PLEC

Summary

PLEC (plectin, HGNC:9069) is a protein-coding gene on chromosome 8q24.3, encoding Plectin (Q15149). Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.

Plectin is a prominent member of an important family of structurally and in part functionally related proteins, termed plakins or cytolinkers, that are capable of interlinking different elements of the cytoskeleton. Plakins, with their multi-domain structure and enormous size, not only play crucial roles in maintaining cell and tissue integrity and orchestrating dynamic changes in cytoarchitecture and cell shape, but also serve as scaffolding platforms for the assembly, positioning, and regulation of signaling complexes (reviewed in PMID: 9701547, 11854008, and 17499243). Plectin is expressed as several protein isoforms in a wide range of cell types and tissues from a single gene located on chromosome 8 in humans (PMID: 8633055, 8698233). Until 2010, this locus was named plectin 1 (symbol PLEC1 in human; Plec1 in mouse and rat) and the gene product had been referred to as “hemidesmosomal protein 1” or “plectin 1, intermediate filament binding 500kDa”. These names were superseded by plectin. The plectin gene locus in mouse on chromosome 15 has been analyzed in detail (PMID: 10556294, 14559777), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and an unusual 5’ transcript complexity of plectin isoforms. Eleven exons (1-1j) have been identified that alternatively splice directly into a common exon 2 which is the first exon to encode plectin’s highly conserved actin binding domain (ABD). Three additional exons (-1, 0a, and 0) splice into an alternative first coding exon (1c), and two additional exons (2alpha and 3alpha) are optionally spliced within the exons encoding the acting binding domain (exons 2-8). Analysis of the human locus has identified eight of the eleven alternative 5’ exons found in mouse and rat (PMID: 14672974); exons 1i, 1j and 1h have not been confirmed in human. Furthermore, isoforms lacking the central rod domain encoded by exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759). The short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (PMID: 14559777). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (PMID: 10556294, 12542521, 17389230) it appears that each cell type (tissue) contains a unique set (proportion and composition) of plectin isoforms, as if custom-made for specific requirements of the particular cells. Concordantly, individual isoforms were found to carry out distinct and specific functions (PMID: 14559777, 12542521, 18541706). In 1996, a number of groups reported that patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) lacked plectin expression in skin and muscle tissues due to defects in the plectin gene (PMID: 8698233, 8941634, 8636409, 8894687, 8696340). Two other subtypes of plectin-related EBS have been described: EBS-pyloric atresia (PA) and EBS-Ogna. For reviews of plectin-related diseases see PMID: 15810881, 19945614. Mutations in the plectin gene related to human diseases should be named based on the position in NM_000445 (variant 1, isoform 1c), unless the mutation is located within one of the other alternative first exons, in which case the position in the respective Reference Sequence should be used.

Source: NCBI Gene 5339 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder (Definitive, ClinGen) — +9 more curated relationships
• GWAS associations: 59
• Clinical variants (ClinVar): 6,607 total — 106 pathogenic, 41 likely-pathogenic
• Phenotypes (HPO): 146
• Druggable target: yes
• MANE Select transcript: NM_201384

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9069
Approved symbol	PLEC
Name	plectin
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	PCN, PLTN
Ensembl gene	ENSG00000178209
Ensembl biotype	protein_coding
OMIM	601282
Entrez	5339

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 16 protein_coding, 1 retained_intron

ENST00000322810, ENST00000345136, ENST00000354589, ENST00000354958, ENST00000356346, ENST00000357649, ENST00000398774, ENST00000436759, ENST00000527096, ENST00000527303, ENST00000528025, ENST00000532346, ENST00000685198, ENST00000687971, ENST00000693060, ENST00000915283, ENST00000915284

RefSeq mRNA: 9 — MANE Select: NM_201384 NM_000445, NM_001410941, NM_201378, NM_201379, NM_201380, NM_201381, NM_201382, NM_201383, NM_201384

CCDS: CCDS43769, CCDS43770, CCDS43771, CCDS43772, CCDS43773, CCDS43774, CCDS43775, CCDS47936, CCDS94359

Canonical transcript exons

ENST00000345136 — 32 exons

Exon	Start	End
ENSE00001243927	143926784	143926882
ENSE00001243936	143926977	143927081
ENSE00001243948	143927252	143927335
ENSE00001243956	143927410	143927766
ENSE00001244001	143929646	143929829
ENSE00001244010	143929936	143930062
ENSE00001244019	143930144	143930298
ENSE00001244024	143930384	143930536
ENSE00001244034	143931534	143931659
ENSE00001244041	143931937	143932032
ENSE00001244050	143932130	143932234
ENSE00001244070	143932635	143932712
ENSE00001244123	143933197	143933351
ENSE00001244129	143933998	143934091
ENSE00001244136	143934318	143934445
ENSE00001244144	143934635	143934730
ENSE00001244151	143934810	143934929
ENSE00001244160	143935011	143935117
ENSE00001244165	143935198	143935313
ENSE00001244172	143935848	143936014
ENSE00001244232	143915153	143922395
ENSE00001295392	143929103	143929281
ENSE00001301489	143932793	143933111
ENSE00001309447	143922504	143925884
ENSE00001315328	143929414	143929571
ENSE00001319048	143927854	143927992
ENSE00001373903	143939350	143939597
ENSE00001741875	143936979	143937071
ENSE00003519962	143937165	143937242
ENSE00003574791	143938631	143938692
ENSE00003693086	143938151	143938240
ENSE00003791226	143932400	143932561

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 105.8735 / max 1621.3543, expressed in 1824 samples.

FANTOM5 promoters (24 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95565	42.6967	1670
95580	11.9802	1442
95590	11.7427	1722
95588	9.5968	1453
95567	4.9991	1371
95566	4.1509	1191
95569	3.6148	1230
95585	3.2775	1254
95578	3.2751	1055
95584	2.9538	1177

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	98.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.19	gold quality
tibial nerve	UBERON:0001323	97.90	gold quality
gastrocnemius	UBERON:0001388	97.68	gold quality
muscle of leg	UBERON:0001383	97.49	gold quality
stromal cell of endometrium	CL:0002255	97.28	gold quality
apex of heart	UBERON:0002098	97.28	gold quality
body of tongue	UBERON:0011876	97.14	gold quality
right coronary artery	UBERON:0001625	97.06	gold quality
mucosa of stomach	UBERON:0001199	97.02	gold quality
nipple	UBERON:0002030	96.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.87	gold quality
triceps brachii	UBERON:0001509	96.76	gold quality
gluteal muscle	UBERON:0002000	96.75	gold quality
muscle organ	UBERON:0001630	96.62	gold quality
descending thoracic aorta	UBERON:0002345	96.35	gold quality
endometrium epithelium	UBERON:0004811	96.33	gold quality
ascending aorta	UBERON:0001496	96.24	gold quality
thoracic aorta	UBERON:0001515	96.24	gold quality
aorta	UBERON:0000947	96.10	gold quality
popliteal artery	UBERON:0002250	96.04	gold quality
tibial artery	UBERON:0007610	96.03	gold quality
left uterine tube	UBERON:0001303	95.97	gold quality
coronary artery	UBERON:0001621	95.97	gold quality
skin of abdomen	UBERON:0001416	95.90	gold quality
skin of leg	UBERON:0001511	95.88	gold quality
left coronary artery	UBERON:0001626	95.86	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.83	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.83	gold quality
lower esophagus	UBERON:0013473	95.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7052	yes	269.73
E-ANND-3	yes	13.54
E-CURD-112	yes	13.09
E-GEOD-110499	no	310.77
E-CURD-11	no	166.83

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF1, TP63

miRNA regulators (miRDB)

107 targeting PLEC, 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-4283	100.00	66.42	2097
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363

Literature-anchored findings (GeneRIF, showing 40)

• cpo has a role in regulating proper nervous system function, including seizure susceptibility (PMID:15687283)
• variation for the diapause phenotype is caused by a single Lys/Ile substitution in one of the six cpo transcripts (PMID:18852464)
• There is no evidence for an association between the cpo I462K polymorphism and ovarian dormancy in Australian fruit flies. (PMID:21689187)
• The results reveal that the downstream cpo SNP does not seem to play any role in diapause induction in European Drosophila populations in contrast to the upstream coding cpo SNP. (PMID:27598401)
• Conserved binding of GCAC motifs by MEC-8, couch potato, and the RBPMS protein family has been reported (PMID:28003515)
• During polarization of peripheral blood T lymphocytes, plectin redistributes to the uropod associated with vimentin and fodrin. This vimentin-plectin-fodrin complex provides a continuous linkage from the nucleus (lamin B) to the cortical cytoskeleton. (PMID:11441066)
• The structure was solved by the molecular-replacement method. In addition, the preparation of selenomethionine-derivative crystals is described. (PMID:12136158)
• Data report the crystal structure of the actin binding domain of plectin and show that this region is sufficient for interaction with F-actin or the cytoplasmic region of integrin alpha6beta4. (PMID:12791251)
• propose a previously unrecognized function of plectin as cytoskeletal regulator of PKC signaling (dislocation of PKCdelta and elevated enzymatic activity), and possibly other signaling events, through sequestration of the scaffolding protein RACK1 (PMID:14966116)
• the involvement of desmoplakin (DP), plectin, and periplakin in the destruction of epithelial cell integrity ensures the efficient elimination of cytoskeleton, but also provides specificity for selectively targeting individual adhesion molecules (PMID:15500642)
• homozygous mutations in the plectin gene (PLEC1)in epidermolysis bullosa with pyloric atresia (PMID:15654962)
• discussion of phenotypic spectrum of plectin mutations [review] (PMID:15810881)
• the CH1 domain of the plectin-ABD associates with the groove between the two FNIII domains of beta4 (PMID:15817481)
• Co-localization, co-immunoprecipitation, and in vitro overlay analyses demonstrated direct interaction of plectin and GFAP. (PMID:16507904)
• Results describe the crystal structure of an N-terminal fragment of the plakin domain of plectin to 2.05 A resolution. (PMID:17397861)
• PLEC1 was differeentially expressed in sclerotic hippocampi compared to non-sclerotic ones. (PMID:17515952)
• A novel functional co-localisation is identified between two plakin cytolinker proteins. (PMID:17662978)
• results reveal that plectin is up-regulated in colorectal adenocarcinoma as well as in bizarre glands and locally invasive tumor nests in tubular adenoma, compared with normal colorectal mucosa (PMID:18084872)
• Thus, plectin appears to interact with CXCR4 and plays an important role in CXCR4 signaling and trafficking and HIV-1 infection. (PMID:18155192)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Data show that intermediate filament recruitment to focal adhesions in endothelial cells requires beta3 integrin, plectin and the microtubule cytoskeleton, and is dependent on microtubule motors. (PMID:19366731)
• BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development. (PMID:19709076)
• missense mutation causes structure of plectin amino terminus alteration so binding to actin and costameric proteins are attenuated (PMID:20016501)
• Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex (PMID:20052759)
• Autosomal recessive forms of epidermolysis bullosa simplex associated with extracutaneous manifestations, such as muscular dystrophy (MIM 226670) or pyloric atresia (MIM 612138), have been linked to genetic mutations in the gene for plectin (PMID:20447487)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• Plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual epidermolysis bullosa simplex (EBS) patient. (PMID:20665883)
• data show that isoform 1f of plectin plays a key role in skeletal muscle function and that disruption of the plectin 1f can cause the LGMD2 phenotype without any dermatologic component as was previously reported with mutations in constant exons of PLEC (PMID:21109228)
• mutational analysis of PLEC1 revealed a homozygous 36 nucleotide insertion (1506_1507ins36) that results in a reduced expression of PLEC1 mRNA and plectin in patients with epidermolysis bullosa simplex and congenital myasthenic syndrome. (PMID:21175599)
• The structure of the plakin domain of plectin reveals a non-canonical SH3 domain interacting with its fourth spectrin repeat. (PMID:21288893)
• degradation of plectin induced by staurosporine-treatment in liver cells resulted in cytoskeleton disruption and induced morphological changes in these cells by affecting the expression and organization of cytokeratin 18. (PMID:21420381)
• plectin deficiency might play an important role in the transformation of human liver cells (PMID:21424933)
• plectin expression was deficient in hepatocellular carcinoma and was probably through post-translational modification (PMID:21469503)
• novel esophageal squamous cell carcinoma marker plectin 1 was identified by mass spectrometry and immunohistochemical analysis (PMID:21743296)
• plectin participates in actin assembly and invasiveness in carcinoma cells in an isoform-specific manner (PMID:21821021)
• The novel FUS-plectin interaction offers new perspectives for understanding the role of FUS and plectin mutations in the pathogenesis of FUS associated diseases (PMID:22240165)
• findings suggest that plectin promotes the migration and invasion of head and neck squamous cell carcinoma (HNSCC) cells through activation of Erk 1/2 kinase and is a potential prognostic biomarker of HNSCC. (PMID:22245045)
• A linker region in the COOH-terminal end and serine residue at position 4645 may be important for the binding of plectin to intermediate filaments. (PMID:22333906)
• results confirm epidermolysis bullosa simplex-pyloric atresia is linked to mutations in distal exons 1-30 and 32 of PLEC; while epidermolysis bullosa simplex-muscular dystrophy is linked to PLEC mutations in all exons, in most cases one of the mutations affects exon 31 (PMID:23289980)
• this study is the first to demonstrate that up-regulation of vimentin and plectin expression positively correlates with the invasion and metastasis of androgen-independent PCA (PMID:23717685)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Plec	ENSMUSG00000022565
rattus_norvegicus	Plec	ENSRNOG00000023781

Paralogs (36): SYNE2 (ENSG00000054654), SPTB (ENSG00000070182), ACTN1 (ENSG00000072110), ACTN2 (ENSG00000077522), DSP (ENSG00000096696), DRP2 (ENSG00000102385), SPTBN1 (ENSG00000115306), MACF1 (ENSG00000127603), FLNC (ENSG00000128591), ACTN4 (ENSG00000130402), SYNE1 (ENSG00000131018), MICAL2 (ENSG00000133816), DTNA (ENSG00000134769), MICAL1 (ENSG00000135596), FLNB (ENSG00000136068), SPTBN5 (ENSG00000137877), DTNB (ENSG00000138101), GAS2L3 (ENSG00000139354), DST (ENSG00000151914), UTRN (ENSG00000152818), SPTBN4 (ENSG00000160460), SPTA1 (ENSG00000163554), CLMN (ENSG00000165959), PKHD1 (ENSG00000170927), SPTBN2 (ENSG00000173898), SYNE3 (ENSG00000176438), SMTNL2 (ENSG00000188176), FLNA (ENSG00000196924), SPTAN1 (ENSG00000197694), DMD (ENSG00000198947), PKHD1L1 (ENSG00000205038), DYTN (ENSG00000232125), MICAL3 (ENSG00000243156), ACTN3 (ENSG00000248746), EPPK1 (ENSG00000261150), GAS2L2 (ENSG00000270765)

Protein

Protein identifiers

Plectin — Q15149 (reviewed: Q15149)

Alternative names: Hemidesmosomal protein 1, Plectin-1

All UniProt accessions (6): Q15149, A0A8I5KSD5, A0A8I5KUE3, A0A8I5KYZ1, E9PMV1, H0YDN1

UniProt curated annotations — full annotation on UniProt →

Function. Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes. Could also bind muscle proteins such as actin to membrane complexes in muscle. May be involved not only in the filaments network, but also in the regulation of their dynamics. Structural component of muscle. Isoform 9 plays a major role in the maintenance of myofiber integrity.

Subunit / interactions. Homodimer or homotetramer. Interacts (via actin-binding domain) with SYNE3. Interacts (via calponin-homology (CH) 1 domain) with VIM (via rod region). Interacts (via N-terminus) with DST isoform 2 (via N-terminus). Interacts with FER. Interacts with TOR1A. Interacts with ANK3. Identified in complexes that contain VIM, EZR, AHNAK, BFSP1, BFSP2, ANK2, PLEC, PRX and spectrin. Interacts with COL17A1. Interacts with KRT14, heterodimers consisting of KRT8 and KRT18, heterodimers consisting of KRT5 and KRT14, heterodimers consisting of KRT14 and KRT15, and heterodimers consisting of KRT1 and KRT10. Interacts with DES and VIM.

Subcellular location. Cytoplasm. Cytoskeleton. Cell junction. Hemidesmosome. Cell projection. Podosome.

Tissue specificity. Widely expressed with highest levels in muscle, heart, placenta and spinal cord.

Post-translational modifications. Phosphorylated by CDK1; regulates dissociation from intermediate filaments during mitosis.

Disease relevance. Epidermolysis bullosa simplex 5C, with pyloric atresia (EBS5C) [MIM:612138] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. EBS5C is an autosomal recessive disorder characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. The disease is caused by variants affecting the gene represented in this entry. Epidermolysis bullosa simplex 5B, with muscular dystrophy (EBS5B) [MIM:226670] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. EBS5B is an autosomal recessive disorder characterized by progressive muscular dystrophy associated with generalized skin blistering. The disease is caused by variants affecting the gene represented in this entry. Epidermolysis bullosa simplex 5A, Ogna type (EBS5A) [MIM:131950] An autosomal dominant form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. EBS5A patients manifest generalized skin bruising, skin fragility with non-scarring blistering and small hemorrhagic blisters on hands. At the ultrastructural level, EBS5A is differentiated from classical epidermolysis bullosa simplex, by the occurrence of blisters originating in basal cells above hemidesmosomes, and abnormal hemidesmosome intracellular attachment plates. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy, limb-girdle, autosomal recessive 17 (LGMDR17) [MIM:613723] A form of limb-girdle muscular dystrophy characterized by early childhood onset of proximal muscle weakness. Limb-girdle muscular dystrophies are characterized by proximal weakness, weakness of the hip and shoulder girdles and prominent asymmetrical quadriceps femoris and biceps brachii atrophy. The disease is caused by variants affecting the gene represented in this entry. A 9 bp deletion containing the initiation codon in exon 1f of PLEC have been found in limb-girdle muscular dystrophy patients. The mutation results in deficient expression of isoform 9 and disorganization of the myofibers, without any effect on the skin. Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive (EBS5D) [MIM:616487] A form of epidermolysis bullosa, a genodermatosis characterized by recurrent blistering, fragility of the skin and mucosal epithelia, and erosions caused by minor mechanical trauma. EBS5D patients have generalized skin blistering that heals with scarring and hyperpigmentation, and severe nail dystrophy. Mucous membranes, heart, and muscle are spared. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The N-terminus interacts with actin, the C-terminus with vimentin, desmin, GFAP, cytokeratins, lamin B; whereas both the N- and the C-terminus can bind integrin beta-4.

Similarity. Belongs to the plakin or cytolinker family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q15149-1	1, Plectin-6	yes
Q15149-2	2, Plectin-1, 1c
Q15149-3	3
Q15149-4	4, Plectin-11, 1a
Q15149-5	5, Plectin-8, 1b
Q15149-6	6, Plectin-10, 1g
Q15149-7	7, Plectin-7, 1d
Q15149-8	8, Plectin-3, 1e
Q15149-9	9, Plectin-2, 1f

RefSeq proteins (9): NP_000436, NP_001397870, NP_958780, NP_958781, NP_958782, NP_958783, NP_958784, NP_958785, NP_958786* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001101	Plectin_repeat	Repeat
IPR001452	SH3_domain	Domain
IPR001589	Actinin_actin-bd_CS	Conserved_site
IPR001715	CH_dom	Domain
IPR005326	Plectin_eS10_N	Domain
IPR018159	Spectrin/alpha-actinin	Repeat
IPR035915	Plakin_repeat_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily
IPR041573	Desmoplakin_Spectrin-like	Domain
IPR041615	Desmoplakin_SH3	Domain
IPR043197	Plakin	Family
IPR049538	PCN-like_spectrin-like_rpt	Repeat

Pfam: PF00307, PF00681, PF03501, PF17902, PF18373, PF21019, PF21020, PF21097

UniProt features (275 total): modified residue 56, helix 56, sequence conflict 41, repeat 37, sequence variant 19, region of interest 18, strand 16, splice variant 13, turn 7, compositionally biased region 7, domain 3, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
4GDO	X-RAY DIFFRACTION	1.7
5J1G	X-RAY DIFFRACTION	1.8
2ODV	X-RAY DIFFRACTION	2.05
1MB8	X-RAY DIFFRACTION	2.15
3PDY	X-RAY DIFFRACTION	2.22
2ODU	X-RAY DIFFRACTION	2.3
4Q59	X-RAY DIFFRACTION	2.3
3F7P	X-RAY DIFFRACTION	2.75
5J1H	X-RAY DIFFRACTION	2.8
5J1I	X-RAY DIFFRACTION	2.8
3PE0	X-RAY DIFFRACTION	2.95
5J1F	X-RAY DIFFRACTION	3
4Q58	X-RAY DIFFRACTION	4
2N03	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for Q15149 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

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 (56): 4411, 4539, 4607, 4613, 4615, 4616, 4618, 4622, 4623, 4626, 4627, 4640, 4642, 4672, 4675, 42, 42, 20, 21, 26 …

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2022090	Assembly of collagen fibrils and other multimeric structures
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-446107	Type I hemidesmosome assembly

MSigDB gene sets: 765 (showing top): MODULE_52, AP1_01, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CELL_CHEMOTAXIS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS

GO Biological Process (39): cell morphogenesis (GO:0000902), leukocyte migration involved in immune response (GO:0002522), keratinocyte development (GO:0003334), nucleus organization (GO:0006997), mitochondrion organization (GO:0007005), intracellular protein localization (GO:0008104), gene expression (GO:0010467), fibroblast migration (GO:0010761), T cell chemotaxis (GO:0010818), skeletal myofibril assembly (GO:0014866), transmission of nerve impulse (GO:0019226), respiratory electron transport chain (GO:0022904), hemidesmosome assembly (GO:0031581), response to food (GO:0032094), peripheral nervous system myelin maintenance (GO:0032287), adherens junction organization (GO:0034332), multicellular organism growth (GO:0035264), wound healing (GO:0042060), regulation of vascular permeability (GO:0043114), protein-containing complex organization (GO:0043933), intermediate filament cytoskeleton organization (GO:0045104), intermediate filament organization (GO:0045109), sarcomere organization (GO:0045214), myoblast differentiation (GO:0045445), skeletal muscle fiber development (GO:0048741), cardiac muscle cell development (GO:0055013), establishment of skin barrier (GO:0061436), cellular response to mechanical stimulus (GO:0071260), cellular response to hydrostatic pressure (GO:0071464), cellular response to fluid shear stress (GO:0071498), tight junction organization (GO:0120193), actomyosin contractile ring assembly actin filament organization (GO:2000689), actin filament organization (GO:0007015), skeletal muscle tissue development (GO:0007519), myelination in peripheral nervous system (GO:0022011), actin cytoskeleton organization (GO:0030036), keratinocyte differentiation (GO:0030216), skin development (GO:0043588), cell motility (GO:0048870)

GO Molecular Function (11): dystroglycan binding (GO:0002162), RNA binding (GO:0003723), structural constituent of cytoskeleton (GO:0005200), structural constituent of muscle (GO:0008307), ankyrin binding (GO:0030506), identical protein binding (GO:0042802), cadherin binding (GO:0045296), actin filament binding (GO:0051015), actin binding (GO:0003779), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (25): podosome (GO:0002102), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), plasma membrane (GO:0005886), brush border (GO:0005903), focal adhesion (GO:0005925), sarcoplasm (GO:0016528), Z disc (GO:0030018), hemidesmosome (GO:0030056), axon (GO:0030424), dendrite (GO:0030425), sarcolemma (GO:0042383), costamere (GO:0043034), myelin sheath (GO:0043209), intermediate filament cytoskeleton (GO:0045111), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cytoskeleton (GO:0005856), intermediate filament (GO:0005882), myofibril (GO:0030016), cell projection (GO:0042995), contractile muscle fiber (GO:0043292), anchoring junction (GO:0070161), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Collagen formation	1
Apoptotic cleavage of cellular proteins	1
Cell junction organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	3
cytoplasm	3
organelle organization	2
structural molecule activity	2
cytoskeleton	2
cytoskeletal protein binding	2
cell-substrate junction	2
neuron projection	2
anatomical structure morphogenesis	1
immune effector process	1
immune response	1
leukocyte migration	1
epithelial cell development	1
keratinocyte differentiation	1
macromolecule localization	1
macromolecule biosynthetic process	1
ameboidal-type cell migration	1
lymphocyte chemotaxis	1
T cell migration	1
myofibril assembly	1
action potential	1
cell communication	1
chemical synaptic transmission	1
nervous system process	1
electron transport chain	1
cellular respiration	1
cell-substrate junction assembly	1
response to nutrient levels	1
response to chemical	1
myelination in peripheral nervous system	1
myelin maintenance	1
cell-cell junction organization	1
multicellular organismal process	1
developmental growth	1
response to wounding	1
tissue regeneration	1
vascular process in circulatory system	1
blood circulation	1
regulation of biological quality	1

Protein interactions and networks

STRING

2644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEC	SYNE3	Q6ZMZ3	998
PLEC	ITGB4	P16144	997
PLEC	COL17A1	Q9UMD9	996
PLEC	DST	Q03001	988
PLEC	CD151	P48509	976
PLEC	HSPB1	P04792	963
PLEC	HSPB2	Q16082	954
PLEC	HSPB3	Q12988	948
PLEC	DMD	P11532	897
PLEC	SYNM	O15061	878
PLEC	DAG1	Q14118	845
PLEC	GFAP	P14136	844
PLEC	DTNA	Q9Y4J8	841
PLEC	SYNE4	Q8N205	837
PLEC	DES	P17661	835

IntAct

339 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HTT	PLEC	psi-mi:“MI:0915”(physical association)	0.670
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
PAK5	AURKA	psi-mi:“MI:0914”(association)	0.640
TJP1	ACTN4	psi-mi:“MI:0914”(association)	0.600
PLEC	KRT14	psi-mi:“MI:0915”(physical association)	0.560
FES	DSP	psi-mi:“MI:0914”(association)	0.560
SBDS	PLEC	psi-mi:“MI:0915”(physical association)	0.540
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
WNK1	PLEC	psi-mi:“MI:0915”(physical association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
ESR1		psi-mi:“MI:0914”(association)	0.460
PLEC	MBTD1	psi-mi:“MI:0915”(physical association)	0.400
PLEC	C2CD3	psi-mi:“MI:0915”(physical association)	0.400
PLEC	PSMD3	psi-mi:“MI:0915”(physical association)	0.400
PLEC	KANSL3	psi-mi:“MI:0915”(physical association)	0.400
PLEC	CNPY3	psi-mi:“MI:0915”(physical association)	0.400
PLEC	NECTIN3-AS1	psi-mi:“MI:0915”(physical association)	0.400
STAT6	PLEC	psi-mi:“MI:0915”(physical association)	0.400
SCG2	PLEC	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (546): PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Affinity Capture-MS), PLEC (Co-fractionation)

ESM2 similar proteins: A0A3B6UES5, A0A3G2LGI8, D3ZHV2, G8JYB2, O46037, O60437, P0CE94, P0CE95, P11533, P12003, P18206, P19826, P26039, P26231, P26234, P30427, P33338, P35220, P35221, P54939, P85972, P90947, Q02328, Q03001, Q04615, Q15149, Q17162, Q3MHM6, Q54K81, Q54MH2, Q59I72, Q64727, Q6ZWR6, Q71LX4, Q8MSU4, Q91ZU6, Q95XZ0, Q9ERE8, Q9H1K6, Q9MBF8

Diamond homologs: A0A1D8PI15, G1T168, O13614, O14112, O77082, O77302, P0DKK8, P0DKK9, P30427, P46783, P46784, P63325, P63326, Q07254, Q08745, Q15149, Q3T0F4, Q90YR4, Q962R9, Q9FFS8, Q9LTF2, Q9NQ39, Q9QXS1, Q9SW09, Q9VB14, Q9VWG3, A0A8M2BID5, A0A8M9PQ61, D3ZHV2, E9Q557, F1LMV6, P15924, P58107, Q8R0W0, Q92817, Q9D952, Q9JI55, O60437, Q9R269, A5D7D1

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	PLEC	phosphorylation
CyclinB/CDK1	down-regulates	PLEC	phosphorylation
TP63	“up-regulates quantity by expression”	PLEC	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 209 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
Signaling by ALK fusions and activated point mutants	8	8.2×	1e-03
Golgi-to-ER retrograde transport	9	8.1×	8e-04
ER to Golgi Anterograde Transport	8	7.2×	2e-03
Intra-Golgi and retrograde Golgi-to-ER traffic	9	6.4×	2e-03
Transport to the Golgi and subsequent modification	8	5.6×	9e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	17	3.9×	8e-04
Membrane Trafficking	15	3.8×	2e-03
Signaling by Rho GTPases	16	3.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

6607 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	106
Likely pathogenic	41
Uncertain significance	3609
Likely benign	1849
Benign	178

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048029	NM_201384.3(PLEC):c.5663del (p.Lys1888fs)	Pathogenic
1048030	NM_201384.3(PLEC):c.9294del (p.Glu3099fs)	Pathogenic
1069886	NM_201384.3(PLEC):c.12418C>T (p.Arg4140Ter)	Pathogenic
1071954	NM_201384.3(PLEC):c.7336G>T (p.Glu2446Ter)	Pathogenic
1073588	NM_201384.3(PLEC):c.13106C>A (p.Ser4369Ter)	Pathogenic
1074096	NM_201384.3(PLEC):c.6510del (p.His2170fs)	Pathogenic
1174482	NM_201384.3(PLEC):c.864GCT[3] (p.Leu292del)	Pathogenic
1292045	NM_201384.3(PLEC):c.2455G>T (p.Glu819Ter)	Pathogenic
1320041	NM_201384.3(PLEC):c.6970C>T (p.Arg2324Ter)	Pathogenic
1323468	NM_201384.3(PLEC):c.1465_1471del (p.Asn489fs)	Pathogenic
1323469	NM_201384.3(PLEC):c.2111G>A (p.Trp704Ter)	Pathogenic
1323471	NM_201384.3(PLEC):c.6195dup (p.Gln2066fs)	Pathogenic
1332728	NM_201384.3(PLEC):c.9312del (p.Tyr3105fs)	Pathogenic
1385604	NM_201384.3(PLEC):c.2551del (p.Val851fs)	Pathogenic
1396569	NM_000445.5(PLEC):c.106_119dup (p.Gly44fs)	Pathogenic
1427195	NM_201384.3(PLEC):c.2503C>T (p.Gln835Ter)	Pathogenic
1453848	NM_201384.3(PLEC):c.10573C>T (p.Gln3525Ter)	Pathogenic
1454360	NM_201384.3(PLEC):c.12926dup (p.Arg4310fs)	Pathogenic
1455035	NM_201384.3(PLEC):c.6664C>T (p.Gln2222Ter)	Pathogenic
1455166	NM_201384.3(PLEC):c.7078G>T (p.Glu2360Ter)	Pathogenic
1456758	NM_201384.3(PLEC):c.9022C>T (p.Arg3008Ter)	Pathogenic
1456815	NM_201384.3(PLEC):c.3874C>T (p.Gln1292Ter)	Pathogenic
1459260	NM_201384.3(PLEC):c.5170C>T (p.Gln1724Ter)	Pathogenic
1459261	NM_201384.3(PLEC):c.4606C>T (p.Gln1536Ter)	Pathogenic
1686892	NM_201384.3(PLEC):c.2726G>A (p.Trp909Ter)	Pathogenic
1686893	NM_201384.3(PLEC):c.875T>C (p.Leu292Pro)	Pathogenic
1937497	NM_201384.3(PLEC):c.9586C>T (p.Gln3196Ter)	Pathogenic
2000033	NM_201384.3(PLEC):c.8776del (p.Glu2926fs)	Pathogenic
2031024	NM_201384.3(PLEC):c.2475dup (p.Asp826Ter)	Pathogenic
208860	NM_201384.3(PLEC):c.1405C>T (p.Gln469Ter)	Pathogenic

SpliceAI

5221 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143922505:T:TA	donor_gain	1.0000
8:143925880:AGCCT:A	acceptor_gain	1.0000
8:143925881:GCCT:G	acceptor_gain	1.0000
8:143925882:CCTC:C	acceptor_gain	1.0000
8:143925883:CT:C	acceptor_gain	1.0000
8:143925885:C:CC	acceptor_gain	1.0000
8:143925892:C:CT	acceptor_gain	1.0000
8:143925894:C:CT	acceptor_gain	1.0000
8:143925895:A:T	acceptor_gain	1.0000
8:143925897:C:CT	acceptor_gain	1.0000
8:143925898:A:T	acceptor_gain	1.0000
8:143926778:CTGTA:C	donor_loss	1.0000
8:143926779:TGTAC:T	donor_loss	1.0000
8:143926780:GTAC:G	donor_loss	1.0000
8:143926781:TAC:T	donor_loss	1.0000
8:143926782:ACCT:A	donor_gain	1.0000
8:143926783:CCTC:C	donor_gain	1.0000
8:143926785:T:TA	donor_gain	1.0000
8:143926788:T:TA	donor_gain	1.0000
8:143926791:T:TA	donor_gain	1.0000
8:143926878:ACGTA:A	acceptor_gain	1.0000
8:143926879:CGTA:C	acceptor_gain	1.0000
8:143926879:CGTAC:C	acceptor_gain	1.0000
8:143926880:GTA:G	acceptor_gain	1.0000
8:143926881:TA:T	acceptor_gain	1.0000
8:143926881:TAC:T	acceptor_loss	1.0000
8:143926883:C:CC	acceptor_gain	1.0000
8:143926883:CTGT:C	acceptor_loss	1.0000
8:143926885:G:GC	acceptor_gain	1.0000
8:143926972:CCTAC:C	donor_loss	1.0000

AlphaMissense

29232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143917287:C:A	W4315C	1.000
8:143917287:C:G	W4315C	1.000
8:143917289:A:G	W4315R	1.000
8:143917289:A:T	W4315R	1.000
8:143917309:A:G	L4308P	1.000
8:143917393:A:T	I4280N	1.000
8:143917510:A:G	L4241P	1.000
8:143917810:A:G	L4141P	1.000
8:143916547:A:G	L4562P	0.999
8:143916658:A:G	L4525P	0.999
8:143916670:C:T	G4521D	0.999
8:143916671:C:G	G4521R	0.999
8:143916685:A:G	L4516P	0.999
8:143916703:G:T	A4510D	0.999
8:143916745:A:G	F4496S	0.999
8:143916886:A:G	L4449P	0.999
8:143916889:A:G	L4448P	0.999
8:143917123:G:T	A4370D	0.999
8:143917126:A:G	F4369S	0.999
8:143917157:A:C	Y4359D	0.999
8:143917240:A:C	I4331S	0.999
8:143917309:A:T	L4308Q	0.999
8:143917319:A:C	Y4305D	0.999
8:143917333:A:T	I4300N	0.999
8:143917336:A:G	L4299P	0.999
8:143917351:G:T	A4294D	0.999
8:143917352:C:G	A4294P	0.999
8:143917393:A:C	I4280S	0.999
8:143917525:A:G	L4236P	0.999
8:143917693:A:G	L4180P	0.999

dbSNP variants (sampled 300 via entrez): RS1000080808 (8:143949905 T>C), RS1000174229 (8:143964390 C>A,T), RS1000264789 (8:143974618 C>A), RS1000331062 (8:143969441 A>G,T), RS1000424957 (8:143945514 G>A), RS1000466907 (8:143969238 C>A,T), RS1000514142 (8:143948783 G>A), RS1000570116 (8:143926160 A>C,T), RS1000581117 (8:143953357 G>A), RS1000671930 (8:143963989 T>C,G), RS1000730220 (8:143958259 C>T), RS1000763340 (8:143958550 C>A,G,T), RS1000779773 (8:143940286 G>A), RS1000835170 (8:143940529 G>A,C), RS1000936491 (8:143940074 G>C)

Disease associations

OMIM: gene MIM:601282 | disease phenotypes: MIM:131950, MIM:226670, MIM:612138, MIM:613723, MIM:616487, MIM:253600, MIM:226730, MIM:131760, MIM:107970

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myasthenic syndrome	Strong	Autosomal recessive
epidermolysis bullosa simplex 5A, Ogna type	Strong	Autosomal dominant
epidermolysis bullosa simplex 5B, with muscular dystrophy	Strong	Autosomal recessive
epidermolysis bullosa simplex 5C, with pyloric atresia	Strong	Autosomal recessive
autosomal recessive limb-girdle muscular dystrophy type 2Q	Strong	Autosomal recessive
PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder	Strong	Autosomal recessive
epidermolysis bullosa simplex	Strong	Autosomal dominant
progressive familial intrahepatic cholestasis	Moderate	Autosomal recessive
aplasia cutis congenita	Supportive	Autosomal dominant
cholestasis	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder	Definitive	AR

Mondo (20): epidermolysis bullosa simplex 5A, Ogna type (MONDO:0007555), epidermolysis bullosa simplex 5B, with muscular dystrophy (MONDO:0009181), epidermolysis bullosa simplex 5C, with pyloric atresia (MONDO:0012807), autosomal recessive limb-girdle muscular dystrophy type 2Q (MONDO:0013390), epidermolysis bullosa simplex with nail dystrophy (MONDO:0014661), autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152), junctional epidermolysis bullosa with pyloric atresia (MONDO:0009183), epidermolysis bullosa simplex (MONDO:0017610), myopathy (MONDO:0005336), arrhythmogenic right ventricular dysplasia 1 (MONDO:0007152), multiple sclerosis (MONDO:0005301), cholestasis (MONDO:0001751), neuromuscular disease caused by qualitative or quantitative defects of plectin (MONDO:0016198), limb-girdle muscular dystrophy (MONDO:0016971), epidermolysis bullosa simplex 1A, generalized severe (MONDO:0007550)

Orphanet (13): Epidermolysis bullosa simplex with pyloric atresia (Orphanet:158684), Plectin-related limb-girdle muscular dystrophy R17 (Orphanet:254361), Epidermolysis bullosa simplex with muscular dystrophy (Orphanet:257), PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement (Orphanet:79401), Autosomal recessive limb-girdle muscular dystrophy (Orphanet:102015), Junctional epidermolysis bullosa with pyloric atresia (Orphanet:79403), Epidermolysis bullosa simplex (Orphanet:304), Uhl anomaly (Orphanet:3403), Qualitative or quantitative defects of plectin (Orphanet:209196), Limb-girdle muscular dystrophy (Orphanet:263), Autosomal dominant generalized epidermolysis bullosa simplex, severe form (Orphanet:79396), Dilated cardiomyopathy (Orphanet:217604), NON RARE IN EUROPE: Multiple sclerosis (Orphanet:802)

HPO phenotypes

146 total (30 of 146 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000070	Ureterocele
HP:0000075	Renal duplication
HP:0000079	Abnormality of the urinary system
HP:0000096	Glomerular sclerosis
HP:0000110	Renal dysplasia
HP:0000126	Hydronephrosis
HP:0000164	Abnormality of the dentition
HP:0000256	Macrocephaly
HP:0000430	Underdeveloped nasal alae
HP:0000463	Anteverted nares
HP:0000478	Abnormality of the eye
HP:0000490	Deeply set eye
HP:0000491	Keratitis
HP:0000508	Ptosis
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000656	Ectropion
HP:0000670	Carious teeth
HP:0000682	Abnormal dental enamel morphology
HP:0000795	Abnormality of the urethra
HP:0000951	Abnormality of the skin
HP:0000972	Palmoplantar hyperkeratosis
HP:0000978	Bruising susceptibility
HP:0000982	Palmoplantar keratoderma
HP:0000989	Pruritus
HP:0001030	Fragile skin
HP:0001034	Hypermelanotic macule
HP:0001056	Milia

GWAS associations

59 associations (top):

Study	Trait	p-value
GCST000759_37	LDL cholesterol	4.000000e-13
GCST000760_15	Cholesterol, total	9.000000e-10
GCST001337_24	Platelet count	5.000000e-10
GCST002147_18	Fibrinogen	1.000000e-09
GCST002221_30	Cholesterol, total	6.000000e-09
GCST002222_45	LDL cholesterol	7.000000e-12
GCST002647_27	Height	1.000000e-09
GCST002898_12	LDL cholesterol	2.000000e-10
GCST003194_15	Fibrinogen levels	6.000000e-10
GCST003262_1071	Post bronchodilator FEV1	3.000000e-06
GCST003262_1072	Post bronchodilator FEV1	3.000000e-06
GCST003262_1073	Post bronchodilator FEV1	4.000000e-06
GCST003262_1092	Post bronchodilator FEV1	3.000000e-06
GCST003262_1134	Post bronchodilator FEV1	5.000000e-06
GCST003262_1135	Post bronchodilator FEV1	5.000000e-06
GCST003262_1136	Post bronchodilator FEV1	5.000000e-06
GCST003262_1138	Post bronchodilator FEV1	5.000000e-06
GCST003262_1152	Post bronchodilator FEV1	4.000000e-06
GCST003262_1153	Post bronchodilator FEV1	4.000000e-06
GCST003262_1154	Post bronchodilator FEV1	4.000000e-06
GCST003262_1155	Post bronchodilator FEV1	4.000000e-06
GCST003262_1176	Post bronchodilator FEV1	1.000000e-06
GCST003818_70	Resting heart rate	1.000000e-15
GCST004122_9	Fibrinogen levels	2.000000e-09
GCST004233_52	LDL cholesterol levels	2.000000e-17
GCST004235_74	Total cholesterol levels	3.000000e-14
GCST004599_67	Mean platelet volume	6.000000e-19
GCST004603_78	Platelet count	7.000000e-33
GCST004607_171	Plateletcrit	2.000000e-18
GCST004616_197	Platelet distribution width	3.000000e-39

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004309	platelet count
EFO:0004314	forced expiratory volume
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0008378	mosquito bite reaction size measurement
EFO:0006874	antisaccade response measurement
EFO:0006336	diastolic blood pressure
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0009963	bipolar I disorder
EFO:0004615	apolipoprotein B measurement
EFO:0004462	PR interval
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0008373	left ventricular ejection fraction measurement
EFO:0004305	erythrocyte count
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002779	Cholestasis	C06.130.120.135
D016110	Epidermolysis Bullosa Simplex	C16.131.831.493.180; C16.320.850.275.180; C17.800.804.493.180; C17.800.827.275.180; C17.800.865.410.180
D009103	Multiple Sclerosis	C10.114.375.500; C10.314.350.500; C20.111.258.250.500
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
C535955	Epidermolysa bullosa simplex and limb girdle muscular dystrophy (supp.)
C567408	Epidermolysis Bullosa Simplex With Pyloric Atresia (supp.)
C535962	Epidermolysis bullosa simplex, Ogna type (supp.)
C535377	Epidermolysis bullosa with pyloric atresia (supp.)
C538640	Limb-girdle muscular dystrophy autosomal recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293240 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

129 measured of 137 human assays (152 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
MLS000103371	EC50	0.00942 nM
3-chloranyl-N-[2-chloranyl-5-(trifluoromethyl)phenyl]-6-(3,5-dimethylpyrazol-1-yl)pyridine-2-carboxamide	EC50	240 nM
SMR000067268	IC50	408 nM
cid_1912988	IC50	498 nM
cid_3759952	EC50	1090 nM
MLS000588669	IC50	1610 nM
MLS000537607	EC50	1800 nM
N-[4-(4-morpholinylsulfonyl)phenyl]-6-oxo-1H-pyridine-3-carboxamide	IC50	1890 nM
3-(4-Carboxy-benzyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-phenylamino-thiazol-3-ium	IC50	2010 nM
2-[5-[(Z)-(2-amino-3,7-dicyano-4,6-dimethyl-1-pyrindin-5-ylidene)methyl]-2-furyl]benzoic acid	IC50	2930 nM
2-[4-[[5-(4-chlorophenyl)-6-ethoxycarbonyl-7-methyl-3-oxidanylidene-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylidene]methyl]phenoxy]ethanoic acid	IC50	3200 nM
MLS000576933	IC50	3550 nM
MLS000664114	IC50	3590 nM
(2S)-3-phenyl-2-[[(2S)-2-[3-(3,5,9-trimethyl-7-oxidanylidene-furo[3,2-g]chromen-6-yl)propanoylamino]propanoyl]amino]propanoic acid	IC50	3600 nM
4-[(2-ethoxybenzyl)amino]phenol	EC50	3630 nM
2-furancarboxylic acid [3-[(E)-3-methoxyprop-1-enyl]-7-methyl-6,8-dioxo-2-benzopyran-7-yl] ester	IC50	3700 nM
(2S)-2-[[2-(3-benzyl-4,8-dimethyl-2-oxochromen-7-yl)oxyacetyl]amino]-3-phenylpropanoic acid	IC50	3860 nM
cid_5989040	IC50	4300 nM
4-[3-[(4-phenylbenzoyl)amino]phenoxy]phthalic acid	IC50	4440 nM
4-bromanyl-N-[(3-bromophenyl)methylideneamino]benzamide	IC50	4510 nM
2-(diethylamino)ethyl 4-[[(Z)-2-cyano-2-[4-(2-oxidanylidenechromen-3-yl)-1,3-thiazol-2-yl]ethenyl]amino]benzoate	EC50	4880 nM
3-(4-nitrophenyl)-2H-phthalazine-1,4-dione	IC50	5220 nM
MLS000588665	IC50	5230 nM
SMR000497405	IC50	5580 nM
SMR000162332	IC50	6710 nM
1-(ethylamino)-3-methyl-3H-naphtho[1,2,3-de]quinoline-2,7-dione	IC50	7290 nM
1,1,3-Trimethyl-2-[3-(1,3,3-trimethyl-1,3-dihydro-indol-2-ylidene)-propenyl]-1H-benzo[e]indolium	IC50	10600 nM
MLS000936640	IC50	10900 nM
3-[3,4-dihydro-1H-isoquinolin-2-yl-[1-(2-methoxyethyl)-5-tetrazolyl]methyl]-7-methoxy-1H-quinolin-2-one	IC50	11800 nM
MLS000779218	IC50	12200 nM
4-[(4-hydroxyanilino)methylene]-2,2,5,5-tetramethyldihydro-3(2H)-furanone	IC50	12200 nM
(5Z)-5-[4-(dimethylamino)benzylidene]-4-(p-anisidino)-3-thiazolin-2-one	IC50	12700 nM
5-bromanyl-N-(3-cyano-1-phenyl-pyrrolo[3,2-b]quinoxalin-2-yl)furan-2-carboxamide	IC50	14000 nM
MLS000714144	IC50	14300 nM
2-[(E)-2-(2-hydroxyphenyl)ethenyl]-1,3,3-trimethyl-5-indol-1-iumcarboxylic acid methyl ester;iodide	IC50	15000 nM
3-[(E)-(5-chloro-2-hydroxyphenyl)diazenyl]-4,5-dihydroxynaphthalene-2,7-disulfonate	EC50	16300 nM
N-butyl-N-[(6-methoxy-2-oxo-1H-quinolin-3-yl)methyl]-4-methylbenzenesulfonamide	IC50	17200 nM
2-[4-[(2-oxo-8-prop-2-enylchromene-3-carbonyl)amino]phenyl]acetic acid	IC50	17300 nM
MLS001003216	IC50	18300 nM
4-[1,3-bis(oxidanylidene)-3a,4,7,7a-tetrahydroisoindol-2-yl]-N-(4-bromophenyl)benzamide	IC50	18600 nM
3-{4-Chloro-5-[(2-chloro-benzoyl)-hydrazonomethyl]-2-oxo-thiazol-3-ylmethyl}-benzoic acid methyl ester	IC50	19000 nM
SMR000208086	IC50	19600 nM
(E)-N-[[4-[(5-ethyl-1,3,4-thiadiazol-2-yl)sulfamoyl]anilino]-sulfanylidenemethyl]-3-(4-propan-2-ylphenyl)-2-propenamide	IC50	22900 nM
3-(4-tert-butylphenyl)-3-{[(4-fluorophenyl)acetyl]amino}propanoic acid	IC50	25600 nM
1-Amino-4-hydroxy-anthraquinone	IC50	25700 nM
2-(diethylamino)ethyl 4-[[(Z)-2-cyano-2-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]ethenyl]amino]benzoate	EC50	30000 nM
1,5-Dimethyl-4-(4-oxo-cyclohexa-2,5-dienylideneamino)-2-phenyl-1,2-dihydro-pyrazol-3-one	IC50	31600 nM
3-(1,3-dioxoisoindol-2-yl)-N-(4-sulfamoylphenyl)benzamide	IC50	40200 nM
MLS000589117	IC50	40600 nM
5-[(5E)-5-[[3,4-bis(phenylmethoxy)phenyl]methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]pentanoic acid	IC50	45400 nM

ChEMBL bioactivities

57 potent at pChembl≥5 of 113 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	Kd	11.04	nM	CHEMBL5653589
7.96	ED50	11.04	nM	CHEMBL5653589
5.82	IC50	1518	nM	CHEMBL88326
5.81	IC50	1560	nM	CHEMBL1511181
5.80	IC50	1600	nM	CHEMBL1405964
5.75	IC50	1792	nM	CHEMBL1993173
5.75	IC50	1771	nM	CHEMBL1503523
5.73	IC50	1852	nM	CHEMBL1334149
5.72	IC50	1893	nM	CHEMBL1585746
5.69	IC50	2041	nM	CHEMBL1354019
5.68	IC50	2094	nM	CHEMBL1389315
5.67	IC50	2138	nM	CHEMBL2028186
5.67	IC50	2165	nM	CHEMBL1304979
5.64	IC50	2307	nM	CHEMBL1300620
5.62	IC50	2391	nM	CHEMBL1348090
5.59	IC50	2543	nM	CHEMBL3190895
5.53	IC50	2932	nM	CHEMBL3193946
5.47	IC50	3405	nM	CHEMBL1532953
5.43	IC50	3734	nM	CHEMBL1415156
5.43	IC50	3743	nM	CHEMBL2000670
5.41	IC50	3910	nM	CHEMBL1440277
5.40	IC50	3958	nM	CHEMBL1346753
5.39	IC50	4032	nM	CHEMBL1308195
5.38	IC50	4214	nM	CHEMBL1334670
5.37	IC50	4266	nM	CHEMBL1447803
5.36	IC50	4371	nM	CHEMBL1320537
5.36	IC50	4382	nM	CHEMBL1529584
5.34	IC50	4514	nM	CHEMBL1438567
5.34	IC50	4550	nM	CHEMBL1455832
5.33	IC50	4658	nM	CHEMBL1546183
5.30	IC50	5040	nM	CHEMBL1416302
5.30	IC50	4982	nM	CHEMBL3192206
5.29	IC50	5126	nM	CHEMBL2028186
5.29	IC50	5110	nM	CHEMBL1454269
5.27	IC50	5412	nM	CHEMBL1334670
5.27	IC50	5406	nM	CHEMBL1469444
5.25	IC50	5607	nM	CHEMBL1985649
5.25	IC50	5665	nM	CHEMBL1559707
5.24	IC50	5753	nM	CHEMBL88326
5.23	IC50	5940	nM	CHEMBL1370375
5.22	IC50	6051	nM	CHEMBL1302170
5.21	IC50	6217	nM	CHEMBL1603065
5.21	IC50	6228	nM	CHEMBL1334149
5.20	IC50	6359	nM	CHEMBL1478085
5.20	IC50	6305	nM	CHEMBL1351935
5.19	IC50	6448	nM	CHEMBL1380232
5.17	IC50	6694	nM	CHEMBL1545384
5.15	IC50	7099	nM	CHEMBL1411702
5.14	IC50	7292	nM	CHEMBL1548333
5.12	IC50	7654	nM	CHEMBL1351543

PubChem BioAssay actives

1 with measured affinity, of 12 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149023: Binding affinity to human PLEC incubated for 45 mins by Kinobead based pull down assay	kd	0.0110	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	decreases expression, increases abundance, affects expression, increases expression, affects cotreatment	5
bisphenol A	increases expression, decreases expression, affects expression, affects cotreatment, increases methylation	4
Tobacco Smoke Pollution	affects expression, decreases expression, decreases methylation, increases expression	4
Cadmium Chloride	increases abundance, increases expression, decreases expression	4
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	4
sodium arsenite	affects binding, increases reaction, decreases expression, increases abundance, increases expression	3
Arsenic	affects methylation, increases expression, decreases expression, increases abundance	3
Benzo(a)pyrene	decreases expression, increases methylation, affects cotreatment, increases expression	3
Estradiol	affects expression, decreases expression	3
bisphenol F	affects cotreatment, decreases expression, increases expression	2
titanium dioxide	decreases expression, decreases methylation	2
Zoledronic Acid	decreases expression	2
Caffeine	decreases expression, affects phosphorylation	2
Cisplatin	affects expression, decreases expression	2
Doxorubicin	affects expression, decreases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Progesterone	decreases expression	2
Quercetin	increases expression, increases phosphorylation	2
Smoke	increases abundance, increases expression, affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
chloroacetaldehyde	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
lead acetate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
beta-lapachone	decreases expression	1

ChEMBL screening assays

12 unique, capped per target: 12 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614066	Binding	PUBCHEM_BIOASSAY: HTS fluorescence polarization-based dose response confirmatory screen for the Siah-1 primary assay utilizing an alternative fluorophore, fluorescein-labeled plectin. (Class of assay: confirmatory) [Related pubchem assays (	PubChem BioAssay data set

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1661	ZR-75-30	Cancer cell line	Female
CVCL_A4GM	U2OS PLEC KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01373918	PHASE4	TERMINATED	Low Dose Fat for the Prevention of Liver Disease in Babies With Gastrointestinal Disorders
NCT01585935	PHASE4	COMPLETED	Preventing Cholestasis Using SMOFLipid®
NCT01998620	PHASE4	UNKNOWN	Efficacy and Safety of S-adenosyl-L-methionine in Treatment of Chronic Hepatitis B Patients With Cholestasis
NCT00120055	PHASE4	COMPLETED	Association Between Systemic Exposure of Atorvastatin and Metabolites and Atorvastatin-induced Myotoxicity
NCT03633565	PHASE4	UNKNOWN	Comparative Study of Strategies for Management of Duchenne Myopathy (DM)
NCT00037102	PHASE4	COMPLETED	Combination Therapy With Avonex and BiMonthly High Dose Intravenous Methotrexate in Multiple Sclerosis
NCT00037115	PHASE4	WITHDRAWN	Induction Therapy With a Single High Dose Bolus of Intravenous Methotrexate With Leucovorin Rescue, Prior to Initiation of AVONEX® Treatment, in Patients Presenting With a First Acute Demyelinating Event.
NCT00146068	PHASE4	COMPLETED	EARLY IFNB-1a and Simvastatin Combination Therapy in Clinically Isolated Syndrome Suggestive of Multiple Sclerosis
NCT00151294	PHASE4	TERMINATED	The Efficacy and Safety of Escitalopram for Depression in Multiple Sclerosis
NCT00176592	PHASE4	COMPLETED	Phase IV Study, Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI
NCT00179478	PHASE4	COMPLETED	Long Term Study of Avonex Therapy Following a First Attack of Multiple Sclerosis
NCT00220922	PHASE4	COMPLETED	A Study to Evaluate the Impact on Skin (Injection Site) Reactions of Using Alcohol Wipes Prior to Daily Injections of Copaxone®.
NCT00239993	PHASE4	COMPLETED	A Study to Evaluate the Impact of Using Warm Compress Prior to Daily Injections of Copaxone®
NCT00240006	PHASE4	COMPLETED	A Study Comparing Shared Solutions® Plus MS Center Support Versus Shared Solutions® Alone
NCT00240032	PHASE4	COMPLETED	A Study to Evaluate the Impact on Skin (Injection Site) Reactions of Taking an Antihistamine (Zyrtec®) or Placebo Prior to Daily Injections of Copaxone®.
NCT00246324	PHASE4	COMPLETED	Safety and Efficacy Study of Doxycycline in Combination With Interferon-B-1a to Treat Multiple Sclerosis
NCT00267319	PHASE4	COMPLETED	FOCUS Fatigue Outcome in Copaxone USers
NCT00381264	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Multiple Sclerosis
NCT00414453	PHASE4	TERMINATED	Trial of Analgesia With Lidocaine or Extended-release Oxycodone for Neuropathic Pain Treatment in Multiple Sclerosis
NCT00423527	PHASE4	COMPLETED	Levetiracetam in Central Pain in Multiple Sclerosis(MS)
NCT00480181	PHASE4	COMPLETED	Efficacy and Safety Evaluation of Nabilone as Adjunctive Therapy to Gabapentin for the Management of Neuropathic Pain in Multiple Sclerosis
NCT00492765	PHASE4	COMPLETED	Simvastatin as an Add-on Treatment to Interferon-beta-1a for the Treatment of Relapsing-Remitting Multiple Sclerosis
NCT00493077	PHASE4	COMPLETED	Safety of Avonex Treatment in Multiple Sclerosis Patients With Neutralizing Antibodies to Interferon Beta Therapy
NCT00536120	PHASE4	COMPLETED	The Effects of Tysabri Treatment on Vaccination Response and Lymphocyte Subsets in Subjects With Relapsing Forms of Multiple Sclerosis
NCT00629642	PHASE4	COMPLETED	Clinical Study of Solifenacin Succinate in Patients With Bladder Symptoms Due to Spinal Cord Injury or Multiple Sclerosis
NCT00638027	PHASE4	COMPLETED	Memantine for Spasticity in MS Patients
NCT00744679	PHASE4	COMPLETED	A Pharmacokinetic (PK) Study of Natalizumab (Tysabri) at Steady State
NCT00752778	PHASE4	TERMINATED	Magnetic Resonance Imaging (MRI) Follow-up of Macrophagic Infiltration in MS Patients Treated With Tysabri
NCT00753792	PHASE4	COMPLETED	Oral Corticotherapy in Megadoses to Treat Multiple Sclerosis During Relapse
NCT00854750	PHASE4	TERMINATED	Modeling and Treating the Pathophysiology of Demyelination in Multiple Sclerosis
NCT00881205	PHASE4	TERMINATED	Rivastigmine in Multiple Sclerosis Patients With Cognitive Impairment
NCT00910598	PHASE4	UNKNOWN	Optical Coherence Tomography: Glatiramer in Clinically Isolated Syndrome or Early Relapsing Remitting Multiple Sclerosis (MS)
NCT00913666	PHASE4	COMPLETED	Pharmacodynamic Study to Better Understand the Therapeutic Response and Immunomodulatory Effects of Avonex in Multiple Sclerosis (MS) Patients and Healthy Volunteers
NCT00915460	PHASE4	COMPLETED	Open-Label Safety Extension Study of Avonex
NCT00942214	PHASE4	COMPLETED	Biomarkers and Response to Natalizumab for Multiple Sclerosis Treatment
NCT00988988	PHASE4	WITHDRAWN	The Effects of Ethyl-Alpha-Guanido-Methyl Ethanoate on Skin Reactions From Glatiramer Acetate Injections
NCT01005095	PHASE4	TERMINATED	The Effects of Interferon Beta Combined With Vitamin D on Relapsing Remitting Multiple Sclerosis Patients
NCT01034579	PHASE4	COMPLETED	The REbif® vs Glatiramer Acetate in Relapsing Multiple Sclerosis Pharmacogenetics Trial
NCT01085318	PHASE4	COMPLETED	Rebif Advanced Magnetic Resonance Imaging (MRI) and Immunology Pilot Trial
NCT01236534	PHASE4	COMPLETED	Lubiprostone in Patients With Multiple Sclerosis Associated Constipation