Leiden Muscular Dystrophy pages

Plectin  (PLEC)

(last modified February 4, 2011)

generated with the help of the Hogeschool Leiden, in particular students Daan van Luijk en Tavares Chin Sue 


Contents



Summary


Plectin (PLEC) was first described by (Pytela and Wiche 1980), as 500 KDa protein that is found in almost all mammalian cells. With 500 KDa, it is one of largest polypeptides known. The protein is identified as a major component of intermediate filaments. It acts as a link between the actin microfilaments, microtubules and intermediate filaments (Liu et al. 1996). Plectin plays an important role in maintaining the mechanical integrity and visco-elastic properties of tissues.
Liu et al. (1996) first reported the cloning of the rat plectine gene by screening a placenta cDNA library with previously published human plectin probes (Wiche 1991) and probes derived from rat plectin. The deduced protein sequences for human and rat plectin are 93% identical. The human plectin gene contains 33 exons that extend over 60 Kb genomic DNA, mapped to 8q24 (Liu et al. 1996). Most of the introns reside within a region encoding the globular N-terminal domain of the molecule. The entire central-rod and C-terminal globular domains are encoded by single large exons of more than 3 kb and 6 kb, respectively.
Variants in the PLEC gene have been found in combination with several genetic diseases. Smith et al. (1996) first identified a duplication mutation in the plectin-gene, in a patient with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD, OMIM 226670). Koss-Harnes et al. (2002) described a point mutation in the gene in a family with autosomal dominant epidermolysis bullosa simplex Ogna type (EBS-OG, OMIM 131950). Finally, Charlesworth et al. (2003) found point mutations and deletions in patients with epidermolysis bullosa simplex with pyloric atresia (EBS-PA, OMIM 612138).


The PLEC gene


Links to other databases:
Gene Symbol nomenclature   EntrezGene    OMIM Gene Map

The plectin gene (Gene symbol PLEC, aliases EBS1, PLEC1, PCN, PLTN) maps to chromosome 8q24 (Liu et al. 1996), is transcribed from telomere to centromere and is flanked by EPPK1 (centromeric) and  PARP10 (telomeric), both in the same transcriptional orientation. The gene measures ~60 Kb and contains 33 exons. The gene contains 7 alternative promoters/exon 01 in intron 2, generating a range of different transcripts. Most of the introns reside within a region encoding the globular N-terminal domain of the molecule. The entire central-rod and C-terminal globular domains are encoded by single large exons of more than 3 kb and 6 kb, respectively. Overall, the organization of the human plectin gene is strikingly similar to that of human dystonin gene (bullous pemphigoid antigen-1, DST).

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. The plectin gene locus in mouse has been analyzed in detail (Fuchs et al. (1999), Rezniczek et al. [2003]), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and, like in human, an unusual 5' transcript complexity of plectin transcript/N-terminal 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). 

Exon Exon size
(in bp)
Intron size
(in bp)
5' cDNA position (in bp) Splice
after
Remarks
1431327-49-5' UTR
219936484-615' UTR, alternative translation initiation site GNE isoforms 3, translation initiation site GNE isoforms 1
01h    alternative promoters/first exon 01h, 5' UTR, alternative translation initiation site
01g    alternative promoters/first exon 01g, 5' UTR, alternative translation initiation site
01f    alternative promoters/first exon 01f, 5' UTR, alternative translation initiation site
01e    alternative promoters/first exon 01e, 5' UTR, alternative translation initiation site
01d    alternative promoters/first exon 01d, 5' UTR, alternative translation initiation site
01c    alternative promoters/first exon 01c, 5' UTR, alternative translation initiation site
01b    alternative promoters/first exon 01b, 5' UTR, alternative translation initiation site
3623901943
4909082563
578933463
6939644243
71675345172
8116806841
9107818003
10120799073
119618910273
1212822611232
139464612513
141558513452
153198015003
16787318193
1716216518973
181059720593
199627721643
2012699722603
211538523863
221558125392
2312710626943
241847428211
2515813230053
26179111031632
271398733423
283577434813
298417038383
301059439223
319989940273
32338110841263
337243 - 7507-translation stop codon, 3'UTR

Legend:
Exon: numbering of exons with the first base of the Met-codon counted as position 1 (see coding DNA Reference Sequence). Exon size: size of exon indicated in basepairs (bp). Intron size: size of intron indicated in basepairs. 5' cDNA position: first base of the exon. Splice after: splicing occurs in between of two coding triplets (0), after the first (1) or the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated region, 3'UTR = 3' untranslated region.

primers for DNA-amplification


The PLEC mRNA


Links to other databases: UniGene: Hs.434248   RefSeq: NM_000445.3

Due to the use of 8 different promoter/first exons, 7 located in intron 2, the PLEC generates a range of transcript variants (see coding DNA Reference Sequence). Transcripts lacking exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759).

By RT-PCR Kazerounian et al. (2002) found that plectin was expressed in all adult and fetal tissues examined, except leukocytes. Only a weak band was obtained from adult brain and thymus.

primers for RNA-amplification


The PLEC protein


Links to other databases: RefSeq: NP_000436.2  UniProt: Q15149

The plectin protein is one of the largest proteins known. Consisting of between 4515 and 4684 amino acids it has a predicted weight of 518-kD. At the N-terminus the protein contains an actin-binding domain homologous to that of the dystrophin family. At its C-terminus plectin shows homology to intermediate filament-associated protein desmoplakin (DSP).

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 have been shown to direct the targeting of the protein isoforms to distinct subcellular locations (Rezniczek et al. 2003).

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.

Similarity to other proteins

Multiple protein sequence alignment for PLEC

PLEC function

PLEC antibodies


PLEC and disease: EBS-MD, EBS-OG and EBS-PA


Links to other databases:   OMIM: 226670, 131950 and 612138

Disease-causing variants in the PLEC gene have been identified in patients with various types of the epidermolysis bullosa simplex (EBS). The three types of EBS were plectin plays a role are; EBS with Muscular Dystrophy (EBS-MD), EBS Ogna Type (EBS-OG) and EBS with Pyloric Atresia (EBS-PA). 

Epidermolysis Bullosa Simplex with Muscular Dystrophy (EBS-MD)

Smith et al. (1996) were the first to describe pathogenic changes in the plectin gene. In a patient with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD, OMIM 226670) they found a homozygous 8-bp duplication mutation (insertion of the sequence GTGGAGGA) leading to a frame shift on protein level.

Epidermolysis Bullosa Simplex, Ogna type (EBS-OG)

In the original Norwegian family with autosomal dominant epidermolysis bullosa simplex Ogna type (EBS-OG, OMIM 131950) reported by Gedde-Dahl (1971), Koss-Harnes et al. (2002) reported a heterozygous C-to-T substiturion in exon 31 of the PLEC1 gene predicted to result in an Arg2110Trp change.

Epidermolysis Bullosa Simplex with Pyloric Atresia (EBS-PA)

In 3 sisters with epidermolysis bullosa simplex with pyloric atresia, Charlesworth et al. (2003) identified a homozygous 14-bp deletion at nucleotide 2727 in the PLEC gene.

PLEC sequence variations - mutations and polymorphisms

Animal models

Andra et al. (1997) iinactivated the plectin gene in mice, revealing an essential function in maintaining the integrity of skin, muscle, and heart cytro-architecture. Targeted mutations result in neanatal death, skin blistering, impaired myofibril integrity, reduced hemidesmosome number and disintegrateion of intercalated disks in the heart. Mice lacking isoform- 1 are viable with no skin blistering but leukocyte recruitment to wounds is impaired.


Miscellaneous




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