title: Characterization of four CD18 mutants in leucocyte adhesion deficient (LAD) patients with differential capacities to support expression and function of the CD11/CD18 integrins LFA-1, Mac-1 and p150,95.
abstract: Leucocyte adhesion deficiency (LAD) is a hereditary disorder caused by mutations in the CD18 (beta2 integrin) gene. Four missense mutations have been identified in three patients. CD18(A270V) supports, at a diminished level, CD11b/CD18 (Mac-1, alphaMbeta2 integrin) and CD11c/CD18 (p150,95, alphaXbeta2 integrin) expression and function but not CD11a/CD18 (LFA-1, alphaLbeta2 integrin) expression. Conversely, CD18(A341P) supports a limited level of expression and function of CD11a/CD18, but not of the other two CD11/CD18 antigens. CD18(C590R) and CD18(R593C) show a decreasing capacity to associate with the CD11a, CD11c and CD11b subunits. Transfectants expressing the CD11a/CD18 with the C590R and R593C mutations are more adhesive than transfectants expressing wild-type LFA-1, and express the reporter epitope of the monoclonal antibody 24 constitutively. Thus, the four mutations affect CD18 differently in its capacities to support CD11/CD18 expression and adhesion. These results not only provide a biochemical account for the clinical diversity of patients with leucocyte adhesion deficiency, but also offer novel insights into the structural basis of interaction between the alpha and beta subunits, which is an integral component in our understanding of integrin-mediated adhesion and its regulation.
authors.affiliation: MRC Immunochemistry Unit, Department of Biochemistry, University of Oxford, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Shaw
authors.forename: A
authors.initials: A
authors.lastname: Al-Shamkhani
authors.forename: L A
authors.initials: LA
authors.lastname: Boxer
authors.forename: C D
authors.initials: CD
authors.lastname: Buckley
authors.forename: A W
authors.initials: AW
authors.lastname: Dodds
authors.forename: N
authors.initials: N
authors.lastname: Klein
authors.forename: S M
authors.initials: SM
authors.lastname: Nolan
authors.forename: I
authors.initials: I
authors.lastname: Roberts
authors.forename: D
authors.initials: D
authors.lastname: Roos
authors.forename: S L
authors.initials: SL
authors.lastname: Scarth
authors.forename: D L
authors.initials: DL
authors.lastname: Simmons
authors.forename: S M
authors.initials: SM
authors.lastname: Tan
authors.forename: S K
authors.initials: SK
authors.lastname: Law
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D018821:CD18 Antigens / Q000235:genetics* / Q000502:physiology; D019556:COS Cells; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D016167:Integrin alphaXbeta2 / Q000235:genetics / Q000502:physiology; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics* / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000502:physiology; D020125:Mutation, Missense; D014162:Transfection
chemical_list: D018821:CD18 Antigens; D018076:DNA, Complementary; D016167:Integrin alphaXbeta2; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen