O94929, P20271, P48059, P49023, P49024, P50464, P52944, Q09476, Q0WSN2, Q13796, Q15942, Q1JQB5, Q2KJ33, Q2TCH4, Q2YDK0, Q3MHZ4, Q3SX26, Q3SX40, Q3SYZ8, Q3T0X8, Q3TJD7, Q55BI0, Q5F464, Q5R7I1, Q5RCF7, Q5TD97, Q5U2Z2, Q5XI07

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 194 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
Long-term potentiation	5	17.8×	7e-04
EPHB-mediated forward signaling	6	11.9×	7e-04
RHOQ GTPase cycle	7	9.5×	7e-04
Voltage gated Potassium channels	5	9.1×	6e-03
Cell death signalling via NRAGE, NRIF and NADE	5	8.2×	8e-03
RHOB GTPase cycle	7	8.1×	1e-03
Potassium Channels	8	8.0×	7e-04
RHOC GTPase cycle	7	7.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cardiac conduction	6	27.9×	7e-05
positive regulation of synaptic transmission, glutamatergic	6	20.7×	3e-04
positive regulation of excitatory postsynaptic potential	5	14.6×	3e-03
action potential	5	9.9×	1e-02
calcium ion transmembrane transport	7	8.2×	3e-03
transport across blood-brain barrier	8	7.9×	2e-03
transmembrane transport	8	7.5×	2e-03
protein localization to plasma membrane	10	6.0×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1541 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	7
Uncertain significance	847
Likely benign	372
Benign	82

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1058214	NM_007078.3(LDB3):c.319A>T (p.Lys107Ter)	Pathogenic
1175152	NM_007078.3(LDB3):c.59del (p.Gly20fs)	Pathogenic
1425088	NM_007078.3(LDB3):c.1439dup (p.Ala482fs)	Pathogenic
1430730	NM_007078.3(LDB3):c.289dup (p.Gln97fs)	Pathogenic
1431435	NM_007078.3(LDB3):c.1653C>A (p.Cys551Ter)	Pathogenic
1453421	NC_000010.10:g.(?88441193)(88722432_?)del	Pathogenic
1473224	NM_007078.3(LDB3):c.1968C>A (p.Tyr656Ter)	Pathogenic
1501667	NM_007078.3(LDB3):c.1806T>A (p.Tyr602Ter)	Pathogenic
2034482	NM_007078.3(LDB3):c.785_818dup (p.Ser274fs)	Pathogenic
2699041	NM_007078.3(LDB3):c.1343del (p.Ser448fs)	Pathogenic
2703332	NM_007078.3(LDB3):c.1074dup (p.Asp359fs)	Pathogenic
2720857	NM_007078.3(LDB3):c.566C>A (p.Ser189Ter)	Pathogenic
2733907	NM_007078.3(LDB3):c.59dup (p.Lys21fs)	Pathogenic
2791443	NM_007078.3(LDB3):c.1086-247_1231+2del	Pathogenic
3654209	NM_007078.3(LDB3):c.392del (p.Gly131fs)	Pathogenic
3661674	NM_007078.3(LDB3):c.16dup (p.Thr6fs)	Pathogenic
3666400	NM_007078.3(LDB3):c.1675del (p.Arg559fs)	Pathogenic
3901869	NM_007078.3(LDB3):c.859+4A>G	Pathogenic
3901871	NM_007078.3(LDB3):c.1881_1884del (p.Gln627fs)	Pathogenic
464289	NM_007078.3(LDB3):c.529del (p.Ala177fs)	Pathogenic
4704645	NM_007078.3(LDB3):c.567_571dup (p.Gln191fs)	Pathogenic
4733575	NM_007078.3(LDB3):c.726del (p.Ser243fs)	Pathogenic
4735394	NM_007078.3(LDB3):c.838C>T (p.Gln280Ter)	Pathogenic
532923	NM_007078.3(LDB3):c.99dup (p.Pro34fs)	Pathogenic
532929	NM_007078.3(LDB3):c.242del (p.Gln81fs)	Pathogenic
532932	NM_007078.3(LDB3):c.196C>T (p.Gln66Ter)	Pathogenic
972383	NM_007078.3(LDB3):c.1457dup (p.Ser486fs)	Pathogenic
997776	NM_007078.3(LDB3):c.1723T>A (p.Phe575Ile)	Pathogenic
997777	NM_007078.3(LDB3):c.1818T>A (p.Phe606Leu)	Pathogenic
3650743	NM_007078.3(LDB3):c.245+1G>A	Likely pathogenic

SpliceAI

3346 predictions. Top by Δscore:

Variant	Effect	Δscore
10:86668783:GG:G	donor_gain	1.0000
10:86668784:GG:G	donor_gain	1.0000
10:86679516:GAA:G	donor_gain	1.0000
10:86679519:G:GG	donor_gain	1.0000
10:86691895:GGA:G	acceptor_gain	1.0000
10:86692061:ATTCA:A	donor_gain	1.0000
10:86692062:TTCA:T	donor_gain	1.0000
10:86692063:TCA:T	donor_gain	1.0000
10:86692066:G:GG	donor_gain	1.0000
10:86692533:A:AG	acceptor_gain	1.0000
10:86692534:G:GG	acceptor_gain	1.0000
10:86692570:AGGT:A	donor_loss	1.0000
10:86692571:GGT:G	donor_loss	1.0000
10:86692572:G:C	donor_loss	1.0000
10:86692573:T:A	donor_loss	1.0000
10:86718141:GGGG:G	donor_gain	1.0000
10:86718142:GGGG:G	donor_gain	1.0000
10:86718726:GGAA:G	acceptor_gain	1.0000
10:86718843:GAAAG:G	donor_gain	1.0000
10:86718844:AAAGG:A	donor_loss	1.0000
10:86718846:AGG:A	donor_loss	1.0000
10:86718847:GGTA:G	donor_loss	1.0000
10:86718848:GTA:G	donor_loss	1.0000
10:86726253:G:GG	donor_gain	1.0000
10:86668785:G:GG	donor_gain	0.9900
10:86668786:T:A	donor_loss	0.9900
10:86668787:G:GT	donor_loss	0.9900
10:86679492:C:G	donor_gain	0.9900
10:86680076:CTACA:C	acceptor_loss	0.9900
10:86680079:CA:C	acceptor_loss	0.9900

AlphaMissense

4710 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:86668728:T:A	W13R	1.000
10:86668728:T:C	W13R	1.000
10:86668730:G:C	W13C	1.000
10:86668730:G:T	W13C	1.000
10:86668731:G:C	G14R	1.000
10:86668732:G:A	G14D	1.000
10:86668734:T:C	F15L	1.000
10:86668735:T:C	F15S	1.000
10:86668735:T:G	F15C	1.000
10:86668736:C:A	F15L	1.000
10:86668736:C:G	F15L	1.000
10:86668737:C:A	R16S	1.000
10:86668737:C:G	R16G	1.000
10:86668738:G:C	R16P	1.000
10:86668741:T:A	L17Q	1.000
10:86668741:T:C	L17P	1.000
10:86668741:T:G	L17R	1.000
10:86668746:G:A	G19R	1.000
10:86668746:G:C	G19R	1.000
10:86668746:G:T	G19W	1.000
10:86668747:G:A	G19E	1.000
10:86668747:G:T	G19V	1.000
10:86668749:G:C	G20R	1.000
10:86668749:G:T	G20C	1.000
10:86668750:G:A	G20D	1.000
10:86668750:G:T	G20V	1.000
10:86668755:G:C	D22H	1.000
10:86668758:T:C	F23L	1.000
10:86668759:T:C	F23S	1.000
10:86668759:T:G	F23C	1.000

dbSNP variants (sampled 300 via entrez): RS1000017053 (10:86703383 G>A,C), RS1000020884 (10:86687214 G>A,C), RS1000048881 (10:86710761 T>G), RS1000062127 (10:86666731 G>A), RS1000088741 (10:86735607 C>T), RS1000111297 (10:86678298 A>G), RS1000172813 (10:86715654 GC>G), RS1000233302 (10:86678515 T>A), RS1000351525 (10:86709662 G>A,T), RS1000408662 (10:86667078 G>A), RS1000469266 (10:86725523 A>C,G), RS1000547986 (10:86736001 TG>T), RS1000572880 (10:86717449 A>G), RS1000722399 (10:86720755 T>C), RS1000729564 (10:86684318 AG>A)

Disease associations

OMIM: gene MIM:605906 | disease phenotypes: MIM:609452, MIM:601493, MIM:621237, MIM:115195, MIM:174900, MIM:192600, MIM:115200, MIM:601419, MIM:115197, MIM:613251, MIM:604169

GenCC curated gene-disease

Disease	Classification	Inheritance
myofibrillar myopathy 4	Strong	Autosomal dominant
dilated cardiomyopathy 1C	Strong	Autosomal dominant
cardiomyopathy, dilated, 2l	Strong	Autosomal recessive
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
familial dilated cardiomyopathy	Limited	Autosomal recessive
hypertrophic cardiomyopathy	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Disputed	AD
dilated cardiomyopathy 1C	Limited	AD
arrhythmogenic right ventricular cardiomyopathy	Disputed	AD
cardiomyopathy, dilated, 2l	Strong	AR

Mondo (22): myofibrillar myopathy 4 (MONDO:0012277), dilated cardiomyopathy 1C (MONDO:0011094), long QT syndrome (MONDO:0002442), cardiomyopathy, dilated, 2l (MONDO:0979236), cardiomyopathy (MONDO:0004994), hypertrophic cardiomyopathy 2 (MONDO:0007266), juvenile polyposis syndrome (MONDO:0017380), familial hypertrophic cardiomyopathy (MONDO:0024573), dilated cardiomyopathy (MONDO:0005021), familial isolated dilated cardiomyopathy (MONDO:0700335), familial dilated cardiomyopathy (MONDO:0016333), hypertrophic cardiomyopathy (MONDO:0005045), hypertrophic cardiomyopathy 1 (MONDO:0008647), myofibrillar myopathy (MONDO:0018943), dilated cardiomyopathy 1A (MONDO:0007269)

Orphanet (14): Late-onset distal myopathy, Markesbery-Griggs type (Orphanet:98912), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260), Rare cardiomyopathy (Orphanet:167848), Juvenile polyposis syndrome (Orphanet:2929), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Familial dilated cardiomyopathy (Orphanet:217607), Rare hypertrophic cardiomyopathy (Orphanet:217569), Myofibrillar myopathy (Orphanet:593), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Neuromuscular disease (Orphanet:68381), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001254	Lethargy
HP:0001271	Polyneuropathy
HP:0001288	Gait disturbance
HP:0001626	Abnormality of the cardiovascular system
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001640	Cardiomegaly
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0001762	Talipes equinovarus
HP:0002094	Dyspnea
HP:0002151	Increased circulating lactate concentration
HP:0002240	Hepatomegaly
HP:0002505	Loss of ambulation
HP:0002600	Hyporeflexia of lower limbs
HP:0002783	Recurrent lower respiratory tract infections
HP:0002875	Exertional dyspnea
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003112	Abnormal circulating amino acid concentration
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003256	Abnormality of the coagulation cascade

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003262_290	Post bronchodilator FEV1	9.000000e-07
GCST003264_1013	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST004363_3	Plasma androstenedione levels in resected early stage-receptor positive breast cancer	6.000000e-07
GCST006979_596	Heel bone mineral density	2.000000e-09
GCST010796_2613	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_2614	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0007972	androstenedione measurement
EFO:0009270	heel bone mineral density
EFO:0004327	electrocardiography

MeSH disease descriptors (15)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
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
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D009468	Neuromuscular Diseases	C10.668
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
C563307	Cardiomyopathy, Dilated, 1C (supp.)
C567684	Cardiomyopathy, Familial Hypertrophic, 14 (supp.)
C566171	Cardiomyopathy, Familial Hypertrophic, 2 (supp.)
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)
C580316	Myofibrillar Myopathy (supp.)
C563718	Myopathy, Myofibrillar, Zasp-Related (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Benzo(a)pyrene	affects methylation	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Nickel	decreases expression	2
Valproic Acid	affects expression, increases methylation	2
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
trichostatin A	increases expression	1
trimellitic anhydride	decreases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Cadmium	increases abundance, decreases expression	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Etoposide	decreases expression	1
Methapyrilene	increases methylation	1
Smoke	decreases expression	1
Testosterone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D0K7	NIMHi008-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01798992	PHASE4	COMPLETED	Effect of Beta-blockers on Structural Remodeling and Gene Expression in the Failing Human Heart
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
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
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
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