Epidermolysis bullosa simplex with<i>PLEC</i>mutations: new phenotypes and new mutations

Charlesworth, A.; Chiavérini, C.; Chevrant-Breton, J; DelRio, M.; Diociaiuti, Andrea; Dupuis, R. P.; Hachem, May El; Fiblec, Bernard Le; Sankari-Ho, A. M.; Valhquist, Anders; Wierzbicka, E.; Lacour, Jean‐Philippe; Meneguzzi, Guerríno

doi:10.1111/bjd.12202

Cited by 47 publications

(57 citation statements)

References 38 publications

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“…Until now, there are reports of 30 independent cases of EBS-MD, in which the diagnosis was confirmed by identifying the mutation (see Table 1 in Winter and Wiche 2013; and additional cases reported in Charlesworth et al 2013). At the molecular level, EBS-MD is frequently associated with nonsense, insertion, or deletion mutations, resulting in premature stop codons within exon 31, the exon that encodes plectin’s coiled coil rod domain.…”

Section: Plectin In Skinmentioning

confidence: 98%

“…As processing of the rodless variant of plectin remains unaltered by mutations in exon 31 and as the expression of the rodless isoform has been detected in cells of EBS-MD patients (Koster et al 2004; Natsuga et al 2010a, b), it has been postulated that rodless plectin could partially rescue some basic functions of plectin in association with its N- and C-terminal domains. EBS-MD was further found to be caused by several in-frame insertion and deletion mutations in exons located up- or downstream of exon 31 (Charlesworth et al 2013; Winter and Wiche 2013). It is likely that these mutations affect specific protein–protein interactions relevant for the proper functioning of plectin in HDs.…”

Section: Plectin In Skinmentioning

confidence: 99%

“…In general, clinical phenotypes of affected individuals vary considerably with respect to severity of skin blistering. In addition to congenital skin blistering, deformation of the nails and tooth decay were observed in a number of EBS-MD patients, and in some cases, erosive lesions on the oral or laryngeal mucosa, hoarseness, respiratory complications during infancy, and urethral strictures have been reported (Babic et al 2010; Charlesworth et al 2013; Kunz et al 2000; Schara et al 2004). …”

Section: Plectin In Skinmentioning

confidence: 99%

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Plectin–intermediate filament partnership in skin, skeletal muscle, and peripheral nerve

Castañón

Walko

Winter

et al. 2013

Histochem Cell Biol

126

150

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Plectin is a large, 500-kDa, intermediate filament (IF)-associated protein. It acts as a cytoskeletal crosslinker and signaling scaffold, affecting mechanical as well as dynamic properties of the cytoskeleton. As a member of the plakin family of cytolinker proteins, plectin has a multidomain structure that is responsible for its vast binding portfolio. It not only binds to all types of IFs, actin filaments and microtubules, but also to transmembrane receptors, proteins of the subplasma membrane protein skeleton, components of the nuclear envelope, and several kinases with known roles in migration, proliferation, and energy metabolism of cells. Due to alternative splicing, plectin is expressed as various isoforms with differing N-terminal heads that dictate their differential subcellular targeting. Through specific interactions with other proteins at their target sites and their ability to bind to all types of IFs, plectin molecules provide strategically located IF anchorage sites within the cytoplasm of cells. In this review, we will present an overview of the structural features and functional properties of plectin and discuss recent progress in defining the role of its isoforms in stress-prone tissues and the implicated diseases, with focus on skin, skeletal muscle, and Schwann cells of peripheral nerve.

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Section: Plectin In Skinmentioning

confidence: 98%

Section: Plectin In Skinmentioning

confidence: 99%

Section: Plectin In Skinmentioning

confidence: 99%

See 1 more Smart Citation

Plectin–intermediate filament partnership in skin, skeletal muscle, and peripheral nerve

Castañón

Walko

Winter

et al. 2013

Histochem Cell Biol

126

150

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“…PLEC mutations in EBS[2,11,41,45,[69][70][71]. This case harboured adult-onset dilated cardiomyopathy.…”

mentioning

confidence: 87%

“…There is only one reported prenatal diagnosis for one foetus whose sibling suffered from EBS-PA [40]. A few EBS-PA cases survived longer after surgery [23,41]. These cases typically showed mild cutaneous phenotypes resembling EBS-MD, although these cases have not developed MD so far.…”

Section: Ebs-pamentioning

confidence: 99%

Plectin-related skin diseases

Natsuga

2015

Journal of Dermatological Science

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Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants

et al. 2022

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IMPORTANCEEpidermolysis bullosa simplex with muscular dystrophy (EBS-MD) is an autosomal recessive disorder caused by pathogenic variants in PLEC1, which encodes plectin. It is characterized by mild mucocutaneous fragility and blistering and muscle weakness. Translational readthrough-inducing drugs, such as repurposed aminoglycoside antibiotics, may represent a valuable therapeutic alternative for untreatable rare diseases caused by nonsense variants. OBJECTIVE To evaluate whether systemic gentamicin, at a dose of 7.5 mg/kg/d for 14 consecutive days, is clinically beneficial in a patient with EBS-MD. DESIGN, SETTING, AND PARTICIPANTSA single patient in Madrid, Spain, received 2 treatment courses with gentamicin on July 2019 and February 2020 with a follow-up period of 120 and 150 days, respectively. RESULTSIn this case report of a woman in her 30s with EBS-MD, before gentamicin treatment, the patient had mucocutaneous involvement, skeletal and respiratory muscle weakness, and myalgia that negatively affected her quality of life. Outcomes were evaluated with extensive laboratory tests and clinical scales. No nephrotoxic or ototoxic effects were detected after intravenous gentamicin administration. Gentamicin treatment was followed by plectin expression in the skin for at least 5 months. Although minimal changes were noted in skeletal muscle function (as measured by the Hammersmith functional motor scale and its expanded version: 6/40 to 7/40 and from 10/66 to 11/66, respectively) and respiratory musculature (maximal inspiratory and expiratory pressures D0 vs D16, MIP: 2.86 vs 3.63 KPa and MEP: 2.93 vs 4.63 KPa), myalgia disappeared (VAS dropped from 6 to 0), and quality of life improved (EuroQoL-5D-3L pain and anxiety dropped from 2 to 1). CONCLUSIONS AND RELEVANCEThe findings of this single case report suggest that gentamicin treatment may help suppress PLEC1 premature termination codons and induce plectin expression in EBS-MD primary keratinocytes and skin. Our study suggests that gentamicin may play an important role in treating EBS-MD owing to nonsense variants.

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Epidermolysis bullosa simplex withPLECmutations: new phenotypes and new mutations

Cited by 47 publications

References 38 publications

Plectin–intermediate filament partnership in skin, skeletal muscle, and peripheral nerve

Plectin–intermediate filament partnership in skin, skeletal muscle, and peripheral nerve

Plectin-related skin diseases

Evaluation of Systemic Gentamicin as Translational Readthrough Therapy for a Patient With Epidermolysis Bullosa Simplex With Muscular Dystrophy Owing to PLEC1 Pathogenic Nonsense Variants

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