title: A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency.
abstract: Canine leukocyte adhesion deficiency (CLAD) is a fatal immunodeficiency disease found in Irish setters. The clinical manifestations of CLAD are very similar to LAD in humans and BLAD in cattle, which are both caused by mutations in ITGB2 encoding the leukocyte integrin beta-2 subunit (CD18). Sequence analysis of the ITGB2 coding sequence from a CLAD dog and a healthy control revealed a single missense mutation, Cys36Ser. This cysteine residue is conserved among all beta integrins, and the mutation most likely disrupts a disulfide bond. The mutation showed a complete association with CLAD in Irish setters and was not found in a sample of dogs from other breeds. The causative nature of this mutation was confirmed by transduction experiments using retroviral vectors and human LAD EBV B-cells. The normal canine CD18 formed heterodimers with the human CD11 subunit, whereas gene transfer of the mutant CD18 resulted in very low levels of CD11/CD18 expression. The identification of the causative mutation for CLAD now makes it possible to identify carrier animals with a simple diagnostic DNA test, and it forms the basis for using CLAD as a large animal model for the development and evaluation of clinical treatments for human LAD.
authors.affiliation: Department of Animal Breeding and Genetics, Swedish University of Agricultural Sciences, Uppsala, S-751 24, Sweden.
authors.forename: J M
authors.initials: JM
authors.lastname: Kijas
authors.forename: T R
authors.initials: TR
authors.lastname: Bauer
authors.forename: S
authors.initials: S
authors.lastname: Gäfvert
authors.forename: S
authors.initials: S
authors.lastname: Marklund
authors.forename: G
authors.initials: G
authors.lastname: Trowald-Wigh
authors.forename: A
authors.initials: A
authors.lastname: Johannisson
authors.forename: A
authors.initials: A
authors.lastname: Hedhammar
authors.forename: M
authors.initials: M
authors.lastname: Binns
authors.forename: R K
authors.initials: RK
authors.lastname: Juneja
authors.forename: D D
authors.initials: DD
authors.lastname: Hickstein
authors.forename: L
authors.initials: L
authors.lastname: Andersson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018821:CD18 Antigens / Q000235:genetics*; D004195:Disease Models, Animal; D004283:Dog Diseases / Q000235:genetics*; D004285:Dogs; D005822:Genetic Vectors; D006801:Humans; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000503:physiopathology / Q000662:veterinary*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014161:Transduction, Genetic
chemical_list: D018821:CD18 Antigens