* 600065

INTEGRIN, BETA-2; ITGB2


Alternative titles; symbols

LEUKOCYTE CELL ADHESION MOLECULE CD18; CD18


Other entities represented in this entry:

LEUKOCYTE-ASSOCIATED ANTIGENS CD18/11A, CD18/11B, CD18/11C, INCLUDED

HGNC Approved Gene Symbol: ITGB2

Cytogenetic location: 21q22.3     Genomic coordinates (GRCh38): 21:44,885,953-44,928,815 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.3 Leukocyte adhesion deficiency 116920 AR 3

TEXT

Description

The leukocyte cell adhesion molecule belongs to the class of cell membrane glycoproteins known as integrins, which are alpha-beta heterodimers. The alpha subunits vary in size from 120 to 180 kD and each is noncovalently associated with a beta subunit (90 to 110 kD). There are 8 known beta subunits and 14 known alpha subunits. Although the alpha and beta subunits could in theory associate to give more than 100 integrin heterodimers, the diversity is restricted and different combinations are associated with different cell types (Hynes, 1992).


Nomenclature

The beta-2 integrin chain gene is designated ITGB2 and the leukocyte antigen has been designated CD18. The 3 alpha integrin chains associated individually with the beta-2 chain as a heterodimer have gene designations of ITGAL (153370), ITGAM (120980), and ITGAX (151510), and leukocyte antigen designations of CD11A, CD11B, and CD11C, respectively.

The 3 integrin molecules associated with leukocyte adhesion deficiency have leukocyte antigen designations of (1) CD18/CD11A: also referred to as LFA-1, Leu CAMa, and integrin beta-2/alpha-L; (2) CD18/CD11B: also referred to as CR3, Leu CAMb, Mac-1, Mo1, OKM-1, and integrin beta-2/alpha-M; (3) CD18/CD11C: also referred to as p150 (p150, 95), Leu CAMc, and integrin beta-2/alpha-X (Barclay et al., 1993).


Evolution

This glycoprotein family is conserved in mouse and human.


Gene Function

By quantitative fluorescence flow cytometric analysis, Taylor et al. (1988) showed that the expression of CD18 was increased in lymphoblastoid cells from persons with Down syndrome, consistent with the location of the gene on chromosome 21.

Bianchi et al. (2000) showed that JAB1 (604850) interacts with the cytoplasmic domain of the beta-2 subunit of the alpha-L/beta-2 integrin LFA-1. They demonstrated that a fraction of JAB1 colocalizes with LFA-1 at the cell membrane and that LFA-1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP1 complexes to their DNA consensus site and increased transactivation of an AP1-dependent promoter. Bianchi et al. (2000) suggested that signaling through the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1 nuclear localization. This represented a new pathway for integrin-dependent modulation of gene expression.

By yeast 2-hybrid analysis and leukocyte adhesion assays, Ostermann et al. (2002) demonstrated that under both static and physiologic flow conditions, JAM1 (605721), through its membrane-proximal domain 2, is a ligand of the LFA-1 integrin that contributes to the LFA-1-dependent transendothelial migration of CD45RO (151460)-positive memory T cells expressing the CXCR4 (162643) chemokine receptor and of neutrophils. These interactions also facilitated LFA-1-mediated arrest of T cells. Activation of endothelium with inflammatory cytokines enhanced memory T-cell transmigration. Ostermann et al. (2002) suggested that a complex interplay of heterophilic binding of LFA-1 to JAM1 and homophilic trans-interactions of JAM1 may provide a molecular 'zipper' for leukocyte transmigration.

Lu and Cyster (2002) studied the mechanisms that control localization of marginal zone B cells. They demonstrated that marginal zone B cells express elevated levels of the integrins LFA-1 and alpha-4-beta-1 (see 192975 and 135630), and that the marginal zone B cells bind to the ligands ICAM1 (147840) and VCAM1 (192225). These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA-1 and alpha-4-beta-1 causes a rapid and selective release of B cells from the marginal zone. Furthermore, lipopolysaccharide-triggered marginal zone B cell relocalization involves downregulation of integrin-mediated adhesion. Lu and Cyster (2002) concluded that their studies identified key requirements for marginal zone B cell localization and established a role for integrins in peripheral lymphoid tissue compartmentalization.

In a patient with features of Glanzmann thrombasthenia (see 173470) and leukocyte adhesion deficiency-1 (LAD1; 116920), McDowall et al. (2003) identified a novel form of integrin dysfunction involving ITGB1 (135630), ITGB2, and ITGB3 (173470). ITGB2 and ITGB3 were constitutively clustered. Although all 3 integrins were expressed on the cell surface at normal levels and were capable of function following extracellular stimulation, they could not be activated via the 'inside-out' signaling pathways.

Kim et al. (2003) investigated cytoplasmic conformational changes in the integrin LFA1 (alpha-L, 153370; beta-2) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein-fused and yellow fluorescent protein-fused alpha-L and beta-2 cytoplasmic domains. In the resting state these domains were close to each other, but underwent significant spatial separation upon either intracellular activation of integrin adhesiveness (inside-out signaling) or ligand binding (outside-in signaling). Thus, bidirectional integrin signaling is accomplished by coupling extracellular conformational changes to an unclasping and separation of the alpha and beta cytoplasmic domains, which Kim et al. (2003) noted as a distinctive mechanism for transmitting information across the plasma membrane.

Cherry et al. (2004) generated T-cell clones expressing less than half the wildtype amount of RHOH (602037), a leukocyte-specific inhibitory Rho family member. Resting cells expressed constitutively adhesive LFA1 and bound spontaneously to ICAM1, ICAM2 (146630), and ICAM3 (146631). Reconstituting RHOH mRNA levels reverted the adhesion phenotype to that of relatively nonadhesive wildtype cells. Treatment of peripheral blood lymphocytes with RHOH RNA interference altered the nonadhesive phenotype. Cherry et al. (2004) concluded that RHOH is required for maintenance of lymphocyte LFA1 in a nonadhesive state.

Lammermann et al. (2008) studied the interplay between adhesive, contractile, and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro. The authors ablated genes encoding integrin heterodimeric partners ITGA5 (135620), ITGB1 (135630), ITGB2, and ITGB7 (147559) from murine leukocytes and demonstrated that functional integrins do not contribute to migration in 3-dimensional environments. Instead, these cells migrate by the sole force of actin network expansion, which promotes protrusive flowing of the leading edge. Myosin II-dependent contraction is required only on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus.


Gene Structure

Weitzman et al. (1991) determined that the ITGB2 gene spans approximately 40 kb and contains 16 exons.


Mapping

Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is located on chromosome 21. The method used involved somatic cell hybrids between mouse and human lymphocytes, indirect immunofluorescence, and cell sorting. By somatic cell hybridization, Akao et al. (1987) confirmed the chromosomal assignment. By human-mouse T-cell fusion studies, Marlin et al. (1986) also showed that the beta subunit maps to chromosome 21. Using a cDNA probe for in situ hybridization, Solomon et al. (1988) localized the ITGB2 (CD18) gene to 21q22.1-qter. Petersen et al. (1991) assigned CD18 to 21q22.3 and positioned it in that band relative to 15 other genes or DNA markers.


Molecular Genetics

Mutations in the beta-2 subunit of the leukocyte cell adhesion molecule have been found to cause the autosomal recessive disorder of neutrophil function known as leukocyte adhesion deficiency. LAD is characterized by recurrent bacterial infections and a lack of beta-2/alpha-L (see 153370), beta-2/alpha-M (see 120980), and beta-2/alpha-X (see 151510) expression.

In a patient with LAD deficiency, Arnaout et al. (1990) identified compound heterozygous mutations in the CD18 gene (600065.0001-600065.0002).

In 2 patients with LAD deficiency, Wardlaw et al. (1990) identified mutations in the CD18 gene (600065.0003; 600065.0004).

Rivera-Matos et al. (1995) described an infant in whom clinical signs suggesting Hirschsprung disease were the initial manifestation of LAD. Chromosome studies showed a deletion of the distal third of the long arm of one chromosome 21, and flow cytometric studies confirmed the defective expression of CD18. Leukocyte adhesion deficiency was suspected because of leukocytosis, poor wound healing, frequent infections, and biopsy specimens showing a paucity of neutrophils. It seems quite possible that the patient indeed had Hirschsprung disease as well as leukocyte adhesion deficiency. Aganglionic megacolon is a frequent finding in trisomy 21 and preliminary evidence for a genetic modifier of Hirschsprung disease on 21q22 has been presented (600156).


Animal Model

Wilson et al. (1993) found that a hypomorphic mutation in CD18, generated by gene targeting in mice, showed in homozygosity increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain by Bullard et al. (1996), virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed changes of a type found in human psoriasis (177900) and other hyperproliferative inflammatory skin disorders. No bacterial or fungal organisms were found to be involved in the pathogenesis of the disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. The findings of Bullard et al. (1996) were notable since no comparable skin disease had been reported in humans or cattle with LAD deficiency type I and since this disorder did not occur in mice when the mutation was studied on a C57BL/6 or 129/Sv background. From backcross experiments the authors suggested that a small number of genes (perhaps as few as one), in addition to CD18, determined susceptibility to the disorder.

Vazquez-Torres et al. (1999) reported that Salmonella is transported from the gastrointestinal tract to the bloodstream by CD18-expressing phagocytes, and that CD18-deficient mice are resistant to dissemination of Salmonella to the liver and spleen after oral administration. Vazquez-Torres et al. (1999) hypothesized that the CD18-dependent pathway of extraintestinal dissemination may be important for the development of systemic immunity to gastrointestinal pathogens, because oral challenge with Salmonella pathogenicity island-1 (SPI1)-deficient S. typhimurium elicits a specific systemic IgG humoral immune response, despite an inability to stimulate production of specific mucosal IgA.

Lee et al. (2003) generated mice lacking Cd18. In vitro, activated lymphocytes from these mice had normal Th1 and Th2 cytokine production. The Cd18 -/- mice were more resistant than C57BL/6 mice to challenge with Leishmania major, but they were also resistant to allergic lung inflammation, even though they produced amounts of T cell-dependent allergen-specific antibody comparable to wildtype mice. The authors found that disease production required the homing of Th2 cells (IL4-positive) to the lungs, and this migration was impaired in Cd18 -/- mice and in mice treated with anti-Cd18. Lee et al. (2003) proposed that integrin blockade could be a tactic for selectively excluding Th2 cells under diverse inflammatory conditions.

Miura et al. (2005) found that Cd18-null mice had defective osteoclastogenesis due to reduced expression of the osteogenic master regulator Runx2 (600211). Radiographic analysis of Cd18-null mice showed reduced bone mineral density and features of osteoporosis. Cd18 was expressed by bone marrow stromal stem cells, and constitutive overexpression of Cd18 in this cell population in normal mice enhanced bone formation. The authors suggested that LAD patients may be predisposed to develop osteoporosis.


ALLELIC VARIANTS ( 15 Selected Examples):

.0001 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ARG593CYS
  
RCV000799618...

Arnaout et al. (1990) found that a patient with leukocyte adhesion deficiency (LAD1; 116920) was compound heterozygous for 2 mutations in the CD18 gene: arg593-to-cys and lys196-to-thr. These amino acids lie in regions necessary for normal cell surface expression of CD18 and possibly other integrin-beta subunits. Arnaout et al. (1990) demonstrated that each mutant allele resulted in impaired CD18 expression on the cell surface membrane of transfected COS M6 cells.


.0002 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, LYS196THR
  
RCV000010067

For discussion of the lys196-to-thr (K196T) mutation in the CD18 gene that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency (LAD1; 116920) by Arnaout et al. (1990), see 600065.0001.


.0003 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, LEU149PRO
  
RCV000010068

In a patient (patient 14) with moderately severe leukocyte adhesion deficiency (LAD1; 116920), Wardlaw et al. (1990) demonstrated a T-to-C transition in the CD18 gene, resulting in substitution of proline for leucine-149. Cotransfection of the beta subunit cDNA containing this mutation with the wildtype alpha subunit of LFA-1 in a mammalian expression system resulted in no expression of LFA-1. Normal life of the mutant beta subunits and previous demonstration of the lack of alpha/beta complex formation during biosynthesis in the patient's cells suggested a defect in association with the alpha subunit. Loss of functional expression of this beta-subunit mutation suggests that it lies in a site critical for association with the alpha subunit. (In MIM10, this mutation was incorrectly listed as pro149-to-leu. The wildtype residue is leu (Bairoch, 1994).)


.0004 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY169ARG
  
RCV000010069

In a patient (patient 2) with severe leukocyte adhesion deficiency (LAD1; 116920), Wardlaw et al. (1990) demonstrated a G-to-A transition in the CD18 gene, resulting in a glycine-to-arginine change at amino acid 169 of the beta subunit. As in the case of the leu149-to-pro mutation, there appeared to be interference with association between the mutant beta subunit and the normal alpha subunit.


.0005 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, INITIATION MUTATION
  
RCV000010070

Sligh et al. (1989) found an ATG-to-AAG alteration in the initiation codon of the CD18 gene in a patient with moderately severe leukocyte adhesion deficiency (LAD1; 116920). In fact, the patient was a genetic compound; the particular mutation was found in the patient and in the father.


.0006 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ARG586TRP AND 12-BP INS
  
RCV000990357...

In a patient with partial leukocyte adhesion deficiency (LAD1; 116920) who was previously reported by Arnaout et al. (1984), Nelson et al. (1992) demonstrated 2 mutant alleles in the CD18 gene. The allele from the mother contained 2 mutations: a 12-bp insertion resulting in an in-frame addition of 4 amino acids (pro-ser-ser-gln) between proline-247 and glutamic acid-248, and a 1756C-T nucleotide transition resulting in an arg586-to-trp substitution in the CD18 protein. The 12-bp insertion arose by a single C-to-A transversion in the 3-prime terminus of an intron, generating an aberrant splice acceptor site. COS cells cotransfected with a normal alpha chain gene (CD11B) and the mother's doubly mutant allele showed no surface expression of CD18; when transfected with the arg586-to-trp mutant gene, expression was 22% of normal. The other allele, which was not present in either parent, contained a 1052A-G transition, resulting in an asn351-to-ser (N351S; 600065.0008) substitution.


.0007 MOVED TO 600065.0006


.0008 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ASN351SER
  
RCV000010073

For discussion of the 1052A-G transition in the CD18 gene, resulting in substitution of serine for asparagine-351 (N351S), that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency-1 (LAD1; 116920) by Nelson et al. (1992), see 600065.0006.


.0009 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, PRO178LEU
  
RCV000010074

In a child with severe leukocyte adhesion deficiency (LAD1; 116920), Back et al. (1992) found compound heterozygous mutations in the CD18 gene. One allele had a C-to-T transition at nucleotide 606, resulting in substitution of leucine for proline at amino acid 178. The change occurred in a region that is highly conserved among the integrin beta subunits and where previous defects had been identified in LAD. The other allele had a 220-bp deletion in the cDNA coding for a portion of the extracellular domain, which resulted in a frameshift and a premature stop codon. The deleted region corresponded to exon 13 of the ITGB2 (CD18) gene. The patient had previously been reported by Bowen et al. (1982) and Beatty et al. (1984).


.0010 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ASP128ASN
  
RCV000010075

In a patient with leukocyte adhesion deficiency (LAD1; 116920), Matsuura et al. (1992) identified a G-to-A transition at nucleotide 454 of the CD18 gene, which resulted in an asp128-to-asn substitution. The asp128 residue is located in a region which is crucial for the association of beta subunits with alpha subunits and is strictly conserved among the integrin beta subunits.


.0011 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, IVSDS, G-A, +1
  
RCV000087127

In a patient with leukocyte adhesion deficiency (LAD1; 116920), Matsuura et al. (1992) identified a G-to-A substitution at the first nucleotide of the splice donor site of a 1.2-kb intron in the CD18 gene.


.0012 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY284SER
  
RCV000705990...

In an 18-year-old girl reported by Bowen et al. (1982) with moderately severe leukocyte adhesion deficiency-1 (LAD1; 116920), Back et al. (1993) found a single base substitution in the CD18 gene resulting in a glycine284-to-serine substitution. The change occurred in a highly conserved region of the extracellular domain in which several other mutations had been identified.


.0013 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, SER138PRO
  
RCV000010078

Hogg et al. (1999) described a patient with clinical features compatible with a markedly severe phenotype of leukocyte adhesion deficiency (LAD1; 116920) who was found to express the beta-2 integrins LFA-1 and Mac-1 at 40 to 60% of normal levels. This level of expression should be adequate for normal integrin function, but both the patient's Mac-1 on neutrophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule-1 (ICAM1; 147840), or to display a beta-2 integrin activation epitope after adhesion-inducing stimuli. Unexpectedly, divalent cation treatment induced the patient's T cells to bind to ICAM2 (146630) and ICAM3 (146631). Sequencing of the patient's 2 CD18 alleles revealed compound heterozygosity of 2 missense mutations, S138P and G273R (600065.0014). Both mutations were in the beta-2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion-dependent adhesion site (MIDAS) motif. After transfection of K562 cells with alpha subunits, the mutated S138P beta-subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. Thus, the patient exhibited failure of the beta-2 integrins to function despite adequate levels of cell surface expression.

The 15-year-old patient studied by Hogg et al. (1999) first presented as an infant with severe and recurrent skin infections requiring prolonged treatment with intravenous antibiotics and surgery to remove necrotic tissue. In spite of attentive oral hygiene, the patient suffered from severe periodontitis and gingivitis. Otitis media and chest infections had also been consistent features. Organisms isolated from infected sites included Staphylococcus aureus, Pseudomonas, and Streptococcus species. The neutrophil count was persistently elevated, reaching peaks of more than 10 times normal at times of infection. Phagocytosis by the patient's neutrophils was less than 25% that of a healthy adult control. On the other hand, respiratory burst was either normal or slightly enhanced, and intracellular killing of S. epidermidis was within normal limits. Therefore, although the uptake of the organisms was faulty, intracellular processes by which phagocytes deal with bacteria appeared normal.


.0014 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY273ARG
  
RCV000355931...

For discussion of the gly273-to-arg (G273R) substitution in the ITGB2 gene that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency-1 (LAD1; 116920) by Hogg et al. (1999), see 600065.0013.


.0015 LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, IVS4AS, 169-BP DEL, -37
   RCV000010080

By studying a herpesvirus saimiri-transformed T cell line from a patient with severe leukocyte adhesion deficiency (LAD1; 116920), Allende et al. (2000) identified a 169-bp genomic deletion in the ITGB2 gene (from -37 of intron 4 to +132 of exon 5) that abolished the intron 4 acceptor splicing site, resulting in the total skipping of exon 5. The genomic deletion led to a 171-bp in-frame mRNA deletion (nucleotides 329 to 500) that resulted in the absence of cell surface and cytoplasmic CD18 expression. Functional analysis showed a severe, selective T-cell activation impairment in the CD2 but not the CD3 pathway. The male patient, whose father was not known and who had no family history of LAD, died at age 12 months after unsuccessful bone marrow transplants at 7 and 10 months of age.


See Also:

REFERENCES

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  29. Hynes, R. O. Integrins: versatility, modulation and signaling in cell adhesion. Cell 69: 11-25, 1992. [PubMed: 1555235, related citations] [Full Text]

  30. Kehrli, M. E., Jr., Ackermann, M. R., Shuster, D. E., van der Maaten, M. J., Schmalstieg, F. C., Anderson, D. C., Hughes, B. J. Bovine leukocyte adhesion deficiency: beta(2) integrin deficiency in young Holstein cattle. Am. J. Path. 140: 1489-1492, 1992. [PubMed: 1605311, related citations]

  31. Kim, M., Carman, C. V., Springer, T. A. Bidirectional transmembrane signaling by cytoplasmic domain separation in integrins. Science 301: 1720-1725, 2003. [PubMed: 14500982, related citations] [Full Text]

  32. Kishimoto, T. K., Hollander, N., Roberts, T. M., Anderson, D. C., Springer, T. A. Heterogeneous mutations in the beta subunit common to the LFA-1, Mac-1, and p150,95 glycoproteins cause leukocyte adhesion deficiency. Cell 50: 193-202, 1987. [PubMed: 3594570, related citations] [Full Text]

  33. Kishimoto, T. K., O'Connor, K., Lee, A., Roberts, T. M., Springer, T. A. Cloning of the beta subunit of the leukocyte adhesion proteins: homology to an extracellular matrix receptor defines a novel supergene family. Cell 48: 681-690, 1987. [PubMed: 3028646, related citations] [Full Text]

  34. Kobayashi, K., Fujita, K., Okino, F., Kajii, T. An abnormality of neutrophil adhesion: autosomal recessive inheritance associated with missing neutrophil glycoproteins. Pediatrics 73: 606-610, 1984. [PubMed: 6718115, related citations]

  35. Krauss, J. C., Mayo-Bond, L. A., Rogers, C. E., Weber, K. L., Todd, R. F., III, Wilson, J. M. An in vivo animal model of gene therapy for leukocyte adhesion deficiency. J. Clin. Invest. 88: 1412-1417, 1991. [PubMed: 1680882, related citations] [Full Text]

  36. Lammermann, T., Bader, B. L., Monkley, S. J., Worbs, T., Wedlich-Soldner, R., Hirsch, K., Keller, M., Forster, R., Critchley, D. R., Fassler, R., Sixt, M. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453: 51-55, 2008. [PubMed: 18451854, related citations] [Full Text]

  37. Lee, S.-H., Prince, J. E., Rais, M., Kheradmand, F., Shardonofsky, F., Lu, H., Beaudet, A. L., Smith, C. W., Soong, L., Corry, D. B. Differential requirement for CD18 in T-helper effector homing. Nature Med. 9: 1281-1286, 2003. [PubMed: 14502280, related citations] [Full Text]

  38. Lu, T. T., Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297: 409-412, 2002. [PubMed: 12130787, related citations] [Full Text]

  39. Marlin, S. D., Morton, C. C., Anderson, D. C., Springer, T. A. LFA-1 immunodeficiency disease: definition of the genetic defect and chromosomal mapping of alpha and beta subunits of the lymphocyte function-associated antigen 1 (LFA-1) by complementation in hybrid cells. J. Exp. Med. 164: 855-867, 1986. [PubMed: 3528378, related citations] [Full Text]

  40. Matsuura, S., Kishi, F., Tsukahara, M., Nunoi, H., Matsuda, I., Kobayashi, K., Kajii, T. Leukocyte adhesion deficiency: identification of novel mutations in two Japanese patients with a severe form. Biochem. Biophys. Res. Commun. 184: 1460-1467, 1992. [PubMed: 1590804, related citations] [Full Text]

  41. McDowall, A., Inwald, D., Leitinger, B., Jones, A., Liesner, R., Klein, N., Hogg, N. A novel form of integrin dysfunction involving beta-1, beta-2, and beta-3 integrins. J. Clin. Invest. 111: 51-60, 2003. [PubMed: 12511588, images, related citations] [Full Text]

  42. Miura, Y., Miura, M., Gronthos, S., Allen, M. R., Cao, C., Uveges, T. E., Bi, Y., Ehirchiou, D., Kortesidis, A., Shi, S., Zhang, L. Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis. Proc. Nat. Acad. Sci. 102: 14022-14027, 2005. [PubMed: 16172402, images, related citations] [Full Text]

  43. Nelson, C., Rabb, H., Arnaout, M. A. Genetic cause of leukocyte adhesion molecule deficiency: abnormal splicing and a missense mutation in a conserved region of CD18 impair cell surface expression of beta-2 integrins. J. Biol. Chem. 267: 3351-3357, 1992. [PubMed: 1346613, related citations]

  44. Niethammer, D., Dieterle, U., Kleihauer, E., Wildfeuer, A., Haferkamp, O., Hitzig, W. H. An inherited defect in granulocyte function: impaired chemotaxis, phagocytosis and intracellular killing of microorganisms. Helv. Paediat. Acta 30: 537-541, 1976. [PubMed: 1270326, related citations]

  45. Ostermann, G., Weber, K. S. C., Zernecke, A., Schroder, A., Weber, C. JAM-1 is a ligand of the beta-2 integrin LFA-1 involved in transendothelial migration of leukocytes. Nature Immun. 3: 151-158, 2002. [PubMed: 11812992, related citations] [Full Text]

  46. Petersen, M. B., Slaugenhaupt, S. A., Lewis, J. G., Warren, A. C., Chakravarti, A., Antonarakis, S. E. A genetic linkage map of 27 markers on human chromosome 21. Genomics 9: 407-419, 1991. [PubMed: 1674496, related citations] [Full Text]

  47. Pierce, M. W., Remold-O'Donnell, E., Todd, R. F., III, Arnaout, M. A. N-terminal sequence of human leukocyte glycoprotein Mo1: conservation across species and homology to platelet IIb/IIIa. Biochim. Biophys. Acta 874: 368-371, 1986. [PubMed: 3539202, related citations] [Full Text]

  48. Rivera-Matos, I. R., Rakita, R. M., Mariscalco, M. M., Elder, F. F. B., Dreyer, S. A., Cleary, T. G. Leukocyte adhesion deficiency mimicking Hirschsprung disease. J. Pediat. 127: 755-757, 1995. [PubMed: 7472832, related citations] [Full Text]

  49. Rosmarin, A. G., Caprio, D., Levy, R., Simkevich, C. CD18 (beta-2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity. Proc. Nat. Acad. Sci. 92: 801-805, 1995. [PubMed: 7846055, related citations] [Full Text]

  50. Ross, G. D., Thompson, R. A., Walport, M. J., Springer, T. A., Watson, J. V., Ward, R. H. R., Lida, J., Newman, S. L., Harrison, R. A., Lachmann, P. J. Characterization of patients with an increased susceptibility to bacterial infections and a genetic deficiency of leukocyte membrane complement receptor type three (CR3) and the related membrane antigen LFA-1. Blood 66: 882-890, 1985. [PubMed: 3899217, related citations]

  51. Ross, G. D. Clinical and laboratory features of patients with an inherited deficiency of neutrophil membrane complement receptor type 3 (CR3) and the related membrane antigens LFA-1 and p150,95. J. Clin. Immun. 6: 107-113, 1986. [PubMed: 3519653, related citations] [Full Text]

  52. Shuster, D. E., Kehrli, M. E., Jr., Ackermann, M. R., Gilbert, R. O. Identification and prevalence of a genetic defect that causes leukocyte adhesion deficiency in Holstein cattle. Proc. Nat. Acad. Sci. 89: 9225-9229, 1992. [PubMed: 1384046, related citations] [Full Text]

  53. Sligh, J. E., Jr., Anderson, D. C., Beaudet, A. L. A mutation in the initiation codon of the CD18 gene in a patient with the moderate phenotype of leukocyte adhesion deficiency. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A219, 1989.

  54. Solomon, E., Palmer, R. W., Hing, S., Law, S. K. A. Regional localization of CD18, the beta-subunit of the cell surface adhesion molecule LFA-1, on human chromosome 21 by in situ hybridization. Ann. Hum. Genet. 52: 123-128, 1988. [PubMed: 3073708, related citations] [Full Text]

  55. Springer, T. A., Miller, L. J., Anderson, D. C. p150,95, the third member of the Mac-1, LFA-1 human leukocyte adhesion glycoprotein family. J. Immun. 136: 240-245, 1986. [PubMed: 3510003, related citations]

  56. Springer, T. A., Teplow, D. B., Dreyer, W. J. Sequence homology of the LFA-1 and Mac-1 leukocyte adhesion glycoproteins and unexpected relation to leukocyte interferon. Nature 314: 540-542, 1985. [PubMed: 3887182, related citations] [Full Text]

  57. Springer, T. A., Thompson, W. S., Miller, L. J., Schmalstieg, F. C., Anderson, D. C. Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis. J. Exp. Med. 160: 1901-1918, 1984. [PubMed: 6096477, related citations] [Full Text]

  58. Suomalainen, H. A., Gahmberg, C. G., Patarroyo, M., Beatty, P. G., Schroder, J. Genetic assignment of GP90, leukocyte adhesion glycoprotein to human chromosome 21. Somat. Cell Molec. Genet. 12: 297-302, 1986. [PubMed: 2872730, related citations] [Full Text]

  59. Suomalainen, H. A., Gahmberg, C. G., Patarroyo, M., Schroder, J. GP90 (Leu-CAM antigen) is coded for by genes on chromosome 21. (Abstract) Cytogenet. Cell Genet. 40: 755, 1985.

  60. Taylor, G. M., Williams, A., D'Souza, S. W., Fergusson, W. D., Donnai, D., Fennell, J., Harris, R. The expression of CD18 is increased on trisomy 21 (Down syndrome) lymphoblastoid cells. Clin. Exp. Immun. 71: 324-328, 1988. [PubMed: 2964960, related citations]

  61. Todd, R. F., III, Freyer, D. R. The CD11/CD18 leukocyte glycoprotein deficiency. Hemat. Oncol. Clin. North Am. 2: 13-31, 1988. [PubMed: 3279017, related citations]

  62. van der Meer, J. W. M., van Zwet, T. L., van Furth, R. New familial defect in microbicidal function of polymorphonuclear leucocytes. Lancet 306: 630-632, 1975. Note: Originally Volume II. [PubMed: 52003, related citations] [Full Text]

  63. Vazquez-Torres, A., Jones-Carson, J., Baumler, A. J., Falkow, S., Valdivia, R., Brown, W., Le, M., Berggren, R., Parks, W. T., Fang, F. C. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401: 804-808, 1999. [PubMed: 10548107, related citations] [Full Text]

  64. Vedder, N. B., Winn, R. K., Rice, C. L., Chi, E. Y., Arfors, K.-E., Harlan, J. M. A monoclonal antibody to the adherence-promoting leukocyte glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and resuscitation in rabbits. J. Clin. Invest. 81: 939-944, 1988. [PubMed: 3278007, related citations] [Full Text]

  65. Wardlaw, A. J., Hibbs, M. L., Stacker, S. A., Springer, T. A. Distinct mutations in two patients with leukocyte adhesion deficiency and their functional correlates. J. Exp. Med. 172: 335-345, 1990. [PubMed: 1694220, related citations] [Full Text]

  66. Weening, R. S., Roos, D., Weemaes, C. M. R., Homan-Muller, J. W. T., van Schaik, M. L. J. Defective initiation of the metabolic stimulation in phagocytizing granulocytes: a new congenital defect. J. Lab. Clin. Med. 88: 757-768, 1976. [PubMed: 185306, related citations]

  67. Weitzman, J. B., Wells, C. E., Wright, A. H., Clark, P. A., Law, S. K. A. The gene organisation of the human beta-2 integrin subunit (CD18). FEBS Lett. 294: 97-103, 1991. [PubMed: 1683838, related citations] [Full Text]

  68. Wilson, J. M., Ping, A. J., Krauss, J. C., Mayo-Bond, L., Rogers, C. E., Anderson, D. C., Todd, R. F., III. Correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer. Science 248: 1413-1416, 1990. [PubMed: 1972597, related citations] [Full Text]

  69. Wilson, R. W., Ballantyne, C. M., Smith, C. W., Montgomery, C., Bradley, A., O'Brien, W. E., Beaudet, A. L. Gene targeting yields a CD18-mutant mouse for study of inflammation. J. Immun. 151: 1571-1578, 1993. [PubMed: 8101543, related citations]

  70. Yorifuji, T., Wilson, R. W., Beaudet, A. L. Retroviral mediated expression of CD18 in normal and deficient human bone marrow progenitor cells. Hum. Molec. Genet. 2: 1443-1448, 1993. [PubMed: 7902162, related citations] [Full Text]


Ada Hamosh - updated : 6/12/2008
Patricia A. Hartz - updated : 3/10/2006
Paul J. Converse - updated : 10/26/2005
Ada Hamosh - updated : 9/26/2003
Paul J. Converse - updated : 9/24/2003
Denise L. M. Goh - updated : 4/16/2003
Ada Hamosh - updated : 9/11/2002
Paul J. Converse - updated : 4/29/2002
Paul J. Converse - updated : 5/18/2000
Ada Hamosh - updated : 4/14/2000
Ada Hamosh - updated : 10/20/1999
Victor A. McKusick - updated : 3/3/1999
Creation Date:
Victor A. McKusick : 7/28/1994
alopez : 01/02/2024
carol : 08/22/2022
carol : 02/22/2022
carol : 05/17/2021
carol : 05/06/2021
carol : 05/05/2021
carol : 05/04/2021
carol : 04/09/2021
terry : 04/03/2009
terry : 3/31/2009
alopez : 6/17/2008
alopez : 6/17/2008
terry : 6/12/2008
wwang : 3/27/2006
terry : 3/10/2006
mgross : 11/8/2005
terry : 10/26/2005
alopez : 10/16/2003
alopez : 9/29/2003
terry : 9/26/2003
mgross : 9/24/2003
carol : 4/16/2003
alopez : 9/11/2002
alopez : 9/11/2002
tkritzer : 9/11/2002
mgross : 4/29/2002
mgross : 5/18/2000
alopez : 4/18/2000
terry : 4/14/2000
terry : 12/1/1999
alopez : 10/20/1999
terry : 10/20/1999
alopez : 9/7/1999
carol : 3/8/1999
terry : 3/3/1999
alopez : 3/2/1999
psherman : 8/1/1998
terry : 6/4/1998
dholmes : 5/12/1998
mark : 6/12/1997
terry : 4/19/1996
mark : 4/10/1996
terry : 4/4/1996
mark : 1/22/1996
joanna : 1/16/1996
mark : 7/20/1995
mark : 4/10/1995
pfoster : 3/1/1995
pfoster : 10/17/1994
pfoster : 10/3/1994

* 600065

INTEGRIN, BETA-2; ITGB2


Alternative titles; symbols

LEUKOCYTE CELL ADHESION MOLECULE CD18; CD18


Other entities represented in this entry:

LEUKOCYTE-ASSOCIATED ANTIGENS CD18/11A, CD18/11B, CD18/11C, INCLUDED

HGNC Approved Gene Symbol: ITGB2

Cytogenetic location: 21q22.3     Genomic coordinates (GRCh38): 21:44,885,953-44,928,815 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
21q22.3 Leukocyte adhesion deficiency 116920 Autosomal recessive 3

TEXT

Description

The leukocyte cell adhesion molecule belongs to the class of cell membrane glycoproteins known as integrins, which are alpha-beta heterodimers. The alpha subunits vary in size from 120 to 180 kD and each is noncovalently associated with a beta subunit (90 to 110 kD). There are 8 known beta subunits and 14 known alpha subunits. Although the alpha and beta subunits could in theory associate to give more than 100 integrin heterodimers, the diversity is restricted and different combinations are associated with different cell types (Hynes, 1992).


Nomenclature

The beta-2 integrin chain gene is designated ITGB2 and the leukocyte antigen has been designated CD18. The 3 alpha integrin chains associated individually with the beta-2 chain as a heterodimer have gene designations of ITGAL (153370), ITGAM (120980), and ITGAX (151510), and leukocyte antigen designations of CD11A, CD11B, and CD11C, respectively.

The 3 integrin molecules associated with leukocyte adhesion deficiency have leukocyte antigen designations of (1) CD18/CD11A: also referred to as LFA-1, Leu CAMa, and integrin beta-2/alpha-L; (2) CD18/CD11B: also referred to as CR3, Leu CAMb, Mac-1, Mo1, OKM-1, and integrin beta-2/alpha-M; (3) CD18/CD11C: also referred to as p150 (p150, 95), Leu CAMc, and integrin beta-2/alpha-X (Barclay et al., 1993).


Evolution

This glycoprotein family is conserved in mouse and human.


Gene Function

By quantitative fluorescence flow cytometric analysis, Taylor et al. (1988) showed that the expression of CD18 was increased in lymphoblastoid cells from persons with Down syndrome, consistent with the location of the gene on chromosome 21.

Bianchi et al. (2000) showed that JAB1 (604850) interacts with the cytoplasmic domain of the beta-2 subunit of the alpha-L/beta-2 integrin LFA-1. They demonstrated that a fraction of JAB1 colocalizes with LFA-1 at the cell membrane and that LFA-1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP1 complexes to their DNA consensus site and increased transactivation of an AP1-dependent promoter. Bianchi et al. (2000) suggested that signaling through the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1 nuclear localization. This represented a new pathway for integrin-dependent modulation of gene expression.

By yeast 2-hybrid analysis and leukocyte adhesion assays, Ostermann et al. (2002) demonstrated that under both static and physiologic flow conditions, JAM1 (605721), through its membrane-proximal domain 2, is a ligand of the LFA-1 integrin that contributes to the LFA-1-dependent transendothelial migration of CD45RO (151460)-positive memory T cells expressing the CXCR4 (162643) chemokine receptor and of neutrophils. These interactions also facilitated LFA-1-mediated arrest of T cells. Activation of endothelium with inflammatory cytokines enhanced memory T-cell transmigration. Ostermann et al. (2002) suggested that a complex interplay of heterophilic binding of LFA-1 to JAM1 and homophilic trans-interactions of JAM1 may provide a molecular 'zipper' for leukocyte transmigration.

Lu and Cyster (2002) studied the mechanisms that control localization of marginal zone B cells. They demonstrated that marginal zone B cells express elevated levels of the integrins LFA-1 and alpha-4-beta-1 (see 192975 and 135630), and that the marginal zone B cells bind to the ligands ICAM1 (147840) and VCAM1 (192225). These ligands are expressed within the marginal zone in a lymphotoxin-dependent manner. Combined inhibition of LFA-1 and alpha-4-beta-1 causes a rapid and selective release of B cells from the marginal zone. Furthermore, lipopolysaccharide-triggered marginal zone B cell relocalization involves downregulation of integrin-mediated adhesion. Lu and Cyster (2002) concluded that their studies identified key requirements for marginal zone B cell localization and established a role for integrins in peripheral lymphoid tissue compartmentalization.

In a patient with features of Glanzmann thrombasthenia (see 173470) and leukocyte adhesion deficiency-1 (LAD1; 116920), McDowall et al. (2003) identified a novel form of integrin dysfunction involving ITGB1 (135630), ITGB2, and ITGB3 (173470). ITGB2 and ITGB3 were constitutively clustered. Although all 3 integrins were expressed on the cell surface at normal levels and were capable of function following extracellular stimulation, they could not be activated via the 'inside-out' signaling pathways.

Kim et al. (2003) investigated cytoplasmic conformational changes in the integrin LFA1 (alpha-L, 153370; beta-2) in living cells by measuring fluorescence resonance energy transfer between cyan fluorescent protein-fused and yellow fluorescent protein-fused alpha-L and beta-2 cytoplasmic domains. In the resting state these domains were close to each other, but underwent significant spatial separation upon either intracellular activation of integrin adhesiveness (inside-out signaling) or ligand binding (outside-in signaling). Thus, bidirectional integrin signaling is accomplished by coupling extracellular conformational changes to an unclasping and separation of the alpha and beta cytoplasmic domains, which Kim et al. (2003) noted as a distinctive mechanism for transmitting information across the plasma membrane.

Cherry et al. (2004) generated T-cell clones expressing less than half the wildtype amount of RHOH (602037), a leukocyte-specific inhibitory Rho family member. Resting cells expressed constitutively adhesive LFA1 and bound spontaneously to ICAM1, ICAM2 (146630), and ICAM3 (146631). Reconstituting RHOH mRNA levels reverted the adhesion phenotype to that of relatively nonadhesive wildtype cells. Treatment of peripheral blood lymphocytes with RHOH RNA interference altered the nonadhesive phenotype. Cherry et al. (2004) concluded that RHOH is required for maintenance of lymphocyte LFA1 in a nonadhesive state.

Lammermann et al. (2008) studied the interplay between adhesive, contractile, and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro. The authors ablated genes encoding integrin heterodimeric partners ITGA5 (135620), ITGB1 (135630), ITGB2, and ITGB7 (147559) from murine leukocytes and demonstrated that functional integrins do not contribute to migration in 3-dimensional environments. Instead, these cells migrate by the sole force of actin network expansion, which promotes protrusive flowing of the leading edge. Myosin II-dependent contraction is required only on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus.


Gene Structure

Weitzman et al. (1991) determined that the ITGB2 gene spans approximately 40 kb and contains 16 exons.


Mapping

Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is located on chromosome 21. The method used involved somatic cell hybrids between mouse and human lymphocytes, indirect immunofluorescence, and cell sorting. By somatic cell hybridization, Akao et al. (1987) confirmed the chromosomal assignment. By human-mouse T-cell fusion studies, Marlin et al. (1986) also showed that the beta subunit maps to chromosome 21. Using a cDNA probe for in situ hybridization, Solomon et al. (1988) localized the ITGB2 (CD18) gene to 21q22.1-qter. Petersen et al. (1991) assigned CD18 to 21q22.3 and positioned it in that band relative to 15 other genes or DNA markers.


Molecular Genetics

Mutations in the beta-2 subunit of the leukocyte cell adhesion molecule have been found to cause the autosomal recessive disorder of neutrophil function known as leukocyte adhesion deficiency. LAD is characterized by recurrent bacterial infections and a lack of beta-2/alpha-L (see 153370), beta-2/alpha-M (see 120980), and beta-2/alpha-X (see 151510) expression.

In a patient with LAD deficiency, Arnaout et al. (1990) identified compound heterozygous mutations in the CD18 gene (600065.0001-600065.0002).

In 2 patients with LAD deficiency, Wardlaw et al. (1990) identified mutations in the CD18 gene (600065.0003; 600065.0004).

Rivera-Matos et al. (1995) described an infant in whom clinical signs suggesting Hirschsprung disease were the initial manifestation of LAD. Chromosome studies showed a deletion of the distal third of the long arm of one chromosome 21, and flow cytometric studies confirmed the defective expression of CD18. Leukocyte adhesion deficiency was suspected because of leukocytosis, poor wound healing, frequent infections, and biopsy specimens showing a paucity of neutrophils. It seems quite possible that the patient indeed had Hirschsprung disease as well as leukocyte adhesion deficiency. Aganglionic megacolon is a frequent finding in trisomy 21 and preliminary evidence for a genetic modifier of Hirschsprung disease on 21q22 has been presented (600156).


Animal Model

Wilson et al. (1993) found that a hypomorphic mutation in CD18, generated by gene targeting in mice, showed in homozygosity increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain by Bullard et al. (1996), virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed changes of a type found in human psoriasis (177900) and other hyperproliferative inflammatory skin disorders. No bacterial or fungal organisms were found to be involved in the pathogenesis of the disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. The findings of Bullard et al. (1996) were notable since no comparable skin disease had been reported in humans or cattle with LAD deficiency type I and since this disorder did not occur in mice when the mutation was studied on a C57BL/6 or 129/Sv background. From backcross experiments the authors suggested that a small number of genes (perhaps as few as one), in addition to CD18, determined susceptibility to the disorder.

Vazquez-Torres et al. (1999) reported that Salmonella is transported from the gastrointestinal tract to the bloodstream by CD18-expressing phagocytes, and that CD18-deficient mice are resistant to dissemination of Salmonella to the liver and spleen after oral administration. Vazquez-Torres et al. (1999) hypothesized that the CD18-dependent pathway of extraintestinal dissemination may be important for the development of systemic immunity to gastrointestinal pathogens, because oral challenge with Salmonella pathogenicity island-1 (SPI1)-deficient S. typhimurium elicits a specific systemic IgG humoral immune response, despite an inability to stimulate production of specific mucosal IgA.

Lee et al. (2003) generated mice lacking Cd18. In vitro, activated lymphocytes from these mice had normal Th1 and Th2 cytokine production. The Cd18 -/- mice were more resistant than C57BL/6 mice to challenge with Leishmania major, but they were also resistant to allergic lung inflammation, even though they produced amounts of T cell-dependent allergen-specific antibody comparable to wildtype mice. The authors found that disease production required the homing of Th2 cells (IL4-positive) to the lungs, and this migration was impaired in Cd18 -/- mice and in mice treated with anti-Cd18. Lee et al. (2003) proposed that integrin blockade could be a tactic for selectively excluding Th2 cells under diverse inflammatory conditions.

Miura et al. (2005) found that Cd18-null mice had defective osteoclastogenesis due to reduced expression of the osteogenic master regulator Runx2 (600211). Radiographic analysis of Cd18-null mice showed reduced bone mineral density and features of osteoporosis. Cd18 was expressed by bone marrow stromal stem cells, and constitutive overexpression of Cd18 in this cell population in normal mice enhanced bone formation. The authors suggested that LAD patients may be predisposed to develop osteoporosis.


ALLELIC VARIANTS 15 Selected Examples):

.0001   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ARG593CYS
SNP: rs137852609, gnomAD: rs137852609, ClinVar: RCV000799618, RCV003407313

Arnaout et al. (1990) found that a patient with leukocyte adhesion deficiency (LAD1; 116920) was compound heterozygous for 2 mutations in the CD18 gene: arg593-to-cys and lys196-to-thr. These amino acids lie in regions necessary for normal cell surface expression of CD18 and possibly other integrin-beta subunits. Arnaout et al. (1990) demonstrated that each mutant allele resulted in impaired CD18 expression on the cell surface membrane of transfected COS M6 cells.


.0002   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, LYS196THR
SNP: rs137852610, gnomAD: rs137852610, ClinVar: RCV000010067

For discussion of the lys196-to-thr (K196T) mutation in the CD18 gene that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency (LAD1; 116920) by Arnaout et al. (1990), see 600065.0001.


.0003   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, LEU149PRO
SNP: rs137852611, ClinVar: RCV000010068

In a patient (patient 14) with moderately severe leukocyte adhesion deficiency (LAD1; 116920), Wardlaw et al. (1990) demonstrated a T-to-C transition in the CD18 gene, resulting in substitution of proline for leucine-149. Cotransfection of the beta subunit cDNA containing this mutation with the wildtype alpha subunit of LFA-1 in a mammalian expression system resulted in no expression of LFA-1. Normal life of the mutant beta subunits and previous demonstration of the lack of alpha/beta complex formation during biosynthesis in the patient's cells suggested a defect in association with the alpha subunit. Loss of functional expression of this beta-subunit mutation suggests that it lies in a site critical for association with the alpha subunit. (In MIM10, this mutation was incorrectly listed as pro149-to-leu. The wildtype residue is leu (Bairoch, 1994).)


.0004   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY169ARG
SNP: rs137852612, ClinVar: RCV000010069

In a patient (patient 2) with severe leukocyte adhesion deficiency (LAD1; 116920), Wardlaw et al. (1990) demonstrated a G-to-A transition in the CD18 gene, resulting in a glycine-to-arginine change at amino acid 169 of the beta subunit. As in the case of the leu149-to-pro mutation, there appeared to be interference with association between the mutant beta subunit and the normal alpha subunit.


.0005   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, INITIATION MUTATION
SNP: rs387906411, ClinVar: RCV000010070

Sligh et al. (1989) found an ATG-to-AAG alteration in the initiation codon of the CD18 gene in a patient with moderately severe leukocyte adhesion deficiency (LAD1; 116920). In fact, the patient was a genetic compound; the particular mutation was found in the patient and in the father.


.0006   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ARG586TRP AND 12-BP INS
SNP: rs5030672, gnomAD: rs5030672, ClinVar: RCV000990357, RCV001212520, RCV001376111, RCV001723557, RCV001729344, RCV003914825

In a patient with partial leukocyte adhesion deficiency (LAD1; 116920) who was previously reported by Arnaout et al. (1984), Nelson et al. (1992) demonstrated 2 mutant alleles in the CD18 gene. The allele from the mother contained 2 mutations: a 12-bp insertion resulting in an in-frame addition of 4 amino acids (pro-ser-ser-gln) between proline-247 and glutamic acid-248, and a 1756C-T nucleotide transition resulting in an arg586-to-trp substitution in the CD18 protein. The 12-bp insertion arose by a single C-to-A transversion in the 3-prime terminus of an intron, generating an aberrant splice acceptor site. COS cells cotransfected with a normal alpha chain gene (CD11B) and the mother's doubly mutant allele showed no surface expression of CD18; when transfected with the arg586-to-trp mutant gene, expression was 22% of normal. The other allele, which was not present in either parent, contained a 1052A-G transition, resulting in an asn351-to-ser (N351S; 600065.0008) substitution.


.0007   MOVED TO 600065.0006


.0008   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ASN351SER
SNP: rs137852613, ClinVar: RCV000010073

For discussion of the 1052A-G transition in the CD18 gene, resulting in substitution of serine for asparagine-351 (N351S), that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency-1 (LAD1; 116920) by Nelson et al. (1992), see 600065.0006.


.0009   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, PRO178LEU
SNP: rs137852614, gnomAD: rs137852614, ClinVar: RCV000010074

In a child with severe leukocyte adhesion deficiency (LAD1; 116920), Back et al. (1992) found compound heterozygous mutations in the CD18 gene. One allele had a C-to-T transition at nucleotide 606, resulting in substitution of leucine for proline at amino acid 178. The change occurred in a region that is highly conserved among the integrin beta subunits and where previous defects had been identified in LAD. The other allele had a 220-bp deletion in the cDNA coding for a portion of the extracellular domain, which resulted in a frameshift and a premature stop codon. The deleted region corresponded to exon 13 of the ITGB2 (CD18) gene. The patient had previously been reported by Bowen et al. (1982) and Beatty et al. (1984).


.0010   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, ASP128ASN
SNP: rs137852615, gnomAD: rs137852615, ClinVar: RCV000010075

In a patient with leukocyte adhesion deficiency (LAD1; 116920), Matsuura et al. (1992) identified a G-to-A transition at nucleotide 454 of the CD18 gene, which resulted in an asp128-to-asn substitution. The asp128 residue is located in a region which is crucial for the association of beta subunits with alpha subunits and is strictly conserved among the integrin beta subunits.


.0011   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, IVSDS, G-A, +1
SNP: rs201752283, gnomAD: rs201752283, ClinVar: RCV000087127

In a patient with leukocyte adhesion deficiency (LAD1; 116920), Matsuura et al. (1992) identified a G-to-A substitution at the first nucleotide of the splice donor site of a 1.2-kb intron in the CD18 gene.


.0012   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY284SER
SNP: rs137852616, gnomAD: rs137852616, ClinVar: RCV000705990, RCV001266603, RCV002254903

In an 18-year-old girl reported by Bowen et al. (1982) with moderately severe leukocyte adhesion deficiency-1 (LAD1; 116920), Back et al. (1993) found a single base substitution in the CD18 gene resulting in a glycine284-to-serine substitution. The change occurred in a highly conserved region of the extracellular domain in which several other mutations had been identified.


.0013   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, SER138PRO
SNP: rs137852617, ClinVar: RCV000010078

Hogg et al. (1999) described a patient with clinical features compatible with a markedly severe phenotype of leukocyte adhesion deficiency (LAD1; 116920) who was found to express the beta-2 integrins LFA-1 and Mac-1 at 40 to 60% of normal levels. This level of expression should be adequate for normal integrin function, but both the patient's Mac-1 on neutrophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule-1 (ICAM1; 147840), or to display a beta-2 integrin activation epitope after adhesion-inducing stimuli. Unexpectedly, divalent cation treatment induced the patient's T cells to bind to ICAM2 (146630) and ICAM3 (146631). Sequencing of the patient's 2 CD18 alleles revealed compound heterozygosity of 2 missense mutations, S138P and G273R (600065.0014). Both mutations were in the beta-2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion-dependent adhesion site (MIDAS) motif. After transfection of K562 cells with alpha subunits, the mutated S138P beta-subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. Thus, the patient exhibited failure of the beta-2 integrins to function despite adequate levels of cell surface expression.

The 15-year-old patient studied by Hogg et al. (1999) first presented as an infant with severe and recurrent skin infections requiring prolonged treatment with intravenous antibiotics and surgery to remove necrotic tissue. In spite of attentive oral hygiene, the patient suffered from severe periodontitis and gingivitis. Otitis media and chest infections had also been consistent features. Organisms isolated from infected sites included Staphylococcus aureus, Pseudomonas, and Streptococcus species. The neutrophil count was persistently elevated, reaching peaks of more than 10 times normal at times of infection. Phagocytosis by the patient's neutrophils was less than 25% that of a healthy adult control. On the other hand, respiratory burst was either normal or slightly enhanced, and intracellular killing of S. epidermidis was within normal limits. Therefore, although the uptake of the organisms was faulty, intracellular processes by which phagocytes deal with bacteria appeared normal.


.0014   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, GLY273ARG
SNP: rs137852618, gnomAD: rs137852618, ClinVar: RCV000355931, RCV000768241

For discussion of the gly273-to-arg (G273R) substitution in the ITGB2 gene that was found in compound heterozygous state in a patient with leukocyte adhesion deficiency-1 (LAD1; 116920) by Hogg et al. (1999), see 600065.0013.


.0015   LEUKOCYTE ADHESION DEFICIENCY 1

ITGB2, IVS4AS, 169-BP DEL, -37
ClinVar: RCV000010080

By studying a herpesvirus saimiri-transformed T cell line from a patient with severe leukocyte adhesion deficiency (LAD1; 116920), Allende et al. (2000) identified a 169-bp genomic deletion in the ITGB2 gene (from -37 of intron 4 to +132 of exon 5) that abolished the intron 4 acceptor splicing site, resulting in the total skipping of exon 5. The genomic deletion led to a 171-bp in-frame mRNA deletion (nucleotides 329 to 500) that resulted in the absence of cell surface and cytoplasmic CD18 expression. Functional analysis showed a severe, selective T-cell activation impairment in the CD2 but not the CD3 pathway. The male patient, whose father was not known and who had no family history of LAD, died at age 12 months after unsuccessful bone marrow transplants at 7 and 10 months of age.


See Also:

Abramson et al. (1981); Anderson et al. (1985); Anderson and Springer (1987); Arnaout et al. (1982); Bissenden et al. (1981); Crowley et al. (1980); Dana et al. (1987); Dana et al. (1984); Fischer et al. (1986); Fujita et al. (1985); Fujita et al. (1988); Harvath and Andersen (1979); Hayward et al. (1979); Hibbs et al. (1990); Kehrli et al. (1992); Kishimoto et al. (1987); Kishimoto et al. (1987); Kobayashi et al. (1984); Krauss et al. (1991); Niethammer et al. (1976); Pierce et al. (1986); Rosmarin et al. (1995); Ross et al. (1985); Ross (1986); Shuster et al. (1992); Springer et al. (1986); Springer et al. (1985); Springer et al. (1984); Todd and Freyer (1988); van der Meer et al. (1975); Vedder et al. (1988); Weening et al. (1976); Wilson et al. (1990); Yorifuji et al. (1993)

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Contributors:
Ada Hamosh - updated : 6/12/2008
Patricia A. Hartz - updated : 3/10/2006
Paul J. Converse - updated : 10/26/2005
Ada Hamosh - updated : 9/26/2003
Paul J. Converse - updated : 9/24/2003
Denise L. M. Goh - updated : 4/16/2003
Ada Hamosh - updated : 9/11/2002
Paul J. Converse - updated : 4/29/2002
Paul J. Converse - updated : 5/18/2000
Ada Hamosh - updated : 4/14/2000
Ada Hamosh - updated : 10/20/1999
Victor A. McKusick - updated : 3/3/1999

Creation Date:
Victor A. McKusick : 7/28/1994

Edit History:
alopez : 01/02/2024
carol : 08/22/2022
carol : 02/22/2022
carol : 05/17/2021
carol : 05/06/2021
carol : 05/05/2021
carol : 05/04/2021
carol : 04/09/2021
terry : 04/03/2009
terry : 3/31/2009
alopez : 6/17/2008
alopez : 6/17/2008
terry : 6/12/2008
wwang : 3/27/2006
terry : 3/10/2006
mgross : 11/8/2005
terry : 10/26/2005
alopez : 10/16/2003
alopez : 9/29/2003
terry : 9/26/2003
mgross : 9/24/2003
carol : 4/16/2003
alopez : 9/11/2002
alopez : 9/11/2002
tkritzer : 9/11/2002
mgross : 4/29/2002
mgross : 5/18/2000
alopez : 4/18/2000
terry : 4/14/2000
terry : 12/1/1999
alopez : 10/20/1999
terry : 10/20/1999
alopez : 9/7/1999
carol : 3/8/1999
terry : 3/3/1999
alopez : 3/2/1999
psherman : 8/1/1998
terry : 6/4/1998
dholmes : 5/12/1998
mark : 6/12/1997
terry : 4/19/1996
mark : 4/10/1996
terry : 4/4/1996
mark : 1/22/1996
joanna : 1/16/1996
mark : 7/20/1995
mark : 4/10/1995
pfoster : 3/1/1995
pfoster : 10/17/1994
pfoster : 10/3/1994