title: Inherited junctional epidermolysis bullosa in the German Pointer: establishment of a large animal model.
abstract: Junctional epidermolysis bullosa (JEB) is a genodermatosis suitable for gene therapy because conventional treatments are ineffective. Here, we elucidate the genetic basis of mild JEB in a breed of dogs that display all the clinical traits observed in JEB patients. The condition is associated with reduced expression of laminin 5 caused by a homozygous insertion (4818+207ins6.5 kb) of repetitive satellite DNA within intron 35 of the gene (lama3) for the laminin alpha3 chain. The intronic mutation interferes with maturation of the alpha3 pre-messenger RNA resulting in the coexpression of a transcript with a 227 nucleotide insertion and a wild-type mRNA that encodes scant amounts of the alpha3 polypeptide. Our results show that the amino acid sequence and structure of the canine and human alpha3 chain are highly conserved and that the reduced expression of laminin 5 affects the adhesion and clonogenic potential of the JEB keratinocytes. These JEB dogs provide the opportunity to perform gene delivery in a naturally occurring genodermatosis and to evaluate host tolerance to recombinant laminin 5.
authors.affiliation: INSERM U634, Faculty of Medicine, University Hospital, Nice Cedex, France.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Capt
authors.forename: Flavia
authors.initials: F
authors.lastname: Spirito
authors.forename: Eric
authors.initials: E
authors.lastname: Guaguere
authors.forename: Anne
authors.initials: A
authors.lastname: Spadafora
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Ortonne
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
mesh_terms: D000818:Animals; D001483:Base Sequence; D001706:Biopsy; D001768:Blister / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D015815:Cell Adhesion Molecules / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005091:Exons / Q000235:genetics; D007365:Intercellular Junctions / Q000473:pathology; D007438:Introns / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology; D010375:Pedigree; D012333:RNA, Messenger / Q000032:analysis; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D012333:RNA, Messenger; D000097794:Kalinin