A novel nonsense mutation at E106 of the 2B rod domain of keratin 14 causes dominant epidermolysis bullosa simplex.
Epidermolysis bullosa simplex (EBS) is classified into three main types and is caused, in most cases, by missense mutations in the genes encoding keratin (K) 5 and K14. In this study, we clinically, ultrastructurally, immunohistochemically, and molecularly studied a patient with a dominant EBS, Köbner type. Using sequence analysis of genomic DNA, a novel K14 nonsense mutation was identified. A heterozygous mutation G1231T of KRT14 was found to be associated with the disease in the patient. The mutation created a premature stop codon (amino acid codon 411, residue 106 of the 2B helix) in the K14 molecule. This residue lies in a highly conserved region and was recently found to be absolutely required for molecular stability and intermediate filament assembly in K5 and K14. The E411X (E106X) heterozygous ablation, missing the last 16 amino acid residues of the 2B and the entire tail domain of K14, led to disease but did not result in clumping of keratin filaments. It is the first premature stop codon mutation of K14 found in dominant EBS.
Gu
Li-Hong
LH
Department of Dermatology, Gifu University, School of Medicine, Japan.
Ichiki
Yoshiro
Y
Sato
Miki
M
Kitajima
Yasuo
Y
D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D016110:Epidermolysis Bullosa Simplex / Q000235:genetics* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D053547:Keratin-14; D053555:Keratin-5; D007633:Keratins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012867:Skin / Q000473:pathology
D018389:Codon, Nonsense; C507540:KRT14 protein, human; C503940:KRT5 protein, human; D053547:Keratin-14; D053555:Keratin-5; D007633:Keratins