PDLIM7

Summary

PDLIM7 (PDZ and LIM domain 7, HGNC:22958) is a protein-coding gene on chromosome 5q35.3, encoding PDZ and LIM domain protein 7 (Q9NR12). May function as a scaffold on which the coordinated assembly of proteins can occur.

The protein encoded by this gene is representative of a family of proteins composed of conserved PDZ and LIM domains. LIM domains are proposed to function in protein-protein recognition in a variety of contexts including gene transcription and development and in cytoskeletal interaction. The LIM domains of this protein bind to protein kinases, whereas the PDZ domain binds to actin filaments. The gene product is involved in the assembly of an actin filament-associated complex essential for transmission of ret/ptc2 mitogenic signaling. The biological function is likely to be that of an adapter, with the PDZ domain localizing the LIM-binding proteins to actin filaments of both skeletal muscle and nonmuscle tissues. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 9260 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitral valve prolapse (Limited, GenCC) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 83 total
• MANE Select transcript: NM_005451

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22958
Approved symbol	PDLIM7
Name	PDZ and LIM domain 7
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	ENIGMA
Ensembl gene	ENSG00000196923
Ensembl biotype	protein_coding
OMIM	605903
Entrez	9260

Gene structure

Transcript identifiers

Ensembl transcripts: 53 — 45 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000355572, ENST00000355841, ENST00000359895, ENST00000393546, ENST00000393551, ENST00000463411, ENST00000486828, ENST00000493815, ENST00000503346, ENST00000503827, ENST00000504318, ENST00000504380, ENST00000505074, ENST00000505746, ENST00000506161, ENST00000506537, ENST00000911148, ENST00000911149, ENST00000911150, ENST00000911151, ENST00000911152, ENST00000911153, ENST00000911154, ENST00000911155, ENST00000911156, ENST00000911157, ENST00000911158, ENST00000911159, ENST00000911160, ENST00000911161, ENST00000916411, ENST00000916412, ENST00000916413, ENST00000916414, ENST00000950036, ENST00000950037, ENST00000950038, ENST00000950039, ENST00000950040, ENST00000950041, ENST00000950042, ENST00000950043, ENST00000950044, ENST00000950045, ENST00000950046, ENST00000950047, ENST00000950048, ENST00000950049, ENST00000950050, ENST00000950051, ENST00000950052, ENST00000950053, ENST00000950054

RefSeq mRNA: 3 — MANE Select: NM_005451 NM_005451, NM_203352, NM_213636

CCDS: CCDS4422, CCDS4423, CCDS4424

Canonical transcript exons

ENST00000355841 — 13 exons

Exon	Start	End
ENSE00003481618	177496417	177496523
ENSE00003502640	177492526	177492677
ENSE00003506005	177483394	177483730
ENSE00003534091	177489393	177489627
ENSE00003575891	177491807	177491925
ENSE00003604496	177483867	177483982
ENSE00003608275	177489771	177489832
ENSE00003611688	177490870	177490906
ENSE00003621070	177492405	177492435
ENSE00003662910	177488068	177488248
ENSE00003693248	177484070	177484190
ENSE00003791147	177491010	177491146
ENSE00003841826	177497528	177497604

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 182.4847 / max 1590.8536, expressed in 1826 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65128	176.5023	1826
65120	1.5322	869
65127	1.2681	717
65126	1.0334	655
65125	0.6527	349
65112	0.4196	209
65113	0.4082	169
65110	0.2618	112
65114	0.1581	47
65119	0.1318	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of uterus	UBERON:0009853	99.64	gold quality
ascending aorta	UBERON:0001496	99.61	gold quality
thoracic aorta	UBERON:0001515	99.61	gold quality
right coronary artery	UBERON:0001625	99.61	gold quality
descending thoracic aorta	UBERON:0002345	99.54	gold quality
lower esophagus	UBERON:0013473	99.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.54	gold quality
popliteal artery	UBERON:0002250	99.53	gold quality
tibial artery	UBERON:0007610	99.53	gold quality
left uterine tube	UBERON:0001303	99.52	gold quality
aorta	UBERON:0000947	99.50	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.50	gold quality
mucosa of stomach	UBERON:0001199	99.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.42	gold quality
left coronary artery	UBERON:0001626	99.39	gold quality
endocervix	UBERON:0000458	99.07	gold quality
stromal cell of endometrium	CL:0002255	98.97	gold quality
coronary artery	UBERON:0001621	98.96	gold quality
lower esophagus mucosa	UBERON:0035834	98.78	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.77	gold quality
right ovary	UBERON:0002118	98.74	gold quality
gastrocnemius	UBERON:0001388	98.56	gold quality
tibial nerve	UBERON:0001323	98.20	gold quality
left ovary	UBERON:0002119	98.14	gold quality
ectocervix	UBERON:0012249	98.05	gold quality
adenohypophysis	UBERON:0002196	98.03	gold quality
muscle of leg	UBERON:0001383	97.89	gold quality
right uterine tube	UBERON:0001302	97.88	gold quality
triceps brachii	UBERON:0001509	97.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.66	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	75.39
E-HCAD-10	yes	46.89
E-HCAD-1	yes	35.76
E-MTAB-8410	yes	34.56
E-ANND-3	yes	13.82
E-HCAD-11	yes	10.81
E-GEOD-93593	yes	8.32

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, ATF1, BCL3, CEBPG, CEBPZ, CREB1, DNMT1, DNMT3A, ESR1, HR, ID1, ID3, IRF5, JUNB, MAX, MXD1, MYC, NCOA2, NFKB2, NFKBIA, NFKBIB, NKX3-1, POU4F2, RBPJ, RELA, SP1, SP3, SPI1, SPIB, STAT6, TBX5, TCF3, TFAP2A, TP53, USF1, USF2, XBP1, ZNF316

miRNA regulators (miRDB)

27 targeting PDLIM7, 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-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1912-3P	99.32	67.40	936
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-1295B-5P	99.03	67.50	810
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-891A-3P	98.05	67.99	970
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-4474-3P	96.97	65.87	870
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-7108-5P	96.42	66.17	598
HSA-MIR-6805-5P	95.79	64.86	670

Literature-anchored findings (GeneRIF, showing 36)

• isolated the complementary DNA (cDNA) for the human homologue of LMP-1 from an adult human heart cDNA library and showed that when overexpressed it is osteoinductive (PMID:11874232)
• LIM-1 potentiates bone morphogenetic protein responsiveness via a novel interaction with Smurf1 resulting in decreased ubiquitination of Smads (PMID:16611643)
• Enigma is involved in insulin-induced Glut 4 translocation by regulating cortical actin remodeling. (PMID:16803868)
• Authors hypothesize that the HIV-1 TAT interacting protein can fuse with PDLIM7 and that the fusion proteins could be easily transduced through biological membranes and have biological activity. (PMID:17126496)
• When transferred into mouse muscle fibers, a truncated form of LMP-1 induces pluripotent myoblastic C2C12 cells to differentiate into osteoblastic lineage. (PMID:17805464)
• LMP-1 was expressed primarily in predentin, odontoblasts and blood vessel endothelial cells of healthy teeth. LMP-1 expression was found in unmineralized reparative dentin, odontoblast-like cells and pulp fibroblasts in teeth with caries and pulpitis. (PMID:18215669)
• These studies provide evidence that overexpression of IGFBP-6 suppresses human and murine osteoblast differentiation, that IGFBP-6 and LMP-1 physically interact, and supports the conclusion that this interaction may be functionally relevant. (PMID:18395833)
• LMP1 mediates serine 256 phosphorylation and nuclear entry of Annexin A2 via PLC-PKCalpha/PKCbeta pathway. (PMID:18412141)
• Immunofluorescence stained cell numbers are increased after 20 MOI AdLMP1-GFP infection concordant with upregulation of mRNA expression. (PMID:18618069)
• absence of any hexosamines (N-acetyl glucosamine or N-acetyl galactosamine) in chemical composition analysis of LMP-1 protein revealed that there is little or no post-translational glycosylation of the LMP-1 polypeptide in lung carcinoma cells (PMID:18989571)
• PAR-2 is a possible mediator cooperating with LMP-1 and MMP9 to influence the progression of nasopharyngeal carcinoma by inducing angiogenesis and promoting lymph node metastasis. (PMID:19269113)
• LMP1 is a downstream gene of TGF-beta1, involved in periodontal ligament cell proliferation. (PMID:20348040)
• SRF and Enigma coexpressed with MDM2 but not p53 in several liver and stomach tumors. (PMID:21060154)
• results suggested that LMP3 could affect the fine balance between cell proliferation/differentiation of mesenchymal cells mostly by modulating the TGF-beta1 signaling pathway (PMID:21061915)
• Gene transfer of LMP3 upregulated Alkaline Phosphatase, Bone Sialoprotein and BMP2 gene expression and increased in vitro matrix mineralization in human PDL cell line. (PMID:22241179)
• findings indicate the existence of a new cell cycle-associated signaling pathway in which LMP1 regulates ERK-mediated Op18/stathmin signaling (PMID:22417000)
• Molecular basis of the overactive osteogenic process may at least in part involve a deregulation of the LMP-related pathway in calvarial cells. (PMID:22982077)
• LMP3 induced the successful osteogenic differentiation of AFSC by inducing the expression of osteogenic markers and osteospecific transcription factors. (PMID:23097599)
• A direct interaction of Jab1 with LMP-1, is reported. (PMID:24078030)
• High Enigma expression is associated with breast neoplasms. (PMID:24466333)
• LMP1 expression suppressed the expression of Runx2 and BMP-2 in OS cells. (PMID:24762763)
• These results are consistent with a model in which binding of OspE to PDLIM7 during infection regulates the activity of PKC isoforms that bind to the PDLIM7 LIM domain. (PMID:25124035)
• LMP-1 mRNA level was regulated in a dose-dependent manner after transfection (PMID:25336289)
• The results suggest local transduction with LMP-1 gene promotes osteogenesis and mineralization in distraction osteogenesis. (PMID:25641592)
• The results showed that LMP-1 inhibited cell apoptosis and induced survivin expression in nasal natural killer/T-cell lymphoma (PMID:25760809)
• LMOD1, SYNPO2, PDLIM7, PLN, and SYNM down-regulation reflect the altered phenotype of smooth muscle cells in vascular disease and could be early sensitive markers of SMC dedifferentiation. (PMID:27470516)
• A role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells. (PMID:29789718)
• In enigma siRNA-transfected cells, cell viability, and the protein levels of AKT and survivin decreased. (PMID:29848705)
• Cox proportional-hazards regression indicated that high LMP1 expression and the nasal floor thickness >2.0 mm or nasal septum thickness >2.5 mm were the independent risk factors for poor OS of ENKTL-NT (HR=3.0655, p=0.028; HR=2.3650, p=0.0452, respectively). (PMID:30356034)
• Forces acting on integrins recruit Enigma family proteins (PDLIM5 AND PDLIM7) to trigger YAP activation during mechanotransduction. (PMID:30404826)
• reported for the first time the effect of combining Yamanaka factors with hLMP-3 to induce osteoblast cells from MEF both in vitro and in vivo. (PMID:30453092)
• Overexpression of LMP-1 Decreases Apoptosis in Human Nucleus Pulposus Cells via Suppressing the NF-kappaB Signaling Pathway. (PMID:33414896)
• Enigma of the cholesterol paradox in acute myocardial infarction: lessons from an 8-year follow-up of all-cause mortality in an age-matched and sex-matched case-control study with controls from the patients’ recruitment area. (PMID:35896296)
• Epstein-Barr virus in gastric cancer and association with 30 bp del-latent membrane protein 1 polymorphism. (PMID:37222327)
• Regulatory and Interacting Partners of PDLIM7 in Thyroid Cancer. (PMID:38132395)
• PDLIM7 Promotes Tumor Metastasis in Papillary Thyroid Carcinoma via Stabilizing Focal Adhesion Kinase Protein. (PMID:38243825)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pdlim7	ENSDARG00000103854
mus_musculus	Pdlim7	ENSMUSG00000021493
rattus_norvegicus	Pdlim7	ENSRNOG00000013653
drosophila_melanogaster	Zasp52	FBGN0265991
caenorhabditis_elegans		WBGENE00001132

Paralogs (7): PDLIM1 (ENSG00000107438), PDLIM2 (ENSG00000120913), LDB3 (ENSG00000122367), PDLIM4 (ENSG00000131435), PDLIM3 (ENSG00000154553), PDLIM5 (ENSG00000163110), PRICKLE4 (ENSG00000278224)

Protein

Protein identifiers

PDZ and LIM domain protein 7 — Q9NR12 (reviewed: Q9NR12)

Alternative names: LIM mineralization protein, Protein enigma

All UniProt accessions (5): D6RAN1, D6RF83, D6RH06, Q9NR12, H7BYK4

UniProt curated annotations — full annotation on UniProt →

Function. May function as a scaffold on which the coordinated assembly of proteins can occur. May play a role as an adapter that, via its PDZ domain, localizes LIM-binding proteins to actin filaments of both skeletal muscle and nonmuscle tissues. Involved in both of the two fundamental mechanisms of bone formation, direct bone formation (e.g. embryonic flat bones mandible and cranium), and endochondral bone formation (e.g. embryonic long bone development). Plays a role during fracture repair. Involved in BMP6 signaling pathway.

Subunit / interactions. Binds via its LIM zinc-binding 3 domain (LIM 3) to endocytic codes of INSR, but not with those of IGF1R, LDLR, TFRC, or EGFR. Interacts with various PKC isoforms through the LIM zinc-binding domains. Binds to RET in a phosphorylation-independent manner via its LIM zinc-binding domain 2 (LIM 2). Probably part of a complex with SHC and the RET dimer. Interacts with TPM2. Interacts with TBX4 and TBX5.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Isoform 1 and isoform 2 are expressed ubiquitously, however, isoform 2 predominates in skeletal muscle, isoform 1 is more abundant in lung, spleen, leukocytes and fetal liver.

Domain organisation. The LIM zinc-binding 2 (LIM 2) domain interacts with TBX4. The LIM zinc-binding 3 (LIM 3) domain provides the structural basis for recognition of tyrosine-containing tight turn structures. This domain is necessary and sufficient for interaction with TBX5. Anchored to cell periphery via its N-terminal PDZ domain.

Miscellaneous. Did not induce bone induction. Same activity as isoform 1 in bone nodule induction. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (6)

UniProt ID	Names	Canonical?
Q9NR12-1	1, LMP-1	yes
Q9NR12-2	2, LMP-2
Q9NR12-3	3, LMP-3
Q9NR12-4	4
Q9NR12-5	5
Q9NR12-6	6

RefSeq proteins (3): NP_005442, NP_976227, NP_998801 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001781	Znf_LIM	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR050604	PDZ-LIM_domain	Family

Pfam: PF00412, PF00595

UniProt features (35 total): splice variant 8, strand 5, domain 4, modified residue 4, helix 4, region of interest 3, sequence variant 2, mutagenesis site 2, chain 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2Q3G	X-RAY DIFFRACTION	1.11
7RM8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR12-F1	70.91	0.35

Functional residue map

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

Post-translational modifications (4): 103, 111, 247, 78

Mutagenesis-validated functional residues (2):

Position	Phenotype
15–16	loss of binding to tpm2.
63	loss of binding to tpm2.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8853659	RET signaling

MSigDB gene sets: 254 (showing top): BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, WWTAAGGC_UNKNOWN, LFA1_Q6, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, MODULE_493, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, CTATGCA_MIR153, SRF_Q5_01, SRF_C, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1

GO Biological Process (6): ossification (GO:0001503), receptor-mediated endocytosis (GO:0006898), heart development (GO:0007507), actin cytoskeleton organization (GO:0030036), cell differentiation (GO:0030154), muscle structure development (GO:0061061)

GO Molecular Function (4): actin binding (GO:0003779), metal ion binding (GO:0046872), muscle alpha-actinin binding (GO:0051371), protein binding (GO:0005515)

GO Cellular Component (11): stress fiber (GO:0001725), ruffle (GO:0001726), nucleoplasm (GO:0005654), cytosol (GO:0005829), adherens junction (GO:0005912), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), filamentous actin (GO:0031941), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
multicellular organismal process	1
endocytosis	1
animal organ development	1
circulatory system development	1
cytoskeleton organization	1
actin filament-based process	1
cellular developmental process	1
anatomical structure development	1
cytoskeletal protein binding	1
cation binding	1
alpha-actinin binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
cell leading edge	1
plasma membrane bounded cell projection	1
nuclear lumen	1
cytoplasm	1
cell-cell junction	1
cell-substrate junction	1
cytoskeleton	1
I band	1
actin filament	1
protein-containing complex	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDLIM7	PSMB9	P28065	839
PDLIM7	TPM2	P06468	730
PDLIM7	TBX4	P57082	679
PDLIM7	SMURF1	Q9HCE7	678
PDLIM7	CD40	P25942	595
PDLIM7	TNFRSF8	P28908	580
PDLIM7	BMP6	P22004	560
PDLIM7	BMP7	P18075	560
PDLIM7	LIM2	P55344	557
PDLIM7	BMP2	P12643	543
PDLIM7	TBX5	Q99593	528
PDLIM7	PTCH2	Q9Y6C5	521
PDLIM7	TRADD	Q15628	510
PDLIM7	TRAF3	Q13114	510
PDLIM7	PDLIM2	Q96JY6	493

IntAct

289 interactions, top by confidence:

A	B	Type	Score
WWP2	PDLIM7	psi-mi:“MI:0915”(physical association)	0.800
PDLIM7	WWP2	psi-mi:“MI:0915”(physical association)	0.800
PDLIM7	BAG3	psi-mi:“MI:0914”(association)	0.800
BAG3	PDLIM7	psi-mi:“MI:0915”(physical association)	0.800
PDLIM7	TSG101	psi-mi:“MI:0915”(physical association)	0.780
TSG101	PDLIM7	psi-mi:“MI:0915”(physical association)	0.780
PDLIM7	GEM	psi-mi:“MI:0915”(physical association)	0.740
GEM	PDLIM7	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RAB3IP	TRAPPC3	psi-mi:“MI:0914”(association)	0.700
PHF1	PDLIM7	psi-mi:“MI:0915”(physical association)	0.670
ETV7	ETV6	psi-mi:“MI:0914”(association)	0.670
PDLIM7	PHF1	psi-mi:“MI:0915”(physical association)	0.670
ENKD1	PDLIM7	psi-mi:“MI:0915”(physical association)	0.670
LPXN	PCNT	psi-mi:“MI:0914”(association)	0.640
ZNF576	ZBED1	psi-mi:“MI:0914”(association)	0.640
SYT11	TTC1	psi-mi:“MI:0914”(association)	0.640
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
PDLIM7	Hoxa1	psi-mi:“MI:0915”(physical association)	0.570
Hoxa1	PDLIM7	psi-mi:“MI:0915”(physical association)	0.570

BioGRID (373): PDLIM7 (Two-hybrid), PDLIM7 (Two-hybrid), PDLIM7 (Two-hybrid), WWP2 (Two-hybrid), PDLIM7 (Affinity Capture-RNA), PDLIM7 (Affinity Capture-RNA), PDLIM7 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), HBB (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), PDLIM7 (Affinity Capture-MS), PSMF1 (Two-hybrid), PDLIM7 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8F1M4, A8WH69, B1AK53, D3ZQL6, E1BBG2, O43294, O60711, O75112, P36202, P49023, P49024, P50479, P70271, Q09476, Q0VA45, Q2TCH4, Q3MHZ4, Q3SX40, Q3T005, Q3TJD7, Q4V882, Q5R7I1, Q5U464, Q62219, Q62920, Q63618, Q66H76, Q679P3, Q6INU3, Q6P7E4, Q80VP1, Q8BGT6, Q8BYZ1, Q8CI51, Q8K382, Q8N3F8, Q8TDY4, Q8TEH3, Q8VI36, Q91W69

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 130 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
RAB GEFs exchange GTP for GDP on RABs	8	14.2×	4e-05
COPII-mediated vesicle transport	6	14.0×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete vesicle tethering	6	57.2×	2e-07
endoplasmic reticulum to Golgi vesicle-mediated transport	7	9.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	61
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2082 predictions. Top by Δscore:

Variant	Effect	Δscore
5:177483978:ATAGT:A	acceptor_gain	1.0000
5:177483979:TAGT:T	acceptor_gain	1.0000
5:177483980:AGT:A	acceptor_gain	1.0000
5:177483981:GT:G	acceptor_gain	1.0000
5:177483983:C:CA	acceptor_loss	1.0000
5:177483983:C:CC	acceptor_gain	1.0000
5:177483984:T:G	acceptor_loss	1.0000
5:177483989:A:AC	acceptor_gain	1.0000
5:177483989:A:C	acceptor_gain	1.0000
5:177483996:C:CT	acceptor_gain	1.0000
5:177483997:A:T	acceptor_gain	1.0000
5:177484065:GGTAC:G	donor_loss	1.0000
5:177484066:GTAC:G	donor_loss	1.0000
5:177484067:TACCT:T	donor_loss	1.0000
5:177484068:ACC:A	donor_loss	1.0000
5:177484069:C:G	donor_loss	1.0000
5:177484069:CCTCG:C	donor_gain	1.0000
5:177484071:T:TA	donor_gain	1.0000
5:177484090:C:CA	donor_gain	1.0000
5:177484093:T:TA	donor_gain	1.0000
5:177488066:A:AC	donor_gain	1.0000
5:177488067:C:CC	donor_gain	1.0000
5:177488067:CG:C	donor_gain	1.0000
5:177488247:CC:C	acceptor_gain	1.0000
5:177488247:CCCT:C	acceptor_loss	1.0000
5:177488248:CC:C	acceptor_gain	1.0000
5:177488249:C:CA	acceptor_loss	1.0000
5:177490907:C:CC	acceptor_gain	1.0000
5:177490926:C:CT	acceptor_gain	1.0000
5:177490927:A:C	acceptor_gain	1.0000

AlphaMissense

2998 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:177483671:G:C	C449W	1.000
5:177483672:C:G	C449S	1.000
5:177483672:C:T	C449Y	1.000
5:177483673:A:G	C449R	1.000
5:177483673:A:T	C449S	1.000
5:177483698:G:C	F440L	1.000
5:177483698:G:T	F440L	1.000
5:177483700:A:G	F440L	1.000
5:177483714:A:G	L435P	1.000
5:177483725:A:C	C431W	1.000
5:177483726:C:T	C431Y	1.000
5:177483727:A:G	C431R	1.000
5:177483870:A:C	C428W	1.000
5:177483871:C:A	C428F	1.000
5:177483871:C:G	C428S	1.000
5:177483871:C:T	C428Y	1.000
5:177483872:A:G	C428R	1.000
5:177483872:A:T	C428S	1.000
5:177483876:G:C	F426L	1.000
5:177483876:G:T	F426L	1.000
5:177483877:A:C	F426C	1.000
5:177483877:A:G	F426S	1.000
5:177483878:A:G	F426L	1.000
5:177483879:G:C	C425W	1.000
5:177483880:C:A	C425F	1.000
5:177483880:C:G	C425S	1.000
5:177483880:C:T	C425Y	1.000
5:177483881:A:G	C425R	1.000
5:177483881:A:T	C425S	1.000
5:177483888:A:C	H422Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000066525 (5:177494353 C>G), RS1000104763 (5:177486593 T>C,G), RS1000129710 (5:177494052 G>A,C), RS1000295178 (5:177484909 C>T), RS1000369610 (5:177489304 G>A,T), RS1000377681 (5:177491195 G>A,C,T), RS1000433738 (5:177484549 C>G), RS1000652950 (5:177496648 C>A), RS1000816142 (5:177485797 C>A), RS1000963335 (5:177499184 A>T), RS1001310657 (5:177499359 A>G), RS1001451694 (5:177490356 G>A,T), RS1001815481 (5:177493568 G>A), RS1002058330 (5:177484930 C>G,T), RS1002084332 (5:177484712 C>T)

Disease associations

OMIM: gene MIM:605903 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
mitral valve prolapse	Limited	Autosomal dominant
atypical Rett syndrome	Limited	Autosomal dominant

Mondo (2): mitral valve prolapse (MONDO:0004910), atypical Rett syndrome (MONDO:0017746)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005194_201	Coronary artery disease	1.000000e-06
GCST005956_15	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_13	Waist-to-hip ratio adjusted for BMI (age <50)	3.000000e-07
GCST005962_42	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008945	Mitral Valve Prolapse	C14.280.484.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases methylation	5
bisphenol A	increases expression, affects expression	3
Air Pollutants	affects expression, increases abundance, decreases expression, increases expression	3
Benzo(a)pyrene	increases expression	3
sodium arsenite	increases expression	2
entinostat	decreases expression, affects cotreatment	2
Lead	affects expression, decreases expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Acrylamide	decreases expression, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	increases expression	1
lead acetate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	increases expression	1
zinc chromate	decreases expression, increases abundance	1
cupric chloride	increases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05631730	PHASE3	RECRUITING	Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse
NCT01500148	PHASE1	COMPLETED	St. Jude Medical Percutaneous Mitral Valve Repair Study
NCT04299334	PHASE1	UNKNOWN	Neochordae Technique in Mitral Valve Repair
NCT00665301	Not specified	COMPLETED	Cardiac Output Pulmonary Arterial Catheter Compared to FloWave™ 1000
NCT00799565	Not specified	COMPLETED	Mitral Valve Prolapse (MVP) - France Study
NCT01719211	Not specified	UNKNOWN	Genetic Basis of Mitral Valve Prolapse
NCT02105480	Not specified	COMPLETED	Automated Algorithm Based Analysis of Phonocardiograms of Newborns
NCT02432196	Not specified	COMPLETED	CE Mark Study for the Harpoon Medical Device in Poland
NCT02499419	Not specified	UNKNOWN	Exercise Capacity Evaluation in Patients With Non-rheumatic Mitral Valve Prolapse (MVP)
NCT02512341	Not specified	COMPLETED	Automatic Differentiation of Innocent and Pathologic Murmurs in Pediatrics
NCT02552771	Not specified	UNKNOWN	The Canadian Mitral Research Alliance (CAMRA) Trial CardioLink-2
NCT02768870	Not specified	COMPLETED	CE Mark Study for the Harpoon Medical Device
NCT02771275	Not specified	COMPLETED	Safety and Early Feasibility Study of the Harpoon Medical Device (EFS)
NCT02879825	Not specified	COMPLETED	Myocardial Characterization of Arrhythmogenic Mitral Valve Prolapse (STAMP: STretch and Myocardial Characterization in Arrhythmogenic Mitral Valve Prolapse)
NCT03113552	Not specified	RECRUITING	Prognostic Impact of the Location of Mitral Valve Prolapse on the Long-term Results of Mitral Plasty
NCT03285724	Not specified	TERMINATED	Safety and Performance Study of the Harpoon Mitral Valve Repair System
NCT03470155	Not specified	COMPLETED	Operative Mitral Valve Reconstruction in Functional mv Insufficiency With Reduced Systolic Ventricle Function
NCT03506217	Not specified	UNKNOWN	Using Pulse Counter Vigileo-Flotrac System in Transapical Off-pump Minimally Invasive Mitral Valve Repair
NCT03609931	Not specified	UNKNOWN	Patient Specific Mitral Valve Modeling for Surgical Planning and Training
NCT03884426	Not specified	UNKNOWN	Genetic and Phenotypic Characteristics of Mitral Valve Prolapse
NCT04067635	Not specified	UNKNOWN	Primary Mitral Regurgitation Repair
NCT04190602	Not specified	RECRUITING	Multicenter Post-Market Observational Registry of the NeoChord Artificial Chordae Delivery System
NCT04231903	Not specified	COMPLETED	Myocardial Protection in Minimally Invasive Mitral Valve Surgery
NCT04770961	Not specified	UNKNOWN	Erector Spinae Plane Block for Minimally Invasive Mitral Valve Surgery
NCT04852731	Not specified	RECRUITING	STretch and Myocardial Characterization in Arrythmogenic Mitral Valve Prolapse-2
NCT05425628	Not specified	UNKNOWN	European FIH Study - NeoChord Transcatheter Mitral Repair System for Symptomatic Mitral Regurgitation
NCT05562804	Not specified	UNKNOWN	Mitral Valve Prolapse, Arrhythmias and Mitral Valve Surgery
NCT06255457	Not specified	RECRUITING	Ventricular Arrhythmias in Patients Undergoing Mitral Valve Surgery
NCT06341166	Not specified	RECRUITING	Multiparametric SCores for Prediction of Myocardial fIbrosis in Patients With MITral vAlve pRolapse
NCT06378996	Not specified	RECRUITING	Arrhythmic Mitral Valve Prolapse Detection Using Long-term Ambulatory Rhythm Monitoring
NCT06436573	Not specified	COMPLETED	Mitro-annular Disjunction in Cardiac Magnetic Resonance
NCT06738537	Not specified	RECRUITING	Patient-Centered Approach for Treatment Decisions in Mitral Valve Prolapse
NCT06741709	Not specified	NOT_YET_RECRUITING	A Study of Mitral Annular Disjunction in Mitral Valve Prolapse Patients and Arrhythmia Risk
NCT07068633	Not specified	NOT_YET_RECRUITING	Korea VHD Echo Study: Surveillance of Aortic, Mitral & Tricuspid Patients - Insights From Real-world Practice
NCT07103733	Not specified	RECRUITING	PRIMARY Ancillary Substudy
NCT07366723	Not specified	ACTIVE_NOT_RECRUITING	The Role of cardIac magNeTic rEsonance in surGical Decision Making in Patients With Severe pRimAry miTral rEgurgitation
NCT07384871	Not specified	RECRUITING	AI-Based Shape and Function Analysis of Mitral Valve Prolapse Using 3D Ultrasound