PLEC – Epidermolysis bullosa simplex with muscular dystrophy

Plectin, encoded by PLEC (HGNC:9069), is a large cytoskeletal linker protein critical for the mechanical integrity of skin and skeletal muscle. Biallelic PLEC mutations cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), characterized by neonatal skin blistering and late-onset progressive muscle weakness alongside variable myopathy features.

Multiple case reports and series describe at least 11 unrelated EBS-MD probands harboring homozygous or compound heterozygous PLEC loss-of-function and frameshift variants ([PMID:12071635],[PMID:14675180],[PMID:14963703],[PMID:25209331],[PMID:29352809],[PMID:25454730],[PMID:27121971]). Segregation analysis in a consanguineous family with three affected siblings confirms autosomal recessive inheritance ([PMID:14675180]).

The variant spectrum in EBS-MD is dominated by premature termination codons and frameshift mutations, often clustering in exon 31 encoding the plectin rod domain. Representative alleles include c.7159G>T (p.Glu2387Ter) leading to loss of full-length plectin expression.

Patient muscle tissue analyses reveal complete absence or marked reduction of plectin, severe disorganization of the desmin intermediate filament cytoskeleton, desmin-positive aggregate formation, and mitochondrial abnormalities including respiratory chain dysfunction and altered organelle distribution ([PMID:12071635],[PMID:27121971]).

Mouse and cellular models mirror human pathology: conditional PLEC knockouts and isoform-specific rescues demonstrate that plectin deficiency triggers desmin network collapse, myofibrillar degeneration, and mitochondrial defects, highlighting loss-of-function as the primary disease mechanism.

Collectively, the robust genetic and experimental concordance supports a Strong gene-disease association for PLEC and EBS-MD. Genetic testing for PLEC LoF variants enables definitive diagnosis, informs prognosis, and guides multidisciplinary management of skin and muscle complications.

References

• Journal of neuropathology and experimental neurology • 2002 • Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. PMID:12071635
• The Journal of investigative dermatology • 2003 • Identification of a lethal form of epidermolysis bullosa simplex associated with a homozygous genetic mutation in plectin. PMID:14675180
• European journal of pediatrics • 2004 • Severe mucous membrane involvement in epidermolysis bullosa simplex with muscular dystrophy due to a novel plectin gene mutation. PMID:14963703
• International journal of dermatology • 2015 • Compound heterozygous PLEC mutations in a patient of consanguineous parentage with epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia. PMID:25209331
• BMC dermatology • 2018 • A novel PLEC nonsense homozygous mutation (c.7159G>T; p.Glu2387) causes epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia: a case report.* PMID:29352809
• Neuromuscular disorders : NMD • 2015 • Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation. PMID:25454730
• Acta neuropathologica communications • 2016 • Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy. PMID:27121971

Evidence Based Scoring (AI generated)