Submitted to: Blood
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/12/2003
Publication Date: 2/1/2004
Citation: HIXSON, P., SMITH, W.C., SHURIN, S.B., TOSI, M.F. UNIQUE CD18 MUTATIONS INVOLVING A DELETION IN THE EXTRACELLULAR STALK REGION AND A MAJOR TRUNCATION OF THE CYTOPLASMIC DOMAIN IN A PATIENT WITH LEUKOCYTE AHDESION DEFICIENCY TYPE 1. BLOOD. 103(3):1105-1113,2004. Interpretive Summary: Host defense against infection depends on the ability of white blood cells to adhere to and migrate through the walls of blood vessels. Understanding which molecules are critical to these processes has come from studies of humans with inherited mutations in the genes involved. This paper describes the analysis of a unique patient with two different mutations in the gene for a protein called CD18. Such studies represent very basic research into host defense mechanisms and provide insights into possible mechanisms influenced by variations in nutrition. For example, there is published evidence for changes in CD18 expression in cases of obesity. The current study provides new evidence regarding which regions of the CD18 molecule are important in controlling it expression.
Technical 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.