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A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 1999 Jan; Vol. 103 (1), pp. 97-106. - Publication Year :
- 1999
-
Abstract
- In the leukocyte adhesion deficiency (LAD)-1 syndrome, there is diminished expression of beta2(CD18) integrins. This is caused by lesions in the beta2-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 beta2 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 beta2-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 beta2-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 alpha subunits, the mutated S138P beta 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 beta2 integrins to function despite adequate levels of cell-surface expression.
- Subjects :
- Adolescent
CD18 Antigens metabolism
Cell Adhesion Molecules genetics
Cell Adhesion Molecules metabolism
Cell Line
DNA Mutational Analysis
Fibronectins metabolism
Flow Cytometry
Gene Expression genetics
Humans
Leukocyte-Adhesion Deficiency Syndrome physiopathology
Manganese metabolism
Mutation genetics
Neutrophils metabolism
Polymorphism, Genetic genetics
Protein Binding
T-Lymphocytes metabolism
Transfection genetics
CD18 Antigens genetics
Leukocyte-Adhesion Deficiency Syndrome genetics
Lymphocyte Function-Associated Antigen-1 metabolism
Macrophage-1 Antigen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 103
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 9884339
- Full Text :
- https://doi.org/10.1172/JCI3312