title: Unique CD18 mutations involving a deletion in the extracellular stalk region and a major truncation of the cytoplasmic domain in a patient with leukocyte adhesion deficiency type 1.
abstract: Two novel CD18 mutations were identified in a patient who was a compound heterozygote with type 1 leukocyte adhesion deficiency and whose phenotype was typical except that he exhibited hypertrophic scarring. A deletion of 36 nucleotides in exon 12 (1622del36) predicted the net loss of 12 amino acid (aa) residues in the third cysteine-rich repeat of the extracellular stalk region (mut-1). A nonsense mutation in exon 15 (2200G>T), predicted a 36-aa truncation of the cytoplasmic domain (mut-2). Lymphocyte function-associated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) containing the mut-1 beta(2) subunit were expressed at very low levels compared with wild-type (wt) beta(2). Mac-1 and LFA-1 expression with the mut-2 beta(2) subunit were equivalent to results with wt beta(2). Binding function of Mac-1 with mut-2 beta(2) was equivalent to that with wt beta(2). However, binding function of LFA-1 with the mut-2 beta(2) subunit was reduced by 50% versus wt beta(2). It was concluded that (1) the portion of the CD18 stalk region deleted in mut-1 is critical for beta(2) integrin heterodimer expression but the portion of the cytoplasmic domain truncated in mut-2 is not; and (2) the mut-2 cytoplasmic domain truncation impairs binding function of LFA-1 but not of Mac-1. Studies with the patient's neutrophils (PMNs) were consistent with functional impairment of LFA-1 but not of Mac-1.
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018821:CD18 Antigens / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D016022:Case-Control Studies; D002448:Cell Adhesion; D018389:Codon, Nonsense; D018076:DNA, Complementary / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000145:classification / Q000235:genetics* / Q000276:immunology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012397:Rosette Formation; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D018821:CD18 Antigens; D018389:Codon, Nonsense; D018076:DNA, Complementary; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D011994:Recombinant Proteins; D018799:Intercellular Adhesion Molecule-1