ITGB2 gene, also known as CD18, codes for the beta 2 integrin subunit. Integrins are integral cell membrane glycoproteins composed of an alpha chain and a beta chain. Beta 2 integrin, the product of ITGB2, pairs noncovalently with at least four different alpha chain subunit L, M, X and D encoded by the CD11a, CD11b, CD11c, or CD11d gene, forming distinct functional heterodimers complexes: LFA-1 (CD11a/ CD18), Mac-1 (CD11b/CD18), gp150,95 (CD11c/CD18), or CD11d/CD18, respectively. These complexes play major roles in the immune system by mediating important leukocyte adhesion reactions. They are critical for the recruitment of circulating leukocytes to inflammatory sites, in that they are responsible for the establishment of firm adhesion and transendothelial migration. Each complex also has additional distinct functional profiles. For example, CD11a/CD18 plays an important role in lymphocyte proliferation, cell-mediated cytotoxicity, monocyte-lymphocyte and B-T-cell adhesion, and T-helper activity. CD11b/CD18 is an oligospecific receptor that is primarily involved in neutrophil adhesion-dependent functions, such as chemotaxis, phagocytosis, homotypic and heterotypic adhesion, and antibody-dependent cytotoxicity. It shares many of these functions with CD11c/CD18.
ITGB2 gene is located on the long arm of chromosome 21 at 21p22.3 and spans 40 kb of genomic DNA with a coding sequence consisting of 16 exons. The ITGB2 gene is expressed by T and B cells and by macrophages and granulocytes. ITGB2 protein is 769 amino acids long and weighs approximately 85 KDa. This protein exists on the leukocyte surface with individual CD11 subunits.
Several mutations scattered throughout the ITGB2 gene cause leukocyte adhesion deficiency type 1 (LAD1). In this disease, patients lack normal expression of the ITGB2 beta subunit and, as a result, show increased susceptibility to infection due to abnormal leukocyte function. There are two phenotypes of LAD that have been defined, severe and moderate phenotype, which correlate with the severity of the disease and depend on the level of expression of the ITGB2 protein. It was found that the expression of this gene was increased in lymphoblastoid cells from persons with Down syndrome, consistent with the location of the gene on chromosome 21. In addition, it was found that the chromosomal segments housing this gene are involved in rearrangements found in patients with various forms of blood malignancies, including acute myelomonocytic leukemia and the blast phase of chronic myelogenous leukemia. This region also contains the proto-oncogenes ets-1 and ets-2. Microduplications of this region occur in Down's syndrome and may contribute to the increased incidence of leukemia with this disease.
Monies et al. (2017) outlined the genomic landscape of Saudi Arabia based on the findings of 1000 diagnostic panels and exomes. One female patient suffered from inflammatory bowel disease. She had been misdiagnosed with Crohn’s disease earlier and treated with anti-inflammatory agents for several years. Using a multigene panel for immune-system disorders, a homozygous mutation (c.1756C>T, p.R586W) was identified in exon 13 of the patient’s ITGB2 gene, associated with LAD I. This led to a drastically different management and helped illustrate the importance of molecular testing to confirm diagnoses. Further, the atypical presentation of the patient helped expand the phenotype of this disorder.
Fathallah et al. (2001) carried out a molecular study on four unrelated Tunisian families with five children affected by LAD1, to determine the spectrum of the mutations in the ITGB2 gene causing LAD in these families. All those children (one male and four female) were born from related healthy parents. The four female patients had the severe form, while the male patient had the moderate form of the disease. They all had delayed umbilical cord separation and suffered recurrent infections. Immunofluorescence flow cytometry was used to analyze the level of the CD18 subunit expression on the surface of PBMCs from all five patients and their parents. It revealed that the patients with the severe form of the disease had low levels of CD18 expression (1% to 5%). While the male patient had a 16.5% CD18 expression level as compared to the normal control, which is consistent with moderate form of LAD. Beside that, north blot showed that all patients exhibited a normal sized CD18 specific mRNA. RT/PCR strategy was used to generate CD18 specific cDNA fragments. Sequencing of these PCR products revealed that all patients have a novel deletion of the G at position 1497 (1497delG) causing a frameshift and yielding a premature stop codon, 28 residues downstream the deletion. Only one patient was homozygous for this mutation. The second novel mutation was another single bp deletion (1920delG) causing a frameshift and the occurrence of a stop codon 16 residues downstream of the deletion. One patient was found to be compound heterozygous for both deletions (1497delG/1920delG). The third mutation was a previously reported missense mutation (G284S). This mutation was found with 1497delG in the two sister patients whom were found to be compound heterozygous for (1497delG/G284S). The fourth mutation was a missense mutation (R593C) which was previously reported as inherited mutation in other studies. This mutation was found in the male patient who was found to be compound heterozygous for (1497delG/R593C), but no one of the patient's parents carries the R593C mutation. Paternity testing using DNA fingerprinting was used, ruling out an eventual mismatching between this patient and his biological parents. This result confirmed the de novo character of the R593C mutation. Fathallah et al. (2001) suggested that the G284S and R593C mutations are probably truly recurrent mutations that with other already reported mutations might define hot spots mutations in the ITGB2 gene. The mutations were confirmed by sequencing of the genomic DNA for the exons that had the mutations in all the individual studied. Segregation of two CD18 intragenic polymorphic markers Ava II and Xba I with the mutations underlying LAD in the patients was also studied using site tagged sequence analysis (STS). Family studies showed that the 1497delG mutation segregated with both markers, suggesting the presence of a founder effect of this mutation in these patients. Fathallah et al. (2001) also suggested that this mutation was introduced in this population on an ancestral chromosome, tightly linked to the Ava II+ and Xba I+ markers.
Molad et al. (2003) found that circulating neutrophils display significantly increased expression of beta2-integrin molecules on their surface compared to non-Yemenite Jews (327.1 +/- 129.2 vs. 237.0 +/- 133.1; p = 0.002), with no significant correlation to their absolute neutrophil count. In vitro analysis of CD11b and LS expression induced by chemoattractant and G-CSF showed no difference between neutrophils of Yemenite versus non-Yemenite Jews.
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