Shaw, J.M., Al-Shamkhani, A., Boxer, L.A., Buckley, C.D., Dodds, A.W., Klein, N., Nolan, S.M., Roberts, I., Roos, D., Scarth, S.L., Simmons, D.L., Tan, S.M. and Law, S.K.A. (2001) 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. Clinical and Experimental Immunology, 126 (2), 311-318. (doi:10.1046/j.1365-2249.2001.01661.x).
Abstract
Leucocyte adhesion deficiency (LAD) is a hereditary disorder caused by mutations in the CD18 (?2 integrin) gene. Four missense mutations have been identified in three patients. CD18(A270V) supports, at a diminished level, CD11b/CD18 (Mac-1, ?M?2 integrin) and CD11c/CD18 (p150,95, ?X?2 integrin) expression and function but not CD11a/CD18 (LFA-1, ?L?2 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 ? and ? subunits, which is an integral component in our understanding of integrin-mediated adhesion and its regulation.
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