Alternative titles; symbols
HGNC Approved Gene Symbol: PLEC
SNOMEDCT: 398071000, 716701004, 723308003, 726615005;
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38): 8:143,915,153-143,976,745 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | ?Epidermolysis bullosa simplex 5D, generalized intermediate, autosomal recessive | 616487 | Autosomal recessive | 3 |
| Epidermolysis bullosa simplex 5A, Ogna type | 131950 | Autosomal dominant | 3 | |
| Epidermolysis bullosa simplex 5B, with muscular dystrophy | 226670 | Autosomal recessive | 3 | |
| Epidermolysis bullosa simplex 5C, with pyloric atresia | 612138 | Autosomal recessive | 3 | |
| Muscular dystrophy, limb-girdle, autosomal recessive 17 | 613723 | Autosomal recessive | 3 |
The PLEC1 gene encodes plectin-1, a 500-kD intermediate filament-binding protein that is one of the largest polypeptides known. It was originally identified as a major component of intermediate filament preparations obtained from cultured cells (Pytela and Wiche, 1980). It is believed to provide mechanical strength to cells and tissues by acting as a crosslinking element of the cytoskeleton.
Liu et al. (1996) cloned and characterized the human plectin gene by screening a placenta cDNA library with previously published human plectin probes (Wiche et al., 1991) and probes derived from rat plectin. The deduced protein sequences for human and rat plectin are 93% identical.
McLean et al. (1996) also cloned and sequenced the PLEC1 gene. They showed that the predicted 518-kD polypeptide has homology to the actin-binding domain of the dystrophin family at the amino terminus, a central rod domain, and homology to the intermediate filament-associated protein desmoplakin at the carboxy terminus.
By RT-PCR, Kazerounian et al. (2002) surveyed the tissue distribution of several plakin family members, including periplakin (602871), plectin, desmoplakin (125647), BPAG1 (113810), and envoplakin (601590). Plectin was expressed in all adult and fetal tissues examined except leukocytes. Only a weak band was obtained from adult brain and thymus.
Natsuga et al. (2010) determined that human fibroblasts express 2 different plectin isoforms: a 500-kD full-length protein and a 390-kD protein lacking the rod domain. Immunoblot assays found that the quantitative ratio of full-length/rodless plectin was 14.2:1 in fibroblasts, 21.3:1 in keratinocytes, and 1.37:1 in skeletal muscle.
Liu et al. (1996) determined that the coding sequence of the plectin gene contains 32 exons that extend over 32 kb of the human genome. Most of the introns reside within a region encoding the globular N-terminal domain of the molecule, whereas the entire central-rod domain and the entire C-terminal globular domain are encoded by single large exons of more than 3 kb and more than 6 kb, respectively. Overall, the organization of the human plectin gene is strikingly similar to that of human bullous pemphigoid antigen-1 (113810).
Zhang et al. (2004) identified 8 alternative first exons in the PLEC1 gene that are variably spliced to a common set of downstream constant exons. The coding regions of the alternative first exons are all in the same open reading frame. Almost all variable exons correspond to locations of CpG islands, suggesting that there are multiple promoters controlling PLEC1 gene expression. A similar pattern of alternative first exons spliced to constant downstream exons exists in the mouse and rat Plec1 genes.
Lesniewicz et al. (2005) determined that the 3-prime sequence of the mouse Parp10 gene (609564) overlaps on the same strand with the 5-prime sequence of the Plec1 gene. Exons 10 and 11 of the Parp10 gene, which encode the last 109 amino acids and the 3-prime UTR of Parp10, are spliced at different sites to form the untranslated exons -1 and 0a of a Plec1 splice variant. Lesniewicz et al. (2005) identified mouse ESTs containing sequences from both Parp10 and Plec1, but they did not find read-through transcripts.
By fluorescence in situ hybridization, Liu et al. (1996) mapped the plectin gene to 8q24 in a region previously implicated in epidermolysis bullosa simplex of the Ogna type (EBSOG; 131950).
Gache et al. (1996) presented evidence that epidermolysis bullosa simplex with muscular dystrophy (EBSMD; 226670) is due to plectin deficiency. Independently and simultaneously, Smith et al. (1996) observed absence of plectin by antibody staining in affected individuals. EBSMD segregated with markers in the 8q24.13-qter region where the plectin gene is located. They used the rat plectin cDNA sequence to screen the GenBank database for homologous sequences and identified an expressed sequence tag, EST25263, which demonstrated 84% nucleotide homology and 94% protein homology with the 3-prime region of the rat plectin sequence. Using human-specific oligonucleotide primers designed from the sequence data, they screened a monochromosomal somatic cell hybrid panel by PCR amplification and assigned the gene to chromosome 8. Further localization to 8q24.13-qter was achieved using a panel of deletion-translocation hybrids, thus refining the data from fluorescence in situ hybridization analysis that localized the gene to 8q24 (Liu et al., 1996).
McLean et al. (1996) mapped the PLEC1 gene to 8q24.
Lesniewicz et al. (2005) mapped the mouse Plec1 gene to chromosome 15, immediately downstream of and in a head-to-tail orientation with the Parp10 gene.
Epidermolysis Bullosa Simplex 5B, with Muscular Dystrophy
In affected members of a family with epidermolysis bullosa simplex with muscular dystrophy (EBS5B; 226670), Smith et al. (1996) identified a homozygous frameshift mutation in the plectin gene (601282.0001). They speculated that the absence of the large multifunctional cytoskeleton protein could account for structural failure in both muscle and skin.
Pulkkinen et al. (1996) reported ultrastructural studies and molecular genetic analysis of plectin in 2 probands from different families with EBSMD. In a proband and in her affected sister, they detected a homozygous 9-bp deletion mutation (601282.0002). The proband in the second family demonstrated a single nucleotide deletion (601282.0003) which resulted in a frameshift and a premature termination codon 16 bp downstream of the mutation. Based on ultrastructural studies Pulkkinen et al. (1996) concluded that plectin was critical for binding of the intermediate keratin filament network to hemidesmosomal complexes. They also postulated that plectin functioned in muscle as a putative attachment protein mediating binding of actin to membrane complexes.
Epidermolysis Bullosa Simplex 5A, Ogna Type
Koss-Harnes et al. (2002) found the same heterozygous missense mutation (601282.0005) in the original Norwegian family with epidermolysis bullosa simplex Ogna type (EBS5A; 131950) and in an unrelated German family. The authors concluded that these 2 mutations arose about 200 years apart.
Epidermolysis Bullosa Simplex 5C, with Pyloric Atresia
Pfendner and Uitto (2005) reported 4 consanguineous families in which at least 1 member had EBS with pyloric atresia (EBS5C; 612138). All patients had extensive blistering at birth with pyloric atresia, most had aplasia cutis, and all died from complications of the disorder shortly after birth. Molecular analysis confirmed homozygous mutations in the PLEC1 gene (see, e.g., 601282.0007 and 601282.0009). Pfendner and Uitto (2005) noted that 1 of the mutations deleted a region that may be important for plectin interaction with alpha-6 (ITGA6; 147556)/beta-4 (ITGB4; 147557) integrin, and that mutations in the latter genes result in the phenotypically similar junctional EB-PA (e.g., JEB5B, 226730). Thus, pyloric atresia in all of these patients is likely related to perturbed interactions between plectin and alpha-6/beta-4 integrin within attachment structures expressed during gastrointestinal development.
Epidermolysis Bullosa Simplex 5D, With Nail Dystrophy
In 2 Turkish sisters with epidermolysis bullosa simplex and nail dystrophy (EBS5D; 616487), Gostynska et al. (2015) identified homozygosity for a nonsense mutation (R16X; 601282.0014) present only in the 1a isoform of PLEC1. Because isoform-1a is not expressed in either striated or cardiac muscle tissue, the authors stated that they did not expect these patients to develop muscular dystrophy or cardiomyopathy.
In 2 unrelated patients with EBS and nail dystrophy, Tu et al. (2020) identified compound heterozygosity for a missense mutation (L319P; 601282.0015) and 2 different nonsense mutations: R2319X (601282.0013) in one patient and W936X (601282.0016) in the other.
Autosomal Recessive Limb-Girdle Muscular Dystrophy 17
Gundesli et al. (2010) identified a homozygous 9-bp deletion in exon 1f of the PLEC1 gene (601282.0010) in affected members of 3 Turkish families with autosomal recessive limb-girdle muscular dystrophy (LGMDR17; 613723), previously symbolized LGMD2Q, without skin involvement. The deletion was found to affect only the 1f isoform of plectin. Muscle biopsy from an affected individual showed significantly (100-fold) decreased expression of plectin isoform-1f mRNA and a 3-fold decrease of the plectin protein. Electron microscopic studies of patient muscle showed empty spaces between the sarcolemma and the contractile elements of the sarcomere, separation of membranes, loss of myofibrillar organization in some areas, and misalignment of the Z lines. These findings suggested that PLEC1 isoform-1f is a sarcolemma-associated protein with a specific role in skeletal muscle, and that lack of this isoform results in disruption of the myofiber without affecting other tissues.
Natsuga et al. (2010) examined plectin expression patterns in the skin of 3 patients with EBSPA and 6 with EBSMD, all of whom carried mutations in the PLEC1 gene. In EBSPA, expression of all plectin domains was found to be markedly attenuated or completely lost. In EBSMD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. The findings suggested that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBSMD, but that complete loss or marked attenuation of both the full-length and rodless plectin isoforms underlies the more severe EBSPA phenotype. In addition, the majority of EBSMD-associated PLEC1 mutations occurred within the large exon 31 that encodes the plectin rod domain. EBSPA-associated PLEC1 mutations were generally outside of exon 31.
Winter et al. (2015) noted that, in skeletal muscle, the 4 major plectin isoforms, which have distinct N termini, are required for the integrity of myofibers by targeting and anchoring desmin intermediate filaments to Z-disks (isoform-1d), costameres (isoform-1f), mitochondria (isoform-1b), and nuclear and sarcoplasmic reticulum membranes (isoform-1). Winter et al. (2015) found that striated muscle-specific knockdown of Plec1 in mice reduced mitochondrial content and respiratory capacity and altered mitochondrial morphology and position at Z-disk structures in heart and in soleus and gastrocnemius skeletal muscle. Defects in Plec1 -/- muscle increased with age, and gastrocnemius showed the most severe phenotype. Specific knockout of plectin isoform-1b caused severe mitochondrial dysfunction compared with knockout of isoform-1d, with decoupling of mitochondrial networks and mitochondrial enlargement, concomitant with upregulation of the mitochondrial fusion-associated protein Mfn2 (608507).
In a patient with epidermolysis bullosa simplex with muscular dystrophy (EBS5B; 226670), Smith et al. (1996) found a homozygous 8-bp duplication mutation (insertion of the sequence GTGGAGGA) leading to a premature termination codon 14 bp downstream of the insertion. This frameshift mutation was predicted to cause premature termination of translation in the R2C subdomain of the plectin polypeptide within the rod domain predicted to be involved in polymerization. Smith et al. (1996) stated that such a genetic lesion is likely to cause loss of protein expression through nonsense-mediated decay of the predicted 15-kb plectin mRNA. The clinically unaffected parents were heterozygous for this mutation, consistent with the recessive inheritance of the disorder.
In 2 sisters with skin blistering since birth and onset of muscular dystrophy in the third decade (EBS5B; 226670), Pulkkinen et al. (1996) identified a homozygous 9-bp deletion at position 2719 (2719del9) of the plectin gene. The mutation results in a deletion of gln-glu-ala and loss of a BglI restriction site. The clinically unaffected parents were first cousins and the mother was shown to be heterozygous for the deletion.
In a woman with skin blistering and muscle weakness (EBS5B; 226670), Pulkkinen et al. (1996) identified a homozygous 1-bp deletion (5866delC) in the plectin gene. This frameshift creates a premature termination codon which predicts synthesis of a truncated plectin polypeptide and reduced mRNA expression. Both unaffected parents were deceased.
In a 24-year old Hispanic male with muscular dystrophy and epidermolysis bullosa simplex (EBS5B; 226670), McLean et al. (1996) identified a homozygous 8-bp deletion in exon 32 of the PLEC1 gene causing a frameshift and a premature termination codon 42 bp downstream. The clinically unaffected parents, who were first cousins, were found to be heterozygous carriers of the mutation.
In the original Norwegian family with autosomal dominant epidermolysis bullosa simplex Ogna type (EBS5A; 131950) reported by Gedde-Dahl (1971) and in a German family, Koss-Harnes et al. (2002) reported a heterozygous C-to-T transition in exon 31 of the PLEC1 gene resulting in an arg2110-to-trp (R2110W) substitution in the plectin polypeptide.
Has et al. (2020) reported this mutation as c.5998C-T, ARG2000TRP (R2000W).
In 3 sisters with epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138), born of consanguineous Turkish parents, Charlesworth et al. (2003) identified a homozygous 14-bp deletion at nucleotide 2727 in the PLEC1 gene. The deletion was predicted to result in an out-of-frame shift, premature termination, and disruption of the plakin globular domain. The mutation was not identified in 80 control chromosomes. The patients had a severe blistering disorder with onset in utero, aplasia cutis at birth, and evidence of pyloric atresia. All died within hours of birth or by termination of the pregnancy.
In a patient with epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138), Nakamura et al. (2005) identified compound heterozygosity for 2 mutations in the PLEC1 gene: a 913C-T transition in exon 9 resulting in a gln305-to-ter (Q305X) substitution, and a 1344G-A transition at the 3-prime end of exon 12 resulting in abnormal splicing (601282.0008). The patient was born with widespread blisters and ulcers and died at age 16 months. An older brother was similarly affected.
In a Lebanese patient with lethal EBSPA, born of consanguineous parents, Pfendner and Uitto (2005) identified homozygosity for the Q305X mutation.
For discussion of the splice site mutation in the PLEC1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138) by Nakamura et al. (2005), see 601282.0007.
In a child with epidermolysis bullosa simplex with pyloric atresia (EBS5C; 612138), Pfendner and Uitto (2005) identified a homozygous C-to-T transition in exon 33 of the PLEC1 gene, resulting in an arg3029-to-ter (R3029X) substitution.
In affected members of 3 unrelated consanguineous Turkish families with autosomal recessive limb-girdle muscular dystrophy type 2Q (LGMDR17; 613723), Gundesli et al. (2010) identified a homozygous 9-bp deletion (1_9delATGGCCGGC) in exon 1f of the PLEC1 gene. The deletion included the initiation codon. Haplotype analysis indicated a founder effect. The phenotype was characterized by early childhood onset of proximal muscle weakness and atrophy, and, in 1 family, progression of the disorder in adolescence. There was no skin involvement. Muscle biopsy from an affected individual showed significantly (100-fold) decreased expression of plectin isoform-1f mRNA and a 3-fold decrease of the plectin protein. Examination of control skeletal muscle with antibodies against the rod domains of all plectin isoforms showed strong sarcoplasmic staining, but irregular and weak sarcolemmal staining of type 2 fibers, and only rare and faint staining for type 1 fibers. In patient muscle, there was no sarcolemmal staining of type 2 fibers. Electron microscopic studies of patient muscle showed empty spaces between the sarcolemma and the contractile elements of the sarcomere, separation of membranes, loss of myofibrillar organization in some areas, and misalignment of the Z lines. These findings suggested that isoform 1f is a sarcolemma-associated protein with a specific role in skeletal muscle, and that lack of this isoform results in disruption of the myofiber without affecting other tissues.
In 2 unrelated African American patients with epidermolysis bullosa simplex and muscular dystrophy (EBS5B; 226670) with myasthenic features, 1 of whom was previously reported by Banwell et al. (1999), Selcen et al. (2011) identified compound heterozygosity for 2 mutations in the PLEC1 gene: both patients carried a 1-bp duplication (12043dupG) in exon 32, predicted to result in frameshift and premature termination, and another pathogenic PLEC1 mutation. One patient had a 6169C-T transition in exon 31, resulting in a gln2057-to-ter (Q2057X; 601282.0012) substitution, and the other had a 6955C-T transition in exon 31, resulting in an arg2319-to-ter (R2319X; 601282.0013) substitution. Both stop codons abrogated, and the 1-bp duplication disrupted, the IF binding site, a beta-dystroglycan binding site, and an integrin beta-4 binding site.
For discussion of the gln2057-to-ter (Q2057X) mutation in the PLEC1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa simplex and muscular dystrophy (EBS5B; 226670) by Selcen et al. (2011), see 601282.0011.
Epidermolysis Bullosa Simplex 5B, with Muscular Dystrophy
For discussion of the arg2319-to-ter (R2319X) mutation in the PLEC1 gene that was found in compound heterozygous state in a patient with epidermolysis bullosa simplex and muscular dystrophy (EBS5B; 226670) by Selcen et al. (2011), see 601282.0011.
Epidermolysis Bullosa Simplex 5D, Generalized Intermediate, Autosomal Recessive
In a 31-year-old woman with generalized intermediate epidermolysis bullosa simplex and nail dystrophy (EBS5D; 616487), Tu et al. (2020) identified compound heterozygosity for the R2319X mutation in the PLEC gene, and a c.956T-C transition (c.956T-C, NM_000445.5) in exon 9, resulting in a leu319-to-pro (L319P; 601282.0015) substitution. Her unaffected parents were each heterozygous for 1 of the mutations, and an unaffected brother did not carry either mutation. Electron microscopy of a skin biopsy from the proband revealed hypoplastic hemidesmosomes. Immunoblot of cell lysates of HEK293 cells cotransfected with wildtype ITGB4 (147557) and the L319P PLEC mutant showed reduced plectin and beta-4 integrin proteins, suggesting that the misassembled plectin/beta-4 integrin complex enhances protein degradation, resulting in defective hemidesmosome formation.
In 2 Turkish sisters with epidermolysis bullosa simplex and nail dystrophy (EBS5D; 616487), born of consanguineous parents, Gostynska et al. (2015) identified homozygosity for a c.46C-T transition in exon 1a of the PLEC1 gene, resulting in an arg16-to-ter (R16X) substitution present in only the 1a isoform. Quantitative RT-PCR of cultured skin keratinocytes from the sisters showed reduced transcription of 1a compared to controls. Because isoform-1a is not expressed in either striated or cardiac muscle tissue, Gostynska et al. (2015) stated that they did not expect muscular dystrophy or cardiomyopathy to develop in these patients.
For discussion of the c.956T-C transition in exon 9 of the PLEC gene, resulting in a leu319-to-pro (L319P) substitution, that was found in compound heterozygous state in a 31-year-old woman with epidermolysis bullosa simplex and nail dystrophy (EBS5D; 616487) by Tu et al. (2020), see 601282.0013.
In an 18-year-old man with EBS and nail dystrophy, Tu et al. (2020) identified compound heterozygosity for the L319P mutation and a c.2807G-A transition in exon 22 of the PLEC gene, resulting in a trp936-to-ter (W936X; 601282.0016) substitution. His unaffected father was heterozygous for the W936X mutation; DNA was unavailable from his unaffected mother. Electron microscopy of a skin biopsy from the proband revealed hypoplastic hemidesmosomes. Immunoblot of cell lysates of HEK293 cells cotransfected with wildtype ITGB4 (147557) and the L319P PLEC mutant showed reduced plectin and beta-4 integrin proteins, suggesting that the misassembled plectin/beta-4 integrin complex enhances protein degradation, resulting in defective hemidesmosome formation.
For discussion of the c.2807G-A transition (c.2807G-A, NM_000445.5) in exon 22 of the PLEC gene, resulting in a trp936-to-ter (W936X) substitution, that was found in compound heterozygous state in an 18-year-old man with epidermolysis bullosa simplex and nail dystrophy (EBS5D; 616487) by Tu et al. (2020), see 601282.0013.
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