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A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.

ABSTRACT: Plectin is a widely expressed cytomatrix component involved in the attachment of the cytoskeleton to the plasma membrane. We have recently reported that the skin and muscles of three patients affected by epidermolysis bullosa simplex with muscular dystrophy (MD-EBS), a genetic disorder characterized by skin blistering associated with muscle involvement, are not reactive with antibodies specific to plectin. We demonstrated that in the skin, lack of plectin leads to failure of keratin filaments to connect to the plasma membrane via the hemidesmosomes, whereas in the muscle the deficient expression of the molecule correlates with an aberrant localization of desmin in the muscle fibers. In this study we demonstrate that in a MD-EBS kindred with two affected members, the disease results from a homozygous nonsense mutation in the plectin (PLEC1) gene leading to a premature stop codon (CGA to TGA) and decay of the aberrant plectin messenger RNA. The segregation of the mutated allele implicates the mutation in the pathology of the disorder. These results confirm the critical role of plectin in providing cell resistance to mechanical stresses both in the skin and the muscle.

SUBMITTER: Chavanas S

PROVIDER: S-EPMC507667 | biostudies-other | 1996 Nov

REPOSITORIES: biostudies-other

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A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.

Chavanas S S Pulkkinen L L Gache Y Y Smith F J FJ McLean W H WH Uitto J J Ortonne J P JP Meneguzzi G G

The Journal of clinical investigation 19961101 10

Plectin is a widely expressed cytomatrix component involved in the attachment of the cytoskeleton to the plasma membrane. We have recently reported that the skin and muscles of three patients affected by epidermolysis bullosa simplex with muscular dystrophy (MD-EBS), a genetic disorder characterized by skin blistering associated with muscle involvement, are not reactive with antibodies specific to plectin. We demonstrated that in the skin, lack of plectin leads to failure of keratin filaments to ...[more]

PMID: 8941634

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Project description: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.ObjectiveTo 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.

Dataset Information

A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.

Publications

A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.

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