1. INSERM U385, Faculty of Medicine, University of Nice-Sophia Antipolis, France
2. ^*Department of Internal Medicine, Tawam Hospital, Al Ain, United Arab Emirates

Correspondence: Guerrino Meneguzzi, INSERM U385, U.F.R. de Médecine, Avenue de Valombrose, 06107 Nice Cedex 2, France. Email: meneguzz@unice.fr

¹Present address: Gilles Lestringant, Consultant Dermatologist, British Forces in Germany Health Service, BFPO 39 (Germany).

^†Equally contributed to this work.

Received 20 March 2003; Revised 5 May 2003; Accepted 20 May 2003; Published online 8 December 2003.

Abstract

Genetic mutations in 64 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 6 or 4 subunit causing rapid decay of the mutated transcript and absence of 64 integrin. In this study, we disclose the genetic background of lethal junctional epidermolysis bullosa with pyloric atresia in a patient presenting absent expression of 6 integrin despite normal steady-state level of the 64 mRNA. Screening for mutation in the 6 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 -strand of the seven-bladed -propeller structure of the extracellular head of 6 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 -propeller domain conserved among the integrin cell receptors.