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 α3 chain. The intronic mutation interferes with maturation of the α3 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 α3 polypeptide. Our results show that the amino acid sequence and structure of the canine and human α 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. Copyright © 2005 by The Society for Investigative Dermatology, Inc.