A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta 2 integrins Mac-1 and LFA-1

In the leukocyte adhesion deficiency (LAD)-1 syndrome, there is diminished expression of beta 2(CD18) integrins. This is caused by lesions in the beta 2-subunit gene and gives rise to recurrent bacterial infections, impaired pus formation, and poor wound healing. We describe a patient with clinical features compatible with a moderately severe phenotype of LAD-1 but who exp resses the beta 2 integrins lymphocyte function-associated molecule (LFA)-1 and Mac-1 at 40%-60% of normal levels. This level of expression should be adequate for normal integrin function, but both the patient's Mac-1 on neut rophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule (ICAM)-1, respectively, or to display a bet a 2-integrin activation epitope after adhesion-inducing stimuli. Unexpected ly, divalent cation treatment induced the patient's T cells to bind to ICAM -2 and ICAM-3. Sequencing of the patient's two CD18 alleles revealed the mu tations S138P and G273R. Both mutations are in the beta 2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion-dependent adhesion site (MIDAS) motif. After K562 cell transfecti on with a subunits, the mutated S138P beta subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. In summar y, the patient described here exhibits failure of the beta 2 integrins to f unction despite adequate levels of cell-surface expression.