A missense mutation (G1506E) in the adhesion G domain of laminin-5 causes mild junctional epidermolysis bullosa

Maria Scaturro, Patrizia Posteraro, Alessandro Mastrogiacomo, Maria Letizia Zaccaria, Naomi De Luca, Cinzia Mazzanti, Giovanna Zambruno, Daniele Castiglia

Research output: Contribution to journalArticle

Abstract

Laminin-5 is the major adhesion ligand for epithelial cells. Mutations in the genes encoding laminin-5 cause junctional epidermolysis bullosa (JEB), a recessive inherited disease characterized by extensive epithelial-mesenchymal disadhesion. We describe a JEB patient compound heterozygote for two novel mutations in the gene (LAMA3) encoding the laminin α3 chain. The maternal mutation (1644delG) generates mRNA transcripts that undergo nonsense-mediated decay. The paternal mutation results in the Gly1506→Glu substitution (G1506E) within the C-terminal globular region of the α3 chain (G domain). Mutation G1506E affects the proper folding of the fourth module of the G domain and results in the retention of most of the mutated polypeptide within the endoplasmic reticulum (ER). However, scant amounts of the mutated laminin-5 are secreted, undergo physiologic extracellular maturation, and correctly localize within the cutaneous basement membrane zone in patient's skin. Our findings represent the first demonstration of an ER-retained mutant laminin-5 leading to a mild JEB phenotype.

Original languageEnglish
Pages (from-to)96-103
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume309
Issue number1
DOIs
Publication statusPublished - Sep 12 2003

Keywords

  • Inherited blistering skin diseases
  • LAMA3
  • LG module
  • Mutation
  • Protein folding

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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