RBCC

Full text data of ITGB2

ITGB2 (CD18, MFI7) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Integrin beta-2 (Cell surface adhesion glycoproteins LFA-1/CR3/p150,95 subunit beta; Complement receptor C3 subunit beta; CD18; Flags: Precursor)

UniProt P05107
ID ITB2_HUMAN Reviewed; 769 AA.
AC P05107; B3KTS8; D3DSM1; Q16418; Q53HS5; Q9UD72;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 2.
DT 22-JAN-2014, entry version 185.
DE RecName: Full=Integrin beta-2;
DE AltName: Full=Cell surface adhesion glycoproteins LFA-1/CR3/p150,95 subunit beta;
DE AltName: Full=Complement receptor C3 subunit beta;
DE AltName: CD_antigen=CD18;
DE Flags: Precursor;
GN Name=ITGB2; Synonyms=CD18, MFI7;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT HIS-354.
RX PubMed=3028646; DOI=10.1016/0092-8674(87)90246-7;
RA Kishimoto T.K., O'Connor K., Lee A., Roberts T.M., Springer T.A.;
RT "Cloning of the beta subunit of the leukocyte adhesion proteins:
RT homology to an extracellular matrix receptor defines a novel supergene
RT family.";
RL Cell 48:681-690(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-354.
RX PubMed=1683838; DOI=10.1016/0014-5793(91)81351-8;
RA Weitzman J.B., Wells C.E., Wright A.H., Clark P.A., Law S.K.A.;
RT "The gene organisation of the human beta 2 integrin subunit (CD18).";
RL FEBS Lett. 294:97-103(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-354.
RC TISSUE=Synovial cell;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-354.
RC TISSUE=Adipose tissue;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT HIS-354.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-354.
RC TISSUE=Muscle;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 9-769, PARTIAL PROTEIN SEQUENCE, AND
RP VARIANT HIS-354.
RC TISSUE=Spleen;
RX PubMed=2954816;
RA Law S.K.A., Gagnon J., Hildreth J.E., Wells C.E., Willis A.C.,
RA Wong A.J.;
RT "The primary structure of the beta-subunit of the cell surface
RT adhesion glycoproteins LFA-1, CR3 and p150,95 and its relationship to
RT the fibronectin receptor.";
RL EMBO J. 6:915-919(1987).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 124-199, AND VARIANT LAD1 LEU-178.
RC TISSUE=Lymphoblast;
RX PubMed=7509236; DOI=10.1002/humu.1380020606;
RA Ohashi Y., Yambe T., Tsuchiya S., Kikuchi H., Konno T.;
RT "Familial genetic defect in a case of leukocyte adhesion deficiency.";
RL Hum. Mutat. 2:458-467(1993).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 347-355, VARIANTS LAD1 SER-351 AND
RP TRP-586, AND VARIANT HIS-354.
RX PubMed=1346613;
RA Nelson C., Rabb H., Arnaout M.A.;
RT "Genetic cause of leukocyte adhesion molecule deficiency. Abnormal
RT splicing and a missense mutation in a conserved region of CD18 impair
RT cell surface expression of beta 2 integrins.";
RL J. Biol. Chem. 267:3351-3357(1992).
RN [11]
RP INTERACTION WITH COPS5.
RX PubMed=10766246; DOI=10.1038/35007098;
RA Bianchi E., Denti S., Granata A., Bossi G., Geginat J., Villa A.,
RA Rogge L., Pardi R.;
RT "Integrin LFA-1 interacts with the transcriptional co-activator JAB1
RT to modulate AP-1 activity.";
RL Nature 404:617-621(2000).
RN [12]
RP PHOSPHORYLATION AT SER-745; SER-756; THR-758 AND THR-760.
RX PubMed=11700305; DOI=10.1074/jbc.M106856200;
RA Fagerholm S., Morrice N., Gahmberg C.G., Cohen P.;
RT "Phosphorylation of the cytoplasmic domain of the integrin CD18 chain
RT by protein kinase C isoforms in leukocytes.";
RL J. Biol. Chem. 277:1728-1738(2002).
RN [13]
RP INTERACTION WITH RANBP9.
RX PubMed=14722085; DOI=10.1074/jbc.M313515200;
RA Denti S., Sirri A., Cheli A., Rogge L., Innamorati G., Putignano S.,
RA Fabbri M., Pardi R., Bianchi E.;
RT "RanBPM is a phosphoprotein that associates with the plasma membrane
RT and interacts with the integrin LFA-1.";
RL J. Biol. Chem. 279:13027-13034(2004).
RN [14]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-212, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [15]
RP FUNCTION DURING LUNG INJURY.
RX PubMed=18587400; DOI=10.1038/ni.1628;
RA Xu J., Gao X.-P., Ramchandran R., Zhao Y.-Y., Vogel S.M., Malik A.B.;
RT "Nonmuscle myosin light-chain kinase mediates neutrophil
RT transmigration in sepsis-induced lung inflammation by activating beta2
RT integrins.";
RL Nat. Immunol. 9:880-886(2008).
RN [16]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-50 AND ASN-212, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [17]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-50; ASN-116; ASN-212;
RP ASN-213 AND ASN-215, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19349973; DOI=10.1038/nbt.1532;
RA Wollscheid B., Bausch-Fluck D., Henderson C., O'Brien R., Bibel M.,
RA Schiess R., Aebersold R., Watts J.D.;
RT "Mass-spectrometric identification and relative quantification of N-
RT linked cell surface glycoproteins.";
RL Nat. Biotechnol. 27:378-386(2009).
RN [18]
RP X-RAY CRYSTALLOGRAPHY (3.5 ANGSTROMS) OF 23-699 IN COMPLEX WITH ITGAX,
RP GLYCOSYLATION AT ASN-116, DISULFIDE BONDS, CALCIUM-BINDING SITES, AND
RP SUBUNIT.
RX PubMed=20033057; DOI=10.1038/emboj.2009.367;
RA Xie C., Zhu J., Chen X., Mi L., Nishida N., Springer T.A.;
RT "Structure of an integrin with an alphaI domain, complement receptor
RT type 4.";
RL EMBO J. 29:666-679(2010).
RN [19]
RP VARIANTS LAD1 THR-196 AND CYS-593.
RX PubMed=1968911; DOI=10.1172/JCI114529;
RA Arnaout M.A., Dana N., Gupta S.K., Tenen D.G., Fathallah D.M.;
RT "Point mutations impairing cell surface expression of the common beta
RT subunit (CD18) in a patient with leukocyte adhesion molecule (Leu-CAM)
RT deficiency.";
RL J. Clin. Invest. 85:977-981(1990).
RN [20]
RP VARIANTS LAD1 PRO-149 AND ARG-169.
RX PubMed=1694220; DOI=10.1084/jem.172.1.335;
RA Wardlaw A.J., Hibbs M.L., Stacker S.A., Springer T.A.;
RT "Distinct mutations in two patients with leukocyte adhesion deficiency
RT and their functional correlates.";
RL J. Exp. Med. 172:335-345(1990).
RN [21]
RP VARIANT LAD1 ASN-128.
RX PubMed=1590804; DOI=10.1016/S0006-291X(05)80047-6;
RA Matsuura S., Kishi F., Tsukahara M., Nunoi H., Matsuda I.,
RA Kobayashi K., Kajii T.;
RT "Leukocyte adhesion deficiency: identification of novel mutations in
RT two Japanese patients with a severe form.";
RL Biochem. Biophys. Res. Commun. 184:1460-1467(1992).
RN [22]
RP VARIANT LAD1 ARG-169.
RX PubMed=1352501; DOI=10.1002/eji.1830220730;
RA Corbi A., Vara A., Ursa A., Rodriguez M.C.G., Fontan G.,
RA Sanchez-Madrid F.;
RT "Molecular basis for a severe case of leukocyte adhesion deficiency.";
RL Eur. J. Immunol. 22:1877-1881(1992).
RN [23]
RP VARIANT LAD1 LEU-178.
RX PubMed=1347532;
RA Back L.L., Kwok W.W., Hickstein D.D.;
RT "Identification of two molecular defects in a child with leukocyte
RT adherence deficiency.";
RL J. Biol. Chem. 267:5482-5487(1992).
RN [24]
RP VARIANT LAD1 SER-284.
RX PubMed=7686755; DOI=10.1006/bbrc.1993.1712;
RA Back L.A., Kerkering M., Baker D., Bauer T.R., Embree L.J.,
RA Hickstein D.D.;
RT "A point mutation associated with leukocyte adhesion deficiency type 1
RT of moderate severity.";
RL Biochem. Biophys. Res. Commun. 193:912-918(1993).
RN [25]
RP VARIANTS LAD1 PRO-138 AND ARG-273.
RX PubMed=9884339; DOI=10.1172/JCI3312;
RA Hogg N., Stewart M.P., Scarth S.L., Newton R., Shaw J.M., Law S.K.A.,
RA Klein N.;
RT "A novel leukocyte adhesion deficiency caused by expressed but
RT nonfunctional beta2 integrins Mac-1 and LFA-1.";
RL J. Clin. Invest. 103:97-106(1999).
RN [26]
RP VARIANT LAD1 VAL-300.
RX PubMed=20529581;
RA Li L., Jin Y.Y., Cao R.M., Chen T.X.;
RT "A novel point mutation in CD18 causing leukocyte adhesion deficiency
RT in a Chinese patient.";
RL Chin. Med. J. 123:1278-1282(2010).
RN [27]
RP VARIANTS LAD1 TYR-128; THR-239 AND ALA-716.
RX PubMed=20549317; DOI=10.1007/s10875-010-9433-2;
RA Parvaneh N., Mamishi S., Rezaei A., Rezaei N., Tamizifar B.,
RA Parvaneh L., Sherkat R., Ghalehbaghi B., Kashef S., Chavoshzadeh Z.,
RA Isaeian A., Ashrafi F., Aghamohammadi A.;
RT "Characterization of 11 new cases of leukocyte adhesion deficiency
RT type 1 with seven novel mutations in the ITGB2 gene.";
RL J. Clin. Immunol. 30:756-760(2010).
CC -!- FUNCTION: Integrin alpha-L/beta-2 is a receptor for ICAM1, ICAM2,
CC ICAM3 and ICAM4. Integrins alpha-M/beta-2 and alpha-X/beta-2 are
CC receptors for the iC3b fragment of the third complement component
CC and for fibrinogen. Integrin alpha-X/beta-2 recognizes the
CC sequence G-P-R in fibrinogen alpha-chain. Integrin alpha-M/beta-2
CC recognizes P1 and P2 peptides of fibrinogen gamma chain. Integrin
CC alpha-M/beta-2 is also a receptor for factor X. Integrin alpha-
CC D/beta-2 is a receptor for ICAM3 and VCAM1. Triggers neutrophil
CC transmigration during lung injury through PTK2B/PYK2-mediated
CC activation.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta subunit. Beta-2
CC associates with either alpha-L, alpha-M, alpha-X or alpha-D.
CC Interacts with FGR (By similarity). Interacts with COPS5 and
CC RANBP9.
CC -!- INTERACTION:
CC P00519:ABL1; NbExp=4; IntAct=EBI-300173, EBI-375543;
CC P35241:RDX; NbExp=2; IntAct=EBI-300173, EBI-2514878;
CC Q9Y4G6:TLN2; NbExp=5; IntAct=EBI-300173, EBI-1220811;
CC -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane
CC protein.
CC -!- PTM: Both Ser-745 and Ser-756 become phosphorylated when T-cells
CC are exposed to phorbol esters. Phosphorylation on Thr-758 (but not
CC on Ser-756) allows interaction with 14-3-3 proteins.
CC -!- DISEASE: Leukocyte adhesion deficiency 1 (LAD1) [MIM:116920]: LAD1
CC patients have recurrent bacterial infections and their leukocytes
CC are deficient in a wide range of adhesion-dependent functions.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the integrin beta chain family.
CC -!- SIMILARITY: Contains 1 VWFA domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAD96225.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=ITGB2base; Note=ITGB2 mutation db;
CC URL="http://bioinf.uta.fi/ITGB2base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/ITGB2";
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DR EMBL; M15395; AAA59490.1; -; mRNA.
DR EMBL; X64072; CAA45427.1; -; Genomic_DNA.
DR EMBL; X64073; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64074; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64075; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64076; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64077; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64078; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64079; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64080; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64081; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64082; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X64083; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X63924; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X63925; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; X63926; CAA45427.1; JOINED; Genomic_DNA.
DR EMBL; AK095992; BAG53190.1; -; mRNA.
DR EMBL; AK222505; BAD96225.1; ALT_INIT; mRNA.
DR EMBL; AL163300; CAB90553.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09381.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09382.1; -; Genomic_DNA.
DR EMBL; CH471079; EAX09385.1; -; Genomic_DNA.
DR EMBL; BC005861; AAH05861.1; -; mRNA.
DR EMBL; Y00057; CAA68266.1; -; mRNA.
DR EMBL; S81234; AAB21404.1; -; mRNA.
DR PIR; A25967; IJHULM.
DR RefSeq; NP_000202.2; NM_000211.3.
DR RefSeq; NP_001120963.1; NM_001127491.1.
DR UniGene; Hs.375957; -.
DR PDB; 1JX3; Model; -; A=126-364.
DR PDB; 1L3Y; NMR; -; A=535-574.
DR PDB; 1YUK; X-ray; 1.80 A; A=23-125, B=365-482.
DR PDB; 2JF1; X-ray; 2.20 A; T=735-769.
DR PDB; 2P26; X-ray; 1.75 A; A=23-535.
DR PDB; 2P28; X-ray; 2.20 A; A=23-122, B=362-574.
DR PDB; 2V7D; X-ray; 2.50 A; P/Q/R/S=755-764.
DR PDB; 3K6S; X-ray; 3.50 A; B/D/F/H=23-699.
DR PDB; 3K71; X-ray; 3.95 A; B/D/F/H=23-699.
DR PDB; 3K72; X-ray; 3.70 A; B/D=23-699.
DR PDBsum; 1JX3; -.
DR PDBsum; 1L3Y; -.
DR PDBsum; 1YUK; -.
DR PDBsum; 2JF1; -.
DR PDBsum; 2P26; -.
DR PDBsum; 2P28; -.
DR PDBsum; 2V7D; -.
DR PDBsum; 3K6S; -.
DR PDBsum; 3K71; -.
DR PDBsum; 3K72; -.
DR ProteinModelPortal; P05107; -.
DR SMR; P05107; 23-696, 698-763.
DR DIP; DIP-478N; -.
DR IntAct; P05107; 15.
DR MINT; MINT-129139; -.
DR STRING; 9606.ENSP00000303242; -.
DR BindingDB; P05107; -.
DR ChEMBL; CHEMBL2096661; -.
DR DrugBank; DB00641; Simvastatin.
DR PhosphoSite; P05107; -.
DR DMDM; 124056465; -.
DR PaxDb; P05107; -.
DR PRIDE; P05107; -.
DR DNASU; 3689; -.
DR Ensembl; ENST00000302347; ENSP00000303242; ENSG00000160255.
DR Ensembl; ENST00000355153; ENSP00000347279; ENSG00000160255.
DR Ensembl; ENST00000397850; ENSP00000380948; ENSG00000160255.
DR Ensembl; ENST00000397852; ENSP00000380950; ENSG00000160255.
DR Ensembl; ENST00000397857; ENSP00000380955; ENSG00000160255.
DR GeneID; 3689; -.
DR KEGG; hsa:3689; -.
DR UCSC; uc002zgd.2; human.
DR CTD; 3689; -.
DR GeneCards; GC21M046305; -.
DR HGNC; HGNC:6155; ITGB2.
DR HPA; HPA008877; -.
DR HPA; HPA016894; -.
DR MIM; 116920; phenotype.
DR MIM; 600065; gene.
DR neXtProt; NX_P05107; -.
DR Orphanet; 99842; Leukocyte adhesion deficiency type I.
DR PharmGKB; PA29955; -.
DR eggNOG; NOG287997; -.
DR HOGENOM; HOG000252936; -.
DR HOVERGEN; HBG006190; -.
DR InParanoid; P05107; -.
DR KO; K06464; -.
DR OMA; RGRCRCN; -.
DR OrthoDB; EOG7T7GSB; -.
DR PhylomeDB; P05107; -.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P05107; -.
DR ChiTaRS; ITGB2; human.
DR EvolutionaryTrace; P05107; -.
DR GeneWiki; CD18; -.
DR GenomeRNAi; 3689; -.
DR NextBio; 14449; -.
DR PMAP-CutDB; P05107; -.
DR PRO; PR:P05107; -.
DR ArrayExpress; P05107; -.
DR Bgee; P05107; -.
DR CleanEx; HS_ITGB2; -.
DR Genevestigator; P05107; -.
DR GO; GO:0008305; C:integrin complex; NAS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004872; F:receptor activity; IEA:InterPro.
DR GO; GO:0006915; P:apoptotic process; NAS:UniProtKB.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0007267; P:cell-cell signaling; NAS:UniProtKB.
DR GO; GO:0007160; P:cell-matrix adhesion; IEA:InterPro.
DR GO; GO:0006954; P:inflammatory response; NAS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0007229; P:integrin-mediated signaling pathway; NAS:UniProtKB.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IDA:UniProtKB.
DR GO; GO:0007275; P:multicellular organismal development; IEA:InterPro.
DR GO; GO:0030593; P:neutrophil chemotaxis; IDA:UniProtKB.
DR GO; GO:0008360; P:regulation of cell shape; NAS:UniProtKB.
DR GO; GO:0050730; P:regulation of peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR Gene3D; 3.40.50.410; -; 1.
DR InterPro; IPR015812; Integrin_bsu.
DR InterPro; IPR015439; Integrin_bsu-2.
DR InterPro; IPR014836; Integrin_bsu_cyt_dom.
DR InterPro; IPR002369; Integrin_bsu_N.
DR InterPro; IPR012896; Integrin_bsu_tail.
DR InterPro; IPR016201; Plexin-like_fold.
DR InterPro; IPR002035; VWF_A.
DR PANTHER; PTHR10082; PTHR10082; 1.
DR PANTHER; PTHR10082:SF15; PTHR10082:SF15; 1.
DR Pfam; PF08725; Integrin_b_cyt; 1.
DR Pfam; PF07965; Integrin_B_tail; 1.
DR Pfam; PF00362; Integrin_beta; 1.
DR PIRSF; PIRSF002512; Integrin_B; 1.
DR PRINTS; PR01186; INTEGRINB.
DR SMART; SM00187; INB; 1.
DR SMART; SM00423; PSI; 1.
DR SMART; SM00327; VWA; 1.
DR SUPFAM; SSF103575; SSF103575; 1.
DR SUPFAM; SSF69687; SSF69687; 1.
DR PROSITE; PS00022; EGF_1; UNKNOWN_2.
DR PROSITE; PS01186; EGF_2; UNKNOWN_3.
DR PROSITE; PS00243; INTEGRIN_BETA; 3.
DR PROSITE; PS50234; VWFA; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Cell adhesion; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Integrin; Membrane; Metal-binding; Phosphoprotein;
KW Pyrrolidone carboxylic acid; Receptor; Reference proteome; Repeat;
KW Signal; Transmembrane; Transmembrane helix.
FT SIGNAL 1 22
FT CHAIN 23 769 Integrin beta-2.
FT /FTId=PRO_0000016341.
FT TOPO_DOM 23 700 Extracellular (Potential).
FT TRANSMEM 701 723 Helical; (Potential).
FT TOPO_DOM 724 769 Cytoplasmic (Potential).
FT DOMAIN 124 363 VWFA.
FT REPEAT 449 496 I.
FT REPEAT 497 540 II.
FT REPEAT 541 581 III.
FT REPEAT 582 617 IV.
FT REGION 449 617 Cysteine-rich tandem repeats.
FT MOTIF 397 399 Cell attachment site (Potential).
FT METAL 138 138 Calcium; via carbonyl oxygen.
FT METAL 141 141 Calcium.
FT METAL 142 142 Calcium.
FT METAL 347 347 Calcium.
FT MOD_RES 23 23 Pyrrolidone carboxylic acid.
FT MOD_RES 745 745 Phosphoserine; by PKC.
FT MOD_RES 756 756 Phosphoserine.
FT MOD_RES 758 758 Phosphothreonine; by PKC; in vitro.
FT MOD_RES 759 759 Phosphothreonine (Potential).
FT MOD_RES 760 760 Phosphothreonine; by PKC/PRKCA; in vitro.
FT CARBOHYD 50 50 N-linked (GlcNAc...).
FT CARBOHYD 116 116 N-linked (GlcNAc...).
FT CARBOHYD 212 212 N-linked (GlcNAc...).
FT CARBOHYD 213 213 N-linked (GlcNAc...); atypical.
FT CARBOHYD 215 215 N-linked (GlcNAc...); atypical.
FT CARBOHYD 254 254 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 501 501 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 642 642 N-linked (GlcNAc...) (Potential).
FT DISULFID 25 43
FT DISULFID 33 447
FT DISULFID 36 62
FT DISULFID 46 73
FT DISULFID 191 198
FT DISULFID 246 286
FT DISULFID 386 400
FT DISULFID 420 445
FT DISULFID 449 467
FT DISULFID 459 470
FT DISULFID 472 481
FT DISULFID 483 514
FT DISULFID 497 512
FT DISULFID 506 517
FT DISULFID 519 534
FT DISULFID 536 559
FT DISULFID 541 557
FT DISULFID 549 562
FT DISULFID 564 573
FT DISULFID 575 598
FT DISULFID 582 596
FT DISULFID 590 601
FT DISULFID 603 612
FT DISULFID 615 618
FT DISULFID 622 662
FT DISULFID 628 647
FT DISULFID 631 643
FT DISULFID 670 695
FT VARIANT 128 128 D -> N (in LAD1; dbSNP:rs137852615).
FT /FTId=VAR_003984.
FT VARIANT 128 128 D -> Y (in LAD1; dbSNP:rs137852615).
FT /FTId=VAR_065661.
FT VARIANT 138 138 S -> P (in LAD1; dbSNP:rs137852617).
FT /FTId=VAR_013402.
FT VARIANT 149 149 L -> P (in LAD1; dbSNP:rs137852611).
FT /FTId=VAR_003985.
FT VARIANT 169 169 G -> R (in LAD1; dbSNP:rs137852612).
FT /FTId=VAR_003986.
FT VARIANT 178 178 P -> L (in LAD1; dbSNP:rs137852614).
FT /FTId=VAR_003987.
FT VARIANT 196 196 K -> T (in LAD1; dbSNP:rs137852610).
FT /FTId=VAR_003988.
FT VARIANT 239 239 A -> T (in LAD1; dbSNP:rs179363873).
FT /FTId=VAR_065662.
FT VARIANT 273 273 G -> R (in LAD1; dbSNP:rs137852618).
FT /FTId=VAR_013403.
FT VARIANT 284 284 G -> S (in LAD1; dbSNP:rs137852616).
FT /FTId=VAR_003989.
FT VARIANT 300 300 D -> V (in LAD1; dbSNP:rs179363874).
FT /FTId=VAR_065663.
FT VARIANT 351 351 N -> S (in LAD1; dbSNP:rs137852613).
FT /FTId=VAR_003990.
FT VARIANT 354 354 Q -> H (in dbSNP:rs235330).
FT /FTId=VAR_030035.
FT VARIANT 586 586 R -> W (in LAD1; dbSNP:rs5030672).
FT /FTId=VAR_003991.
FT VARIANT 593 593 R -> C (in LAD1; dbSNP:rs137852609).
FT /FTId=VAR_003992.
FT VARIANT 716 716 G -> A (in LAD1; dbSNP:rs179363872).
FT /FTId=VAR_065664.
FT CONFLICT 199 199 Q -> P (in Ref. 8; CAA68266).
FT CONFLICT 279 279 L -> P (in Ref. 4; BAD96225).
FT CONFLICT 526 526 G -> C (in Ref. 3; BAG53190).
FT CONFLICT 630 630 E -> K (in Ref. 3; BAG53190).
FT HELIX 33 37
FT STRAND 44 46
FT HELIX 49 51
FT HELIX 58 61
FT HELIX 65 70
FT HELIX 75 77
FT STRAND 84 88
FT STRAND 91 94
FT STRAND 96 99
FT STRAND 101 107
FT STRAND 113 119
FT STRAND 128 134
FT HELIX 140 144
FT TURN 145 148
FT HELIX 153 158
FT STRAND 165 171
FT TURN 185 188
FT STRAND 205 212
FT HELIX 215 222
FT STRAND 230 233
FT HELIX 236 243
FT HELIX 247 250
FT STRAND 258 262
FT HELIX 272 276
FT STRAND 289 292
FT HELIX 296 298
FT HELIX 304 306
FT HELIX 307 313
FT STRAND 320 322
FT HELIX 324 326
FT HELIX 327 336
FT STRAND 337 339
FT STRAND 342 344
FT HELIX 353 355
FT TURN 356 358
FT HELIX 359 363
FT STRAND 365 371
FT STRAND 378 385
FT STRAND 387 389
FT STRAND 391 402
FT STRAND 409 419
FT STRAND 424 430
FT STRAND 437 443
FT STRAND 452 454
FT HELIX 458 461
FT STRAND 462 466
FT STRAND 469 472
FT STRAND 476 478
FT STRAND 483 487
FT HELIX 490 495
FT STRAND 498 500
FT HELIX 505 508
FT STRAND 509 513
FT STRAND 516 519
FT STRAND 528 531
FT STRAND 536 539
FT STRAND 544 550
FT TURN 552 554
FT STRAND 555 558
FT STRAND 561 564
FT STRAND 568 570
FT STRAND 591 593
FT TURN 609 612
FT TURN 623 625
FT HELIX 626 629
FT TURN 630 633
FT STRAND 643 646
FT STRAND 662 665
FT STRAND 667 669
FT STRAND 671 676
FT STRAND 686 689
FT STRAND 754 762
SQ SEQUENCE 769 AA; 84782 MW; EB9F3C3DF338B4E1 CRC64;
MLGLRPPLLA LVGLLSLGCV LSQECTKFKV SSCRECIESG PGCTWCQKLN FTGPGDPDSI
RCDTRPQLLM RGCAADDIMD PTSLAETQED HNGGQKQLSP QKVTLYLRPG QAAAFNVTFR
RAKGYPIDLY YLMDLSYSML DDLRNVKKLG GDLLRALNEI TESGRIGFGS FVDKTVLPFV
NTHPDKLRNP CPNKEKECQP PFAFRHVLKL TNNSNQFQTE VGKQLISGNL DAPEGGLDAM
MQVAACPEEI GWRNVTRLLV FATDDGFHFA GDGKLGAILT PNDGRCHLED NLYKRSNEFD
YPSVGQLAHK LAENNIQPIF AVTSRMVKTY EKLTEIIPKS AVGELSEDSS NVVQLIKNAY
NKLSSRVFLD HNALPDTLKV TYDSFCSNGV THRNQPRGDC DGVQINVPIT FQVKVTATEC
IQEQSFVIRA LGFTDIVTVQ VLPQCECRCR DQSRDRSLCH GKGFLECGIC RCDTGYIGKN
CECQTQGRSS QELEGSCRKD NNSIICSGLG DCVCGQCLCH TSDVPGKLIY GQYCECDTIN
CERYNGQVCG GPGRGLCFCG KCRCHPGFEG SACQCERTTE GCLNPRRVEC SGRGRCRCNV
CECHSGYQLP LCQECPGCPS PCGKYISCAE CLKFEKGPFG KNCSAACPGL QLSNNPVKGR
TCKERDSEGC WVAYTLEQQD GMDRYLIYVD ESRECVAGPN IAAIVGGTVA GIVLIGILLL
VIWKALIHLS DLREYRRFEK EKLKSQWNND NPLFKSATTT VMNPKFAES
//

MIM 116920
*RECORD*
*FIELD* NO
116920
*FIELD* TI
#116920 LEUKOCYTE ADHESION DEFICIENCY, TYPE I; LAD
;;LAD1;;
LYMPHOCYTE FUNCTION-ASSOCIATED ANTIGEN 1 IMMUNODEFICIENCY;;
read moreLFA1 IMMUNODEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because the genetic defect in
leukocyte adhesion deficiency (also known as LFA-1 immunodeficiency and
by several other designations) has been shown to reside in the gene
encoding the beta-2 integrin chain (ITGB2; 600065), a subunit that is
common to 3 cell adhesion molecules with gene designations ITGAL
(153370), ITGAM (120980), and ITGAX (151510). The leukocyte antigen of
the beta-2 integrin chain gene has been designated CD18.

DESCRIPTION

Leukocyte adhesion deficiency (LAD) is an autosomal recessive disorder
of neutrophil function resulting from a deficiency of the beta-2
integrin subunit of the leukocyte cell adhesion molecule. The leukocyte
cell adhesion molecule is present on the surface of peripheral blood
mononuclear leukocytes and granulocytes and mediates cell-cell and
cell-extracellular matrix adhesion. LAD is characterized by recurrent
bacterial infections; impaired pus formation and wound healing;
abnormalities of a wide variety of adhesion-dependent functions of
granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L,
beta-2/alpha-M, and beta-2/alpha-X expression.

NOMENCLATURE

The 3 alpha-integrin chains that each heterodimerize with the beta-2
chain (ITGAL, ITGAM, and ITGAX) 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).

CLINICAL FEATURES

Beginning in the 1970s, patients were recognized who had recurrent
bacterial infections, defective neutrophil mobility, and delayed
separation of the umbilical cord (e.g., Hayward et al., 1979). Before
the elucidation by Springer et al. (1984, 1986) and Barclay et al.
(1993), extraordinary confusion surrounded the group of patients with
leukocyte dysfunction and deficiency of cell surface antigens (see, for
example, Arnaout et al., 1982; Bowen et al., 1982; Dana et al., 1984).
In the seventh edition of these catalogs (1986), one entry related to
the ITGB2 locus (which is mutant in these patients), but 3 others
described neutrophil dysfunction syndromes now known to be leukocyte
adhesion deficiency. Confusion was created by different investigators
looking at the different alpha subunits which share a common beta
subunit.

Van der Meer et al. (1975) described a 'new' defect in the intracellular
killing of ingested microorganisms. A sister and probably 2 brothers
were affected. During infections, the white blood count was as high as
55,000 per cu mm, mostly neutrophils, with a slight shift to the left.
Other patients with recurring bacterial infections were reported who had
defects in initiation of the neutrophil respiratory burst to particulate
but not soluble stimuli (e.g., Weening et al., 1976; Harvath and
Andersen, 1979), defects in neutrophil chemotaxis and phagocytosis
(e.g., Niethammer et al., 1975), or both (Harvath and Andersen, 1979).
Crowley et al. (1980) were the first to propose that the defects in
neutrophil chemotaxis and phagocytosis were secondary to an abnormality
in cell adhesion.

Using specific monoclonal antibodies, Dana et al. (1984), Beatty et al.
(1984), and others demonstrated deficiency of both the alpha and the
beta subunits of Mac-1 (also designated Mo1, and as beta-2/alpha M in
integrin terminology) in the neutrophils of patients of this type.
Arnaout et al. (1984) and others demonstrated that the LFA-1 alpha-beta
complex (beta-2/alpha-X) is also deficient on patients' neutrophils and
lymphocytes. Springer et al. (1984, 1986) found that a third type of
alpha-beta complex is also deficient on patients' neutrophils and
lymphocytes. Springer et al. (1984, 1986) proposed that the primary
defect in these patients resides in the beta subunit (which is shared by
all 3 deficient proteins) and that the beta subunit is necessary for
cell surface expression on the alpha subunit. Such neutrophils have a
reduced phagocytic and respiratory burst response to bacteria and yeast
as well as a reduced ability to adhere to various substances and migrate
into sites of infection. Most of the clinical features are probably the
result of neutrophil and monocyte deficiency of CR3 (beta-2/alpha-M).

There have been reports of about 30 patients with recurrent bacterial
infections due to deficiency of this family of cell membrane
glycoproteins. Ross (1986) tabulated the findings in reported cases.
Often the first manifestation is infection of the umbilical cord stump,
occasionally progressing to omphalitis (Abramson et al., 1981; Bissenden
et al., 1981). Gingivitis (periodontitis) may be noted with eruption of
the primary teeth. Systemic bacterial infections such as pneumonia,
peritonitis, and deep abscesses are more frequent during infancy and
with complete deficiency.

See review by Todd and Freyer (1988), who found reports of 41 patients
in whom the clinical picture fitted that of CD18/CD11 (beta-2/alpha)
glycoprotein deficiency. At least 4 patients suspected or documented to
have a moderately severe variant (10% expression of CD18/CD11
glycoprotein) have survived to adulthood (Anderson et al., 1985; van der
Meer et al., 1975; Weening et al., 1976) and 3 homozygous persons are
known to have parented affected or presumably heterozygous offspring.

Kobayashi et al. (1984) described a 3-month-old Japanese female infant
with persistent navel infection due to Pseudomonas aeruginosa since
birth and recurrent bacterial skin infections. They found a severe
abnormality of neutrophil adhesion on a surface, leading to a lack of
chemotaxis and mild impairment of phagocytosis. Neutrophil bactericidal
activity and nitroblue tetrazolium reduction were unimpaired. By sodium
dodecyl sulfate polyacrylamide gel electrophoresis of neutrophil
membrane proteins, 2 glycoproteins were shown to be lacking. In both
parents, both glycoproteins were reduced. Fujita et al. (1985) reported
the subsequent birth of a male sib with the same defect. Fujita et al.
(1988) described juvenile rheumatoid arthritis of systemic onset in
these sibs, then aged 5 and 3 years, respectively, who had a severe form
of congenital leukocyte adhesion deficiency.

Etzioni and Harlan (1999) provided a comprehensive review of both type I
(LAD1) and type II LAD (LAD2; 266265). While the functional neutrophil
studies are similar in the 2 LADs, the clinical course is milder in
LAD2. Furthermore, patients with LAD2 present other abnormal features,
such as growth and mental retardation, which are related to the primary
defect in fucose metabolism. Delayed separation of the umbilical cord
occurs in LAD1.

BIOCHEMICAL FEATURES

Kishimoto et al. (1987) identified 5 distinct beta-subunit phenotypes
among LAD patients: an undetectable beta-subunit mRNA and protein
precursor; low levels of beta-subunit mRNA and precursor; an aberrantly
large beta-subunit precursor, probably due to an extra glycosylation
site; an aberrantly small precursor; and a grossly normal precursor.
Mutant beta-subunit precursors from LAD patients failed to associate
with the LFA-1 alpha subunit (alpha-L). Family studies with aberrant
precursors correlated with recessive inheritance of leukocyte adhesion
deficiency.

Marlin et al. (1986) showed that the genetic defect in leukocyte
adhesion deficiency (also known as LFA-1 immunodeficiency and by several
other designations) resides in the beta subunit that is common to 3 cell
adhesion molecules. Boucheix (1987) indicated that a tentative
designation for the beta chain of these 3 proteins is CD18. The 3, each
with a unique alpha chain, are CD11A (153370), CD11B (120980), and CD11C
(151510).

INHERITANCE

The neutrophils from parents and sibs of patients often show half-normal
amounts of CR3/LFA1/p150,95 antigens (CD18/CD11B, CD18/CD11A and
CD18/CD11C, respectively) (Arnaout et al., 1984; Springer et al., 1984).
In other cases, both parents have normal amounts of antigen or only 1
parent has half-normal amounts (Ross et al., 1985; Arnaout et al.,
1984). The only suggestion of a mode of inheritance other than autosomal
recessive came from Crowley et al. (1980), who first proposed that an
adhesion defect exists in this condition. X-linked recessive inheritance
was suggested because only the mother and sister of the affected male
showed evidence of the carrier state; the cells of the father and
brother were functionally normal and had a normal content of the
relevant glycoprotein.

MAPPING

Suomalainen et al. (1985, 1986) showed that the integrin beta-2 gene is
located on chromosome 21.

MOLECULAR GENETICS

Dana et al. (1987) studied 4 unrelated patients with the family of 3
leukocyte adhesion molecules, which they called Leu-CAM. They called the
3 antigens Mo1, LFA-1, and Leu M5. In all 4 patients, they found that B
cells synthesized a normal-sized, beta-subunit precursor that either
failed to 'mature' or matured only partially to the membrane-expressed
form. Furthermore, B cells from all 4 patients had a single
normal-sized, beta-subunit mRNA of about 3.4 kb. Thus, leukocyte
adhesion deficiency in these 4 patients was not due to the absence of
the beta chain gene or to aberrant splicing of its mRNA. The findings
were consistent with a defective beta-subunit gene (ITGB2) resulting in
abnormal posttranslational processing of the synthesized beta molecule.

- Somatic Revertant Mosaicism

Tone et al. (2007) reported an unusual case of somatic revertant
mosaicism in a Japanese infant with LAD1 caused by compound
heterozygosity for 2 truncating mutations in the ITGB2 gene, predicting
complete loss of the CD18 antigen. However, flow cytometric analysis
showed that a small proportion of the patient's memory/effector CD8+ T
cells were CD18+. Sequencing of these CD18+ T cells indicated that they
resulted from spontaneous site-specific single nucleotide reversion of
the inherited paternal mutation. Although these T cells were functional
in vitro, the patient did not show clinical improvement, likely because
no reversion events had occurred in myeloid cells. Tone et al. (2007)
concluded that somatic genetic reversion in a primary immunodeficiency
can occur, but may be undetected in some cases if the changes do not
result in modification of the clinical phenotype.

DIAGNOSIS

Diagnosis of hereditary deficiency of CR3 is facilitated by commercial
availability of monoclonal antibodies specific for the alpha-integrin
chains of CR3 and p150,95.

CLINICAL MANAGEMENT

In a retrospective survey of 162 patients in whom bone marrow
transplantation was performed in 14 European centers between 1969 and
1985, Fischer et al. (1986) found 4 patients with leukocyte adhesion
deficiency. Bone marrow transplantation was successful; engraftment of
donor cells resulted in complete restoration of leukocyte function and
the absence of need for any further treatment in some of these patients.

Wilson et al. (1990) corrected the genetic and functional abnormalities
in a lymphocyte cell line from a patient with LAD by retrovirus-mediated
transduction of a functional ITGB2 (CD18) gene. Yorifuji et al. (1993)
extended this work by reporting the introduction of human CD18 cDNA into
the bone marrow progenitor cells of patients with LAD.

EVOLUTION

This glycoprotein family is conserved in mouse and human.

ANIMAL MODEL

Vedder et al. (1988) showed that use of a monoclonal antibody against
CD18 reduced organ injury and improved survival from hemorrhagic shock
in rabbits. Krauss et al. (1991) developed an in vivo model for gene
therapy of LAD. Recombinant retroviruses were used to transduce a
functional human ITGB2 (CD18) gene into murine bone marrow cells which
were then transplanted into lethally irradiated syngeneic recipients.
Since they had human-specific CD18 monoclonal antibodies and since human
CD18 can form chimeric heterodimers with murine CD11A on the cell
surface, Krauss et al. (1991) were able to do a reliable flow cytometric
assay for human CD18 in transplant recipients. Human CD18 was detected
in leukocytes in a substantial number of transplant recipients for at
least 6 months, suggesting that the gene had been transduced into stem
cells. There were no apparent untoward effects. Expression was
consistently highest and most frequent in granulocytes. Murine
granulocytes demonstrated appropriate posttranscriptional regulation of
human CD18 in response to activation of protein kinase C with PMA.

Kehrli et al. (1992) described beta-2 integrin deficiency in Holstein
cattle. The disorder was characterized by recurrent pneumonia,
ulcerative and granulomatous stomatitis, enteritis with bacterial
overgrowth, periodontitis, delayed wound healing, persistent
neutrophilia, and death at an early age. The underlying genetic defect
was identified as a D128G (asp128-to-gly) amino acid substitution in the
26-amino acid sequence that is completely homologous with human and
murine CD18 protein sequences. In a Holstein calf afflicted with
leukocyte adhesion deficiency, Shuster et al. (1992) found 2 point
mutations: one caused a D128G substitution in a highly conserved
extracellular region where several mutations have been found to cause
human LAD, and the other mutation was silent. All 20 calves tested were
homozygous for the D128G allele. The carrier frequency among Holstein
cattle in the United States was approximately 15% among bulls and 6%
among cows. All cattle with a mutant allele are related to 1 bull, who
through the use of artificial insemination sired many calves in the
1950s and 1960s. It was suggested that the organization of the dairy
industry and the diagnostic test described by Shuster et al. (1992)
would enable nearly complete eradication of bovine LAD within 1 year.

Using homologous recombination, Scharffetter-Kochanek et al. (1998)
created and characterized mice with a CD18 null mutation. These mice
have a phenotype closely resembling type I LAD in humans and cattle,
including leukocytosis, chronic dermatitis, alopecia, and mucocutaneous
infections. Intravital microscopy in these mice revealed a lack of firm
neutrophil attachment to venules in the cremaster muscle in response to
FMLP (see 136537). Scharffetter-Kochanek et al. (1998) also observed
defective T-cell proliferation after stimulation with alloantigen or
staphylococcal enterotoxin A.

*FIELD* SA
Akao et al. (1987); Anderson and Springer (1987); Arnaout et al. (1990);
Back et al. (1993); Back et al. (1992); Bairoch (1994); Hibbs et
al. (1990); Hynes (1992); Kishimoto et al. (1987); Matsuura et al.
(1992); Nelson et al. (1992); Petersen et al. (1991); Pierce et al.
(1986); Sligh et al. (1989); Solomon et al. (1988); Springer et al.
(1985); Taylor et al. (1988); Wardlaw et al. (1990); Weitzman et al.
(1991)
*FIELD* RF
1. Abramson, J. S.; Mills, E. L.; Sawyer, M. K.; Regelman, W. R.;
Nelson, J. D.; Quie, P. G.: Recurrent infections and delayed separation
of the umbilical cord in an infant with abnormal phagocytic cell locomotion
and oxidative response during particle phagocytosis. J. Pediat. 99:
887-894, 1981.

2. Akao, Y.; Utsumi, K. R.; Naito, K.; Ueda, R.; Takahashi, T.; Yamada,
K.: Chromosomal assignments of genes coding for human leukocyte common
antigen, T-200, and lymphocyte function-associated antigen 1, LFA-1
beta subunit. Somat. Cell Molec. Genet. 13: 273-278, 1987.

3. Anderson, D. C.; Schmalstieg, F. C.; Finegold, M. J.; Hughes, B.
J.; Rothlein, R.; Miller, L. J.; Kohl, S.; Tosi, M. F.; Jacobs, R.
L.; Waldrop, T. C.; Goldman, A. S.; Shearer, W. T.; Springer, T. A.
: The severe and moderate phenotypes of heritable Mac-1, LFA-1 deficiency:
their quantitative definition and relation to leukocyte dysfunction
and clinical features. J. Infect. Dis. 152: 668-689, 1985.

4. Anderson, D. C.; Springer, T. A.: Leukocyte adhesion deficiency:
an inherited defect in the Mac-1, LFA-1, and p150,95 glycoproteins. Annu.
Rev. Med. 38: 175-194, 1987.

5. Arnaout, M. A.; Dana, N.; Gupta, S. K.; Tenen, D. G.; Fathallah,
D. M.: Point mutations impairing cell surface expression of the common
beta subunit (CD18) in a patient with leukocyte adhesion molecule
(Leu-CAM) deficiency. J. Clin. Invest. 85: 977-981, 1990.

6. Arnaout, M. A.; Pitt, J.; Cohen, H. J.; Melamed, J.; Rosen, F.
S.; Colten, H. R.: Deficiency of a granulocyte-membrane glycoprotein
(gp150) in a boy with recurrent bacterial infections. New Eng. J.
Med. 306: 693-699, 1982.

7. Arnaout, M. A.; Spits, H.; Terhorst, C.; Pitt, J.; Todd, R. F.,
III: Deficiency of a leukocyte surface glycoprotein (LFA-1) in two
patients with Mo1 deficiency: effects of cell activation on Mo1/LFA-1
surface expression in normal and deficient leukocytes. J. Clin. Invest. 74:
1291-1300, 1984.

8. Back, A. L.; Kerkering, M.; Baker, D.; Bauer, T. R.; Embree, L.
J.; Hickstein, D. D.: A point mutation associated with leukocyte
adhesion deficiency type 1 of moderate severity. Biochem. Biophys.
Res. Commun. 193: 912-918, 1993.

9. Back, A. L.; Kwok, W. W.; Hickstein, D. D.: Identification of
two molecular defects in a child with leukocyte adherence deficiency. J.
Biol. Chem. 267: 5482-5487, 1992.

10. Bairoch, A.: Personal Communication. Geneva, Switzerland 5/13/1994.

11. Barclay, A. N.; Birkeland, M. L.; Brown, M. H.; Beyers, A. D.;
Davis, S. J.; Somoza, C.; Williams, A. F.: The Leukocyte Antigen
Facts Book. New York: Academic Press (pub.) 1993. Pp. 124-127
and 140-141.

12. Beatty, P. G.; Ochs, H. D.; Harlan, J. M.; Price, T. H.; Rosen,
H.; Taylor, R. F.; Hansen, J. A.; Klebanoff, S. J.: Absence of monoclonal-antibody-defined
protein complex in a boy with abnormal leucocyte function. Lancet 323:
535-537, 1984. Note: Originally Volume I.

13. Bissenden, J. G.; Haeney, M. R.; Tarlow, M. J.; Thompson, R. A.
: Delayed separation of the umbilical cord, severe widespread infections
and immunodeficiency. Arch. Dis. Child. 56: 397-399, 1981.

14. Boucheix, C.: Personal Communication. Villejuif, France 1/31/1987.

15. Bowen, T. J.; Ochs, H. D.; Altman, L. C.; Price, T. H.; Van Epps,
D. E.; Brautigan, D. L.; Rosin, R. E.; Perkins, W. D.; Babior, B.
M.; Klebanoff, S. J.; Wedgwood, R. J.: Severe recurrent bacterial
infections associated with defective adherence and chemotaxis in two
patients with neutrophils deficient in a cell-associated glycoprotein. J.
Pediat. 101: 932-940, 1982.

16. Crowley, C. A.; Curnutte, J. T.; Rosin, R. E.; Andre-Schwartz,
J.; Gallin, J. I.; Klempner, M.; Snyderman, R.; Southwick, F. S.;
Stossel, T. P.; Babior, B. M.: An inherited abnormality of neutrophil
adhesion: its genetic transmission and its association with a missing
protein. New Eng. J. Med. 302: 1163-1168, 1980.

17. Dana, N.; Clayton, L. K.; Tennen, D. G.; Pierce, M. W.; Lachmann,
P. J.; Law, S. A.; Arnaout, M. A.: Leukocytes from four patients
with complete or partial Leu-CAM deficiency contain the common beta-subunit
precursor and beta-subunit messenger RNA. J. Clin. Invest. 79: 1010-1015,
1987.

18. Dana, N.; Todd, R. F., III; Pitt, J.; Springer, T. A.; Arnaout,
M. A.: Deficiency of a surface membrane glycoprotein (Mo1) in man. J.
Clin. Invest. 73: 153-159, 1984.

19. Etzioni, A.; Harlan, J. M.: Cell adhesion and leukocyte adhesion
defects.In: Ochs, H. D.; Smith, C. I. E.; Puck, J. M. (eds.): Primary
Immunodeficiency Diseases: A Molecular and Genetic Approach. New
York: Oxford University Press 1999. Pp. 375-388.

20. Fischer, A.; Friedrich, W.; Levinsky, R.; Vossen, J.; Griscelli,
C.; Kubanek, B.; Morgan, G.; Wagemaker, G.; Landais, P.: Bone-marrow
transplantation for immunodeficiencies and osteopetrosis: European
survey, 1968-1985. Lancet 328: 1080-1084, 1986. Note: Originally
Volume II.

21. Fujita, K.; Kobayashi, K.; Kajii, T.: Impaired neutrophil adhesion:
a new patient in a previously reported family. Acta Paediat. Jpn. 27:
527-534, 1985.

22. Fujita, K.; Kobayashi, K.; Okino, F.: Juvenile rheumatoid arthritis
in two siblings with congenital leucocyte adhesion deficiency. Europ.
J. Pediat. 148: 118-119, 1988.

23. Harvath, L.; Andersen, B. R.: Defective initiation of oxidative
metabolism in polymorphonuclear leukocytes. New Eng. J. Med. 300:
1130-1135, 1979.

24. Hayward, A. R.; Leonard, J.; Harvey, B. A. M.; Greenwood, M. C.;
Wood, C. B. S.; Soothill, J. F.: Delayed separation of the umbilical
cord, widespread infections and defective neutrophil mobility. Lancet 313:
1099-1101, 1979. Note: Originally Volume I.

25. Hibbs, M. L.; Wardlaw, A. J.; Stacker, S. A.; Anderson, D. C.;
Lee, A.; Roberts, T. M.; Springer, T. A.: Transfection of cells from
patients with leukocyte adhesion deficiency with an integrin beta
subunit (CD18) restores lymphocyte function-associated antigen-1 expression
and function. J. Clin. Invest. 85: 674-681, 1990.

26. Hynes, R. O.: Integrins: versatility, modulation and signaling
in cell adhesion. Cell 69: 11-25, 1992.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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, 1975.

36. 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.

37. 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.

38. 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.

39. 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.

40. Scharffetter-Kochanek, K.; Lu, H.; Norman, K.; van Nood, N.; Munoz,
F.; Grabbe, S.; McArthur, M.; Lorenzo, I.; Kaplan, S.; Ley, K.; Smith,
C. W.; Montgomery, C. A.; Rich, S.; Beaudet, A. L.: Spontaneous skin
ulceration and defective T cell function in CD18 null mice. J. Exp.
Med. 188: 119-131, 1998.

41. 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.

42. 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 only, 1989.

43. 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.

44. 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.

45. 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.

46. 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.

47. 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.

48. 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 only, 1985.

49. 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.

50. Todd, R. F., III; Freyer, D. R.: The CD11/CD18 leukocyte glycoprotein
deficiency. Hemat. Oncol. Clin. North Am. 2: 13-31, 1988.

51. Tone, Y.; Wada, T.; Shibata, F.; Toma, T.; Hashida, Y.; Kasahara,
Y.; Koizumi, S.; Yachie, A.: Somatic revertant mosaicism in a patient
with leukocyte adhesion deficiency type 1. Blood 109: 1182-1184,
2007.

52. van der Meer, J. W. M.; van Zwet, T. L.; van Furth, R.; Weemaes,
C. M. R.: New familial defect in microbicidal function of polymorphonuclear
leucocytes. Lancet 306: 630-632, 1975. Note: Originally Volume II.

53. 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.

54. 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.

55. 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.

56. 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.

57. 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.

58. 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.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Mouth];
Gingivitis;
[Teeth];
Periodontitis

HEMATOLOGY:
Leukocytosis with predominant granulocytosis (20,000-100,000 /mm3)
common

IMMUNOLOGY:
Perirectal abscesses;
Recurrent staphylococcal and gram-negative infections;
Poor adhesion related functions, such as adhesion to endothelial cells,
chemotaxis, and antibody-dependent cellular cytotoxicity

LABORATORY ABNORMALITIES:
Low levels of CD11/CD18 (LFA-1 or leukocyte function antigen-1) glycoprotein

MISCELLANEOUS:
Corrected by bone marrow transplantation;
Delayed separation of umbilical cord

MOLECULAR BASIS:
Caused by mutations in the beta-2 integrin gene (ITGB2, 600065.0001)

*FIELD* CN
Ada Hamosh - updated: 4/13/2000
Kelly A. Przylepa - revised: 3/10/2000

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 04/13/2000
joanna: 4/13/2000
kayiaros: 3/10/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 7/9/2008
Denise L. M. Goh - updated: 4/16/2003
Paul J. Converse - updated: 10/12/2000
Victor A. McKusick - updated: 10/8/1999

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mgross: 06/05/2009
terry: 2/3/2009
terry: 1/13/2009
terry: 1/9/2009
wwang: 7/16/2008
ckniffin: 7/9/2008
carol: 4/25/2007
carol: 4/16/2003
mcapotos: 10/19/2000
terry: 10/12/2000
mgross: 10/8/1999
alopez: 3/2/1999
alopez: 7/30/1997
mark: 6/11/1995
terry: 3/7/1995
pfoster: 2/14/1995
show: 7/11/1994
carol: 5/16/1994
mimadm: 4/18/1994

MIM 600065
*RECORD*
*FIELD* NO
600065
*FIELD* TI
*600065 INTEGRIN, BETA-2; ITGB2
;;LEUKOCYTE CELL ADHESION MOLECULE CD18; CD18
LEUKOCYTE-ASSOCIATED ANTIGENS CD18/11A, CD18/11B, CD18/11C, INCLUDED
read more*FIELD* TX

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).

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; see, e.g., 600065.0001.
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.

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.

*FIELD* AV
.0001
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, ARG593CYS

Arnaout et al. (1990) found that a patient with LAD (116920) was a
genetic compound for 2 mutations: 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
ITGB2, LYS196THR

See Arnaout et al. (1990).

.0003
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, LEU149PRO

In a patient identified as no. 14 with moderately severe LAD (116920),
Wardlaw et al. (1990) demonstrated a T-to-C transition resulting in
substitution for leucine-149 by proline. 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
improperly listed as pro149-to-leu. The wildtype residue is leu
(Bairoch, 1994).)

.0004
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, GLY169ARG

In a patient identified as no. 2 with severe LAD deficiency (116920),
Wardlaw et al. (1990) demonstrated a G-to-A transition 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
ITGB2, INITIATION MUTATION

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 (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
ITGB2, ARG586TRP

In a patient with partial (type II) deficiency of leukocyte adhesion
molecule, Nelson et al. (1992) demonstrated 2 mutant alleles. The allele
from the mother contained 2 mutations: a 12-bp insertion resulting in an
in-frame addition of 4 amino acids between proline-247 and glutamic
acid-248 (see 600065.0007), and a C1756T nucleotide transition resulting
in an arg586-to-trp substitution in the CD18 protein.

.0007
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, IVS?AS, -12, 12-BP INS

In a patient with partial Leu-CAM deficiency, Nelson et al. (1992) found
2 mutations in the allele inherited from the mother (see 600065.0006). A
12-bp insertion that added 4 amino acids (pro-ser-ser-gln) 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 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.

.0008
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, ASN351SER

In one CD18 allele in a patient with partial Leu-CAM deficiency
previously reported by Arnaout et al. (1984), Nelson et al. (1992) found
an A1052G nucleotide transition, not present in either parent, resulting
in substitution of serine for asparagine-351. The other chromosome
carried 2 mutations, represented by 600065.0006 and 600065.0007.

.0009
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, PRO178LEU

In a child with the severe deficiency form of what they termed leukocyte
adherence deficiency, Back et al. (1992) found in one allele a C-to-T
transition 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 and resulting in a
frameshift into 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
ITGB2, ASP128ASN

Matsuura et al. (1992) identified a G-to-A transition at nucleotide 454
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
ITGB2, IVSDS, G-A, +1

In a patient with leukocyte adhesion deficiency, 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.

.0012
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, GLY284SER

In an 18-year-old girl reported by Bowen et al. (1982) with moderately
severe leukocyte adhesion deficiency, type I, Back et al. (1993) found a
single base substitution resulting in a glycine-to-serine amino acid
substitution at position 284. The change occurred in a highly conserved
region of the extracellular domain of CD18 in which several other
mutations had been identified.

.0013
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, SER138PRO

Hogg et al. (1999) described a patient with clinical features compatible
with a markedly severe phenotype of leukocyte adhesion deficiency type I
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
ITGB2, GLY273ARG

See 600065.0013 and Hogg et al. (1999).

.0015
LEUKOCYTE ADHESION DEFICIENCY
ITGB2, IVS4AS, 169-BP DEL, -37

By studying a herpesvirus saimiri-transformed T cell line from a patient
with severe leukocyte adhesion deficiency (LAD; 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.

*FIELD* SA
Abramson et al. (1981); Anderson et al. (1985); Anderson and Springer
(1987); Arnaout et al. (1982); Bissenden et al. (1981); Boucheix
(1987); 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 (1986); Ross et
al. (1985); 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)
*FIELD* RF
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*FIELD* CN
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

*FIELD* CD
Victor A. McKusick: 7/28/1994

*FIELD* ED
terry: 04/03/2009
terry: 3/31/2009
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
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

RBCC Red Blood Cell Collection

Full text data of ITGB2