title: Rapid decay of alpha6 integrin caused by a mis-sense mutation in the propeller domain results in severe junctional epidermolysis bullosa with pyloric atresia.
abstract: Genetic mutations in alpha6beta4 integrin cause junctional epidermolysis bullosa with pyloric atresia, a genodermatosis characterized by blistering of the skin and pyloric occlusion. The lethal form of junctional epidermolysis bullosa with pyloric atresia has been mainly associated with the presence of premature termination codons in the mRNA encoding either the alpha6 or beta4 subunit causing rapid decay of the mutated transcript and absence of alpha6beta4 integrin. In this study, we disclose the genetic background of lethal junctional epidermolysis bullosa with pyloric atresia in a patient presenting absent expression of alpha6 integrin despite normal steady-state level of the alpha6beta4 mRNA. Screening for mutation in the alpha6 gene detected a homozygous base pair substitution (286 C-to-T), which results in the substitution of a serine with a leucine residue (S47L). The amino acid substitution S47L localizes in the first beta-strand of the seven-bladed beta-propeller structure of the extracellular head of alpha6 integrin, and triggers a rapid proteolysis of the aberrant polypeptides involving the lysosomal degradation pathway. This study provides new insight into the pathogenic effect of a mis-sense mutation affecting a functional domain of a protein, and identifies a critical peptide sequence of the beta-propeller domain conserved among the alpha integrin cell receptors.
authors.affiliation: INSERM U385, Faculty of Medicine, University of Nice-Sophia Antipolis, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Allegra
authors.forename: Laurent
authors.initials: L
authors.lastname: Gagnoux-Palacios
authors.forename: Yannick
authors.initials: Y
authors.lastname: Gache
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roques
authors.forename: Gilles
authors.initials: G
authors.lastname: Lestringant
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Ortonne
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D018076:DNA, Complementary; D000078404:Epidermal Cells; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D006801:Humans; D007231:Infant, Newborn; D039503:Integrin alpha6 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D039663:Integrin beta4 / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology / Q000502:physiology; D008024:Ligands; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011708:Pylorus / Q000002:abnormalities*; D012720:Severity of Illness Index
chemical_list: D018076:DNA, Complementary; D039503:Integrin alpha6; D039663:Integrin beta4; D008024:Ligands