Identification of two molecular defects in a child with leukocyte adherence deficiency.
Children with leukocyte adherence deficiency (LAD), or leukocyte cell adhesion molecule deficiency, experience recurrent, life-threatening bacterial infections related to severe deficiency in surface expression of the leukocyte integrin molecules. The leukocyte integrins consist of a common CD18 (beta) subunit and individual, noncovalently associated alpha subunits designated CD11a, CD11b, and CD11c. Defects in the CD18 subunit prevent surface expression of the CD11/CD18 complexes in children with this disease. We investigated the molecular basis of the disease in a child with the severe deficiency form of LAD and identified two molecular defects in the CD18 subunit. The first defect is a single-base pair C----T transposition resulting in an amino acid substitution of a leucine for a proline at amino acid 178. This amino acid substitution is located in a region that is highly conserved among the integrin beta subunits and where two previous defects have been located in LAD. The second mutation involves a deletion of 220 base pairs in the cDNA coding for a portion of the extracellular domain and results in a frameshift into a premature stop codon. The deleted region corresponds to a single exon in the CD18 gene. Identification of these two molecular defects in a single child with this disease indicates the compound heterozygous nature of the disorder in this child and identifies regions of the CD18 subunit that may be important for CD11/CD18 heterodimer formation and surface expression.
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Medical Research Service, Seattle Veterans Affairs Medical Center, Washington 98108.
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Hickstein
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D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D015153:Blotting, Western; D018821:CD18 Antigens; D002460:Cell Line; D002872:Chromosome Deletion; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D016023:Integrins / Q000235:genetics*; D007962:Leukocytes / Q000276:immunology*; D046911:Macromolecular Substances; D008297:Male; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016133:Polymerase Chain Reaction / Q000379:methods
D015703:Antigens, CD; D018821:CD18 Antigens; D016023:Integrins; D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides