A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency

Canine leukocyte adhesion deficiency (CLAD) is a fatal immunodeficiency dis ease found in Irish setters. The clinical manifestations of CLAD are very s imilar to LAD in humans and BLAD in cattle, which are both caused by mutati ons in ITGB2 encoding the leukocyte integrin beta-2 subunit (CD18). Sequenc e analysis of the ITGB2 coding sequence from a CLAD dog and a healthy contr ol 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 Ir ish setters and was not found in a sample of dogs from other breeds. The ca usative nature of this mutation was confirmed by transduction experiments u sing retroviral vectors and human LAD EBV B-cells. The normal canine CD18 f ormed heterodimers with the human CD11 subunit, whereas gene transfer of th e mutant CD18 resulted in very low levels of CD11/CD18 expression. The iden tification of the causative mutation for CLAD now makes it possible to iden tify carrier animals with a simple diagnostic DNA test, and it forms the ba sis for using CLAD as a large animal model for the development and evaluati on of clinical treatments for human LAD. (C) 1999 Academic Press.