Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy.
In a distinct autosomal recessive variant of epidermolysis bullosa, EB-MD, life-long skin blistering is associated with late-onset muscular dystrophy of unknown etiology. Electron microscopy of these patients' skin suggests that tissue separation occurs intracellularly at the level of the hemidesmosomal inner plaque, which contains plectin, a high molecular weight cytoskeletal associated protein, also expressed in the sarcolemma of the muscle. In this study, we report two patients with EB-MD, each with a homozygous deletion mutation in the plectin gene, PLEC1. In the first case, the proband and her similarly affected sister had a homozygous 9 bp deletion mutation, designated as 2719de19, which resulted in elimination of three amino acids, QEA, in a sequence of 23 amino acids entirely conserved between the mouse and human sequences. The proband in the second family demonstrated a single nucleotide deletion at position 5866, designated as 5866delC, which resulted in frameshift and a premature termination codon for translation 16 bp downstream from the site of deletion. The absence of plectin in the hemidesmosomes, as reflected by negative immunofluorescence with an anti-plectin antibody (HD-1), associated with fragility of basal keratinocytes, implicates plectin as critical for binding of intermediate keratin filament network to hemidesmosomal complexes. The function of plectin as a putative attachment protein also in the muscle would explain the clinical phenotype consisting of cutaneous fragility and muscular dystrophy in EB-MD.
Pulkkinen
L
L
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA 19107-5541, USA.
Smith
F J
FJ
Shimizu
H
H
Murata
S
S
Yaoita
H
H
Hachisuka
H
H
Nishikawa
T
T
McLean
W H
WH
Uitto
J
J
D000818:Animals; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics*; D010375:Pedigree; D051190:Plectin
D007381:Intermediate Filament Proteins; C495332:PLEC protein, human; C495333:Plec protein, mouse; D051190:Plectin