A novel leukocyte adhesion deficiency caused by expressed but nonfunctional [small beta, Greek]2 integrins Mac-1 and LFA-1


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Abstract

In the leukocyte adhesion deficiency (LAD)-1 syndrome, there is diminished expression of [small beta, Greek]2(CD18) integrins. This is caused by lesions in the [small beta, Greek]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 expresses the [small beta, Greek]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 neutrophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule (ICAM)-1, respectively, or to display a [small beta, Greek]2-integrin activation epitope after adhesion-inducing stimuli. Unexpectedly, 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 mutations S138P and G273R. Both mutations are in the [small beta, Greek]2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion-dependent adhesion site (MIDAS) motif. After K562 cell transfection with [small alpha, Greek] subunits, the mutated S138P [small beta, Greek] subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. In summary, the patient described here exhibits failure of the [small beta, Greek]2 integrins to function despite adequate levels of cell-surface expression.J.Clin. Invest. 103:97-106 (1999).

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