PLEC
protein-codingplectin, the group of MicroRNA protein coding host genes|Plakins
Gene summary
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 These names were superseded by plectin.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. [provided by RefSeq, Aug 2011]
- EBS1
- PLEC1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~61.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013390
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0012807
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009181
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013390
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0007555
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0001751
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0007555
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0017610
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013390
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0015762
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0017610
Submitter: LiferaOmics
Genetic evidence – Published PMID: 25712130 – Family 1 – one proband (affected sibling counted under segregation). Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 32725257 – Family 2 – one proband (compound heterozygous: one predicted null + one non-LOF; phase confirmed, each variant evaluated independently). Case-level (non-LOF present in AR model; no consanguinity deduction) = 1.6; Segregation (parental confirmation of variants in trans; conservative assignment) = 0.5; Case-control = 0 Family 2 total = 2.1 PMID: 32725257 total = 3.6 Published genetic evidence total = 3.6 / 12 Genetic evidence – Our case Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous scored once; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Our case contribution = 1.0 / 12 Total genetic evidence (published AR + our case) Published genetic evidence: 3.6 Our additional case: 1.0 Total genetic evidence = 4.6 / 12 Experimental evidence – Published PMID: 25712130 – Functional alteration evidence: patient skin/keratinocyte studies (immunofluorescence, EM, protein analysis) demonstrated reduced/absent plectin at the dermal–epidermal junction with hemidesmosomal abnormalities, supporting loss-of-function pathogenicity. Functional alteration (patient tissue) = 1.0 PMID: 32725257 – Functional alteration evidence: patient skin biopsy showed markedly reduced/absent plectin expression and hemidesmosome defects. Functional alteration (patient tissue) = 1.0 PMID: 32725257 – Functional studies in transfected cells demonstrated that the missense variant impairs plectin stability/interaction (e.g., with β4 integrin), supporting pathogenicity. Functional alteration (non-patient cells) = 0.5 Experimental evidence total = 2.5 / 6 Overall score Genetic evidence = 4.6 Experimental evidence = 2.5 Overall score = 7.1
Inheritance Pattern: AD
Disease ID:MONDO:0007555
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:1060109
Submitter: ClinGen
The PLEC gene encodes plectin, a member of the plakin protein family that acts as an intermediate filament crosslinker. PLEC was first reported in relation to autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; MIM #613723) in 1996 (Smith et al., PMID: 8696340). Subsequently, biallelic variants in PLEC were identified in patients with EBS with pyloric atresia (MIM #612138; PMID: 15654962) and autosomal recessive limb-girdle muscular dystrophy (LGMD; MIM #613723; PMID: 21109228), as well as additional featuress like myasthenia. A heterozygous missense variant has been reported in association with EBS Ogna, a more mild manifestation (MIM #131950; PMID: 11851880). Alternative splicing primarily due to use of alternative first exons produces multiple plectin isoforms with unique tissue-specific expression patterns, subcellular localization, and functions, and the differential effects of variants on the various isoforms has been proposed to contribute to phenotypic variability within the spectrum of plectinopathies (PMID: 22864774, 35815343). For example, isoforms P1, P1b, P1d, and P1f are expressed in sarcomeres, with P1f also preferentially found at the neuromuscular junction, and isoforms P1, P1a, P1c, and P1f are expressed in the epidermis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found overlap in the phenotypes associated with variation in this gene and no difference in molecular mechanism. Therefore, these disorders were lumped and a single curation performed for PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder, autosomal recessive. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Over 100 unique variants have been reported, with the majority expected to result in loss of function (PMID: 35815343). The genetic evidence for this curation includes 11 variants identified in 7 probands (PMID: 21109228, 32605089, 25556389, 28447722, 28824526, 38912134, 25209331, 29352809), including 1 start-lost variant, 5 stop-gained variants, and 5 missense variants. A homozygous 9-bp deletion affecting only the 1f isoform, NM_201378.4:c.1_9del p.(Met1_Gly3del) has been reported in seven probands with LGMD without cutaneous manifestations, shown to segregate with the disease in 3 affected family members, and appears to be a founder variant in the Turkish population (PMID: 21109228, 32605089). The maximum score for genetic evidence (12 pts) was reached. The mechanism of pathogenicity is loss of function. Experimental evidence includes direct interaction with the protein products of other genes associated with muscular dystrophy (PMID: 17389230), reduced P1 and specifically P1f expression in patients homozygous for the c.1_9del (p.Met1_Gly3del) variant, rescue of disrupted acetylcholine receptor clustering and desmin intermediate filament organization observed in PLEC-deficient myotubes by expression of plectin 1f (PMID: 25318670), and recapitulation of disease features in conditional knockout mice (PMID: 25318670, 26019234). In summary, there is Definitive evidence supporting the relationship between PLEC and autosomal recessive PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on April 8, 2025 (SOP Version 11). This gene-disease pair was originally evaluated by the Muscular Dystrophies and Myopathies GCEP on May 9, 2023. It was reevaluated on April 8, 2025. As a result of this re-evaluation, the classification increased from Moderate to Definitive with the expansion of the phenotype from autosomal recessive LGMD to autosomal recessive PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder. Upon re-review of the evidence for this gene, the GCEP decided there was insufficient evidence to split off PLEC-related LGMD based on isoform specificity or phenotype. The re-evaluation includes additional case-level evidence for LGMD with or without skin involvement as well as EBS-MD cases. Additional experimental evidence was also added, including decreased plectin expression in patient muscle biopsy (PMID: 21109228), protein interaction with dystrophin and β-dystroglycan (PMID: 17389230), another mouse model, and a rescue assay (PMID: 25318670).
Inheritance Pattern: AD
Disease ID:MONDO:0007555
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0009181
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0018940
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012807
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012807
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:1060109
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0007145
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Dermatologic; Gastrointestinal; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PLEC variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_201384.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 45 | 1847 | 44 | 1937 | |
| missense | 2 | 3 | 3402 | 271 | 22 | 3700 |
| nonsense | 60 | 23 | 4 | 87 | ||
| start loss | 0 | |||||
| frameshift | 39 | 14 | 4 | 57 | ||
| splice donor/acceptor (+/-2bp) | 2 | 10 | 10 | 22 | ||
| Total | 104 | 50 | 3465 | 2118 | 66 | 5803 |
Highest pathogenic variant AF is 0.000021730195
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_958786.1 | 32 | MANE Select | |
| Ensembl | ENSP00000344848.3 | 32 | MANE Select | |
| RefSeq | NP_000436.2 | 32 | Standard | |
| RefSeq | NP_001397870.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| plecb | Danio rerio | Structure: skeletal muscle Quality: refractivity abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Assembly of collagen fibrils and other multimeric structures
- Alpha6Beta4Integrin
- Collagen formation
- Extracellular matrix organization
- Caspase-mediated cleavage of cytoskeletal proteins
Biological Process
- hemidesmosome assembly
- wound healing
- intermediate filament cytoskeleton organization
Molecular Function
- RNA binding
- actin binding
- structural molecule activity
- structural constituent of cytoskeleton
- protein binding
Cellular Component
- cytoplasm
- cytosol
- intermediate filament
- plasma membrane
- brush border
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000322810
- Coding exons
- 32
- Length
- 61582
- Individuals with no LoFs
- 125079
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 129
- Defined
- 125208
- p
- 0.000515
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.57 | 3516 | 3.11e+3 | 1.13 | 0.000266 | 29384 |
| Missense (PolyPhen) | 960 | 935.18 | 1.0265 | 8772 | ||
| Synonymous | -11.3 | 1988 | 1.44e+3 | 1.38 | 0.000123 | 9776 |
| Loss of Function | 8.45 | 55 | 176 | 0.313 | 0.00000881 | 1941 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00094 | 0.00081 | rare |
| Latino/Admixed American | 0.00036 | 0.00035 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.0014 | 0.0014 | notable |
| Finnish | 0.00092 | 0.00088 | rare |
| European (Non-Finnish) | 0.00033 | 0.00031 | rare |
| South Asian | 0.00058 | 0.00056 | rare |
| Other | 0.00053 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- 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. {ECO:0000269|PubMed:12482924, ECO:0000269|PubMed:21109228}.;
- Disease
- DISEASE: Epidermolysis bullosa simplex with pyloric atresia (EBS- PA) [MIM:612138]: Autosomal recessive genodermatosis characterized by severe skin blistering at birth and congenital pyloric atresia. Death usually occurs in infancy. This disorder is allelic to MD- EBS. {ECO:0000269|PubMed:14675180, ECO:0000269|PubMed:20665883}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epidermolysis bullosa simplex, with muscular dystrophy (MD-EBS) [MIM:226670]: A form of epidermolysis bullosa characterized by the association of blister formation at the level of the hemidesmosome with late-onset muscular dystrophy. {ECO:0000269|PubMed:11159198, ECO:0000269|PubMed:20665883, ECO:0000269|PubMed:21263134, ECO:0000269|PubMed:8894687}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epidermolysis bullosa simplex, Ogna type (O-EBS) [MIM:131950]: A form of intraepidermal epidermolysis bullosa characterized by generalized skin bruising, skin fragility with non-scarring blistering and small hemorrhagic blisters on hands. At the ultrastructural level, it is differentiated from classical cases of K-EBS, WC-EBS and DM-EBS, by the occurrence of blisters originating in basal cells above hemidesmosomes, and abnormal hemidesmosome intracellular attachment plates. {ECO:0000269|PubMed:11851880}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Limb-girdle muscular dystrophy 2Q (LGMD2Q) [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. {ECO:0000269|PubMed:21109228, ECO:0000269|PubMed:25556389, ECO:0000269|PubMed:27234031}. Note=The disease is caused by mutations 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.; DISEASE: Epidermolysis bullosa simplex with nail dystrophy (EBSND) [MIM:616487]: A form of epidermolysis bullosa, a dermatologic disorder characterized by skin blistering. EBSND patients also manifest nail dystrophy. {ECO:0000269|PubMed:25712130}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.299
Intolerance Scores
- LoFtool
- 0.00999
- RVIS EVS
- -6.57
- RVIS percentile EVS
- 0.03
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.948
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |