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 functionassociated antigen 1 (LFA-1) and macrophage antigen-1 (Mac-1) containing the mut-1 ␤ 2 subunit were expressed at very low levels compared with wild-type (wt) ␤ 2 . Mac-1 and LFA-1 expression with the mut-2 ␤ 2 subunit were equivalent to results with wt ␤ 2 . Binding function of Mac-1 with mut-2 ␤ 2 was equivalent to that with wt ␤ 2 . However, binding function of LFA-1 with the mut-2 ␤ 2 subunit was reduced by 50% versus wt ␤ 2 . It was concluded that (1) the portion of the CD18 stalk region deleted in mut-1 is critical for ␤ 2 integrin heterodimer expression but the portion of the cytoplasmic domain truncated in mut-2 is not; and (2) IntroductionImportant insights related to the molecular mechanisms that determine ␤ 2 integrin structure and function have arisen from the study of naturally occurring mutations in the common ␤ 2 subunit of this integrin family. 1,2 A range of mutations in the CD18 gene have been identified in patients with leukocyte adhesion deficiency type 1 (LAD-1), including deletions, truncations, substitutions, frame shifts, and intronic mutations that result in abnormalities of the CD18 protein ranging from absence of protein product, deficient alpha-beta subunit association, and reduced protein size. 1,3-5 All such mutations have resulted in diminished expression of the CD18 integrins on leukocytes, and some mutations also have caused integrin dysfunction. 1,[3][4][5] Patients typically have recurrent bacterial or fungal infections of skin and mucous membranes, impaired mobilization of leukocytes to sites of infection, severe gingivitis/ periodontitis with permanent loss of dentition, and atrophic scarring of wounds. 1,2,6 Laboratory features include a pronounced leukocytosis in the absence of infection, reduced expression of all members of the CD18 or ␤ 2 integrin family on circulating leukocytes, and diminished CD18-dependent leukocyte functions, including cell adhesion, chemotaxis, transendothelial migration, and oxidative burst activation in response to iC3b-coated particles. 1,2,6 We have identified an adult male patient with LAD-1 whose clinical features resemble those of the moderate LAD-1 phenotype, except that his wounds heal with hypertrophic rather than atrophic scarring. His levels of CD18 integrin expression are higher than those of most other reported patients with the moderate phenotype of LAD-1, but the CD18-dependent functions of his leukocytes were similar to those of other moderate phenotype individuals. 1,7 He was found to be a compound heterozygote with 2 novel m...

Regulation of Innate Immune Response toCandida albicansInfections by αMβ2-Pra1p Interaction

“…The observed effect of ␣ M ␤ 2 elimination on C. albicans virulence is consistent with previous reports demonstrating that patients with leukocyte adhesion deficiency type 1 (LAD-1) syndrome showed increased susceptibility to C. albicans infection (7,45,50,53,86). LAD-1 syndrome is a rare hereditary disease characterized by increased susceptibility to infections due to the inability of leukocytes, in particular neutrophils, to migrate from the blood to sites of inflammation.…”

Leukocyte adhesion deficiencies

“…Rarely, a mutation will cause a nonfunctional but normally expressed CD18 molecule (LAD I/variant). A unique CD18 mutation has also been described in a patient who was compound heterozygous at this region, 10 consisting of a standard deletion mutation in the extracellular stalk region, causing a marked decrease in CD18 expression, and a second major truncation mutation of the cytoplasmic domain. The latter mutation mainly caused a significant impaired adhesion capacity of the beta 2 chain to ICAM‐1 but with normal expression levels.…”

Detection of leukocyte adhesion deficiency type 1 in an infant by high-throughput targeted exome sequencing

“…Finally, a review of the literature concerning LAD-I was done by a search of Chinese Biological Medicine 72 [13] 73 [14] 74 [13] 75 [41] 76 [15] 77 [17] 78 [13] 79 [42] 80 [13] 81 [13] 82 [15] 83 [34] 84 [35] 85 [35] 86 [15] 87 [22] 88 [41] 89 [13] 90 [43] 91 [44] 92 [13] 93 [13] 94 [12] 95 [22] 96 [42] - Database and PubMed. The first LAD-I was described in 1984 [10] with more than 300 cases and 96 pathogenic mutations [ Table 2] In conclusion, we presented a case of LAD-I associated with acquired CMV infection, an important opportunistic pathogen in patients who are immunocompromised.…”