Pfendner E, Rouan F, Uitto JProgress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. Exp Dermatol 14:241-249

ArticleinExperimental Dermatology 14(4):241-9 · May 2005with12 Reads
DOI: 10.1111/j.0906-6705.2005.00324.x · Source: PubMed
Abstract
Plectin, a large multidomain adhesive protein with versatile binding functions, is expressed in a number of tissues and cell types. In the skin, plectin is a critical component of hemidesmosomes, interacting with keratin intermediate filaments and beta4 integrin. Mutations in the plectin gene (PLEC1) result in fragility of skin, demonstrating blister formation at the level of hemidesmosomes. These blistering disorders belong to the spectrum of epidermolysis bullosa (EB) phenotypes, and three distinct variants because of plectin mutations have been identified. First, EB with muscular dystrophy, an autosomal recessive syndrome, is frequently caused by premature termination codon-causing mutations leading to the absence of plectin both in the skin and in the muscle. Second, a heterozygous missense mutation (R2110W) in PLEC1 has been documented in patients with EB simplex of the Ogna type, a rare autosomal dominant disorder. Finally, recent studies have disclosed plectin mutations in patients with EB with pyloric atresia, an autosomal recessive syndrome, frequently with lethal consequences. Collectively, these observations attest to the phenotypic spectrum of plectin mutations, and provide the basis for accurate genetic counselling with prognostic implications, as well as for prenatal diagnosis in families at the risk of recurrence of the disease.
    • "Nevertheless,ifrodlessplectinisexpressedtoahigherlevelthan full-lengthplectin,thismaybeanimportantfactorcontributingto theefficiencybywhichthisproteinfunctionallycompensatesforthe lossoffull-lengthplectinintherodlessplectinmice. Giventhattheexpressionlevelofrodlessplectinappearstobe themaindiscriminatingfactorbetweenEBS-MDpatientsandour mousemodel,itistemptingtospeculatethatanincreaseintheex- pressionlevelofrodlessplectincouldalleviatethesymptomsofEBS- MDpatients.ThevastmajorityofEBS-MD–causingmutationsare foundinexon31encodingtheroddomain(Pfendneretal.,2005). Thesemutationsultimatelyresultinnonsense-mediateddecayof rod-containingplectintranscripts.Incontrast,rodlessplectintranscriptsaremaintainedasthesiteofmutationissplicedout .Ifsplicing ofexon31couldbestimulated,morerodlessplectintranscriptscould beformed,resultinginanincreaseinthelevelofrodlessplectinprotein .Similarso-calledexon-skippingstrategiesarebeingdeveloped fortreatmentofneuromusculardiseases(Touzniketal.,2014).Itwill beinterestingtoseewhethersuchstrategiescanbeadaptedtothe treatmentofEBS-MDpatientswithmutationsinexon31. "
    [Show abstract] [Hide abstract] ABSTRACT: Epidermolysis bullosa simplex associated with late-onset muscular dystrophy (EBS-MD) is an autosomal recessive disorder resulting from mutations in the plectin gene. The majority of these mutations occur within the large exon 31 encoding the central rod domain and leave the production of a low-level rodless plectin splice variant unaffected. To investigate the function of the rod domain, we have generated rodless plectin mice through conditional deletion of exon 31. Rodless plectin mice develop normally without signs of skin blistering or muscular dystrophy. Plectin localization and hemidesmosome organization are unaffected in rodless plectin mice. However, super-resolution microscopy revealed a closer juxtaposition of the C-terminus of plectin to the integrin β4 subunit in rodless plectin keratinocytes. Wound healing occurred slightly faster in rodless plectin mice than in wild-type mice, and keratinocytes migration was increased in the absence of the rod domain. The faster migration of rodless plectin keratinocytes is not due to altered biochemical properties, as like full-length plectin, rodless plectin is a dimeric protein. Our data demonstrates that rodless plectin can functionally compensate for the loss of full-length plectin in mice. Thus, the low expression level of plectin rather than the absence of the rod domain dictates the development of EBS-MD. © 2015 by The American Society for Cell Biology.
    Full-text · Article · May 2015
    • "In humans, plectin gene mutations lead to different variants of epidermolysis bullosa simplex (EBS), comprising EBS with muscular dystrophy (EBS-MD), EBS with pyloric atresia, EBS with myasthenic syndrome, and EBS-Ogna, as well as limb-girdle muscular dystrophy type 2Q (MGMD2Q) (Rezniczek et al., 2010; Winter and Wiche, 2012 ). For EBS- MD, the most common form of the disease, the symptoms include severe skin blistering, late onset muscular dystrophy, and in some cases cardiomyopathy, as well as cerebral and cerebellar atrophies (Pfendner et al., 2005; Schr€ oder et al., 2002; Smith et al., 1996). Intriguingly, in one EBS-MD patient, degenerative signs were also found in intramuscular myelinated nerves (Bauer et al., 2001). "
    [Show abstract] [Hide abstract] ABSTRACT: Previous studies have unmasked plectin, a uniquely versatile intermediate filament-associated cytolinker protein, to be essential for skin and skeletal muscle integrity. Different sets of isoforms of the protein were found to stabilize cells mechanically, regulate cytoskeletal dynamics, and serve as a scaffolding platform for signaling molecules. Here, we investigated whether a similar scenario prevails in myelinating Schwann cells. Using isoform-specific antibodies, the two plectin variants predominantly expressed in the cytoplasmic compartment (Cajal bands) of Schwann cells were identified as plectin (P)1 and P1c. Coimmunoprecipitation and immunolocalization experiments revealed complex formation of Cajal band plectin with β-dystroglycan, the core component of the dystrophin glycoprotein complex that in Schwann cells is crucial for the compartmentalization and stabilization of the myelin sheath. To study the functional implications of Schwann cell-specific plectin-β-dystroglycan interaction, we generated conditional (Schwann cell-restricted) plectin knockout mice. Ablation of plectin in myelinating Schwann cells (SCs) was found not to affect myelin sheath formation but to abrogate the tight association of the dystroglycan complex with the intermediate filament cytoskeleton. We show that the disruption of this association leads to the destabilization of the dystroglycan complex combined with increased myelin sheath deformations observed in the peripheral nerve during ageing of the animal.
    Full-text · Article · Aug 2013
    • "EBS has been associated with mutations in at least eight distinct genes (Intong and Murrell, 2012). Although the very rare forms of superficial EBS have been associated with mutations in PKP1 and DSP encoding plakophilin 1 and desmoplakin (Jonkman et al., 2005; McGrath and Mellerio, 2010), the more common type of EBS is usually due to mutations in KRT5 and KRT14 encoding basal cell keratins (Sprecher, 2010), although it is occasionally caused by mutations in other genes including PLEC1, ITGA6, ITGB4, and DST (Jonkman et al., 2002; Pfendner et al., 2005a; Groves et al., 2010). K5 and K14 assemble into 10-nm keratin intermediate filaments that underlie the formation of the cytoskeleton of epithelial cells (Candi et al., 2005). "
    [Show abstract] [Hide abstract] ABSTRACT: Abbreviations: cDNA, complementary DNA; EB, epidermolysis bullosa; EBS, EB simplex
    Article · Jul 2012
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