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

Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and DebRA Molecular Diagnostics Laboratory, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Experimental Dermatology (Impact Factor: 3.76). 05/2005; 14(4):241-9. DOI: 10.1111/j.0906-6705.2005.00324.x
Source: PubMed


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.

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    • "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. "
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    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 · Molecular biology of the cell
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    • "Mutations in type XVII alpha 1 collagen (COL17A1), a hemidesmosomal plaque protein required for tight adherence of basal keratinocytes to the basal lamina, account for a subset of patients featuring elements typical of both EBS and EB junctional (Fontao et al., 2004; Pfendner et al., 2005 "
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    ABSTRACT: Epidermolysis bullosa simplex (EBS) is a rare genetic condition typified by superficial bullous lesions following incident frictional trauma to the skin. Most cases of EBS are due to dominantly acting mutations in keratin 14 (K14) or K5, the type I and II intermediate filament (IF) proteins that copolymerize to form a pancytoplasmic network of 10 nm filaments in basal keratinocytes of epidermis and related epithelia. Defects in K5-K14 filament network architecture cause basal keratinocytes to become fragile, and account for their rupture upon exposure to mechanical trauma. The discovery of the etiology and pathophysiology of EBS was intimately linked to the quest for an understanding of the properties and function of keratin filaments in skin epithelia. Since then, continued cross-fertilization between basic science efforts and clinical endeavors has highlighted several additional functional roles for keratin proteins in the skin, suggested new avenues for effective therapies for keratin-based diseases, and expanded our understanding of the remarkable properties of the skin as an organ system.
    Preview · Article · Mar 2012 · Journal of Investigative Dermatology
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    • "Pathogenic mutations usually consist of nonsense mutations, out of frame insertions or deletions within exon 32 or 33 resulting in a premature termination codon of translation. Premature stop codons not located in the last exon are predicted to lead to down-regulation of the corresponding mRNA through nonsense mediated mRNA decay (Pfendner et al., 2005). However, to date there are no clear genotype/phenotype correlations, and the molecular mechanisms of these plectinopathies remain unclear. "
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    ABSTRACT: Plectin is a versatile cytolinker protein critically involved in the organization of the cytoskeletal filamentous system. The muscle-specific intermediate filament (IF) protein desmin, which progressively replaces vimentin during differentiation of myoblasts, is one of the important binding partners of plectin in mature muscle. Defects of either plectin or desmin cause muscular dystrophies. By cell transfection studies, yeast two-hybrid, overlay and pull-down assays for binding analysis, we have characterized the functionally important sequences for the interaction of plectin with desmin and vimentin. The association of plectin with both desmin and vimentin predominantly depended on its fifth plakin repeat domain and downstream linker region. Conversely, the interaction of desmin and vimentin with plectin required sequences contained within the segments 1A-2A of their central coiled-coil rod domain. This study furthers our knowledge of the interaction between plectin and IF proteins important for maintenance of cytoarchitecture in skeletal muscle. Moreover, binding of plectin to the conserved rod domain of IF proteins could well explain its broad interaction with most types of IFs.
    Full-text · Article · Feb 2011 · European journal of cell biology
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