Possible Involvement of Exon 31 Alternative Splicing in Phenotype and Severity of Epidermolysis Bullosa Caused by Mutations in PLEC1

Sawamura, Daisuke; Goto, Maki; Sakai, Kaori; Nakamura, Hideki; McMillan, James R.; Akiyama, Masashi; Shirado, Osamu; Oyama, Noritaka; Satoh, Masataka; Kaneko, Fumio; Takahashi, Toshiaki; Konno, Hidehiko; Shimizu, Hiroshi

doi:10.1038/sj.jid.5700707

Cited by 21 publications

(32 citation statements)

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“…PLEC1 mutations in four EBS-MD and three EBS-PA cases were previously described in the literature [Kunz et al, 2000;Nakamura et al, 2005;Pulkkinen et al, 1996;Sawamura et al, 2007;Takizawa et al, 1999]. Patients EBS-MD1 and EBS-MD5 were newly identified cases in the present study.…”

Section: Patients and Mutation Detectionmentioning

confidence: 83%

“…Similarly, junctional EB with pyloric atresia (JEB-PA) has been known to be caused by the mutation in the gene encoding a6/b4 integrin (ITGA6; MIM] 147556; ITGB4; MIM] 147557), and about 60 ITGA6 or ITGB4 mutations have been described [Fine et al, 2008;Varki et al, 2006]. Recently, our group and others identified PLEC1 mutations in eight patients with EBS-PA [Nakamura et al, 2005;Sawamura et al, 2007]. EBS-MD and EBS-PA represent distinct clinical phenotypes, although both are caused by PLEC1 mutations.…”

Section: Introductionmentioning

confidence: 95%

“…To date, more than 30 EBS-MD patients have been reported to have PLEC1 mutations [Bauer et al, 2001;Chavanas et al, 1996;Dang et al, 1998;Koss-Harnes et al, 2004;Kunz et al, 2000;McMillan et al, 2007;Mellerio et al, 1997;Pulkkinen et al, 1996;Rouan et al, 2000;Sawamura et al, 2007;Takahashi et al, 2005;Takizawa et al, 1999]. Most reported PLEC1 mutations in EBS-MD patients are located within exon 31 encoding the large rod domain of plectin Sawamura et al, 2007]. In contrast to the phenotype seen in EBS-MD, clinical manifestations of EBS-PA are more severe and are characterized by more generalized blistering and pyloric atresia, which frequently leads to early death in affected patients.…”

Section: Introductionmentioning

confidence: 97%

“…EBS-MD and EBS-PA represent distinct clinical phenotypes, although both are caused by PLEC1 mutations. The exact mechanisms that produce the clinical differences between EBS-MD and EBS-PA subtypes have not been elucidated, although it has been postulated that the severity of EBS patients with PLEC1 mutations could be associated with alternative splicing of plectin [Sawamura et al, 2007;Sonnenberg and Liem, 2007].…”

Section: Introductionmentioning

confidence: 98%

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Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex

et al. 2010

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Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.

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Section: Patients and Mutation Detectionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

See 2 more Smart Citations

Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex

et al. 2010

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“…Une forme létale de l'EBS due aux mutations de la plectine a été récemment détectée. Elle se caractérise par une atrésie pylorique qui s'ajoute à la formation des ampoules cutanées (Pfendner and Uitto, 2005;Sawamura et al, 2007).…”

Section: Différents Types D'épidermolyses Bulleuses Héréditairesunclassified

Impact de l'interféron gamma sur la production de la kératine 15 dans les kératinocytes isolés de la peau de patients atteints d'épidermolyse bulleuse simplex /

Farez¹

2013

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Clinical heterogeneity in epidermolysis bullosa simplex with plectin (PLEC) mutations—A study of six unrelated families from India

Vishwanathan

Srinivasa

Batrani³

et al. 2022

American J of Med Genetics Pt A

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Epidermolysis bullosa simplex (EBS) with plectin mutations is a very rare subtype of EB usually associated with pyloric atresia (PA) or muscular dystrophy (MD). We report six unrelated children between ages 4 and 14 years from India with varied clinical manifestations. Only one had PA, and none has developed MD to date. All except the one with PA presented with early onset blistering along with laryngeal involvement in the form of hoarseness of voice and nail involvement. Patient with PA presented with aplasia cutis and died in the first week. Two patients had predominantly respiratory and gastrointestinal involvement with varying severity while two had features of myasthenic syndrome but no limb-girdle involvement and one patient phenocopied laryngo-onycho-cutaneous (LOC) syndrome. Using whole-exome sequencing, we identified novel mutations in PLEC. Histopathological analysis (Immunofluorescence antigen mapping) showed absence of staining to plectin antibodies. Our observations propose to append a phenotype of EBS, hoarseness of voice and nail dystrophy or LOC-like phenotype with plectin mutations. Long-term follow up is necessary to monitor for the development of muscular dystrophy. K E Y W O R D S antigen mapping, EBS, intermediate filaments, muscular dystrophy, plectin 1 | BACKGROUND Epidermolysis bullosa (EB) is a heterogeneous group of rare, inherited blistering disorders characterized by spontaneous or trauma-induced blisters on the skin and mucous membrane. There are four major types, EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB, with numerous subtypes (Has et al., 2020). Extracutaneous manifestations are typically observed in JEB and DEB.

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Possible Involvement of Exon 31 Alternative Splicing in Phenotype and Severity of Epidermolysis Bullosa Caused by Mutations in PLEC1

Abstract: Colocalization of susceptibility loci for psoriasis (PSORS4) and atopic dermatitis (ATOD2) on human chromosome 1q21. Hum Hered

Cited by 21 publications

References 17 publications

Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex

Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex

Impact de l'interféron gamma sur la production de la kératine 15 dans les kératinocytes isolés de la peau de patients atteints d'épidermolyse bulleuse simplex /

Clinical heterogeneity in epidermolysis bullosa simplex with plectin (PLEC) mutations—A study of six unrelated families from India

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