Full text data of FERMT3
FERMT3
(KIND3, MIG2B, URP2)
[Confidence: high (present in two of the MS resources)]
Fermitin family homolog 3 (Kindlin-3; MIG2-like protein; Unc-112-related protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Fermitin family homolog 3 (Kindlin-3; MIG2-like protein; Unc-112-related protein 2)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00216699
IPI00216699 Splice Isoform 2 Of Unc-112 related protein 2 Probably involved in cell adhesion, lymph soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic Isoform 1 or 2 found at its expected molecular weight found at molecular weight
IPI00216699 Splice Isoform 2 Of Unc-112 related protein 2 Probably involved in cell adhesion, lymph soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic Isoform 1 or 2 found at its expected molecular weight found at molecular weight
Comments
Isoform Q86UX7-2 was detected.
Isoform Q86UX7-2 was detected.
UniProt
Q86UX7
ID URP2_HUMAN Reviewed; 667 AA.
AC Q86UX7; Q8IUA1; Q8N207; Q9BT48;
DT 16-JAN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2003, sequence version 1.
DT 22-JAN-2014, entry version 105.
DE RecName: Full=Fermitin family homolog 3;
DE AltName: Full=Kindlin-3;
DE AltName: Full=MIG2-like protein;
DE AltName: Full=Unc-112-related protein 2;
GN Name=FERMT3; Synonyms=KIND3, MIG2B, URP2;
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] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RX PubMed=12697302; DOI=10.1016/S0925-4439(03)00035-8;
RA Weinstein E.J., Bourner M., Head R., Zakeri H., Bauer C.,
RA Mazzarella R.;
RT "URP1: a member of a novel family of PH and FERM domain-containing
RT membrane-associated proteins is significantly over-expressed in lung
RT and colon carcinomas.";
RL Biochim. Biophys. Acta 1637:207-216(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Thymus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lung, and Lymph;
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 [4]
RP PROTEIN SEQUENCE OF 20-35; 424-438 AND 569-577, IDENTIFICATION BY MASS
RP SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12886250; DOI=10.1038/sj.leu.2402993;
RA Boyd R.S., Adam P.J., Patel S., Loader J.A., Berry J., Redpath N.T.,
RA Poyser H.R., Fletcher G.C., Burgess N.A., Stamps A.C., Hudson L.,
RA Smith P., Griffiths M., Willis T.G., Karran E.L., Oscier D.G.,
RA Catovsky D., Terrett J.A., Dyer M.J.S.;
RT "Proteomic analysis of the cell-surface membrane in chronic
RT lymphocytic leukemia: identification of two novel proteins, BCNP1 and
RT MIG2B.";
RL Leukemia 17:1605-1612(2003).
RN [5]
RP POSSIBLE FUNCTION (ISOFORM 2).
RX PubMed=18280249; DOI=10.1016/j.bbrc.2008.02.024;
RA Wang L., Deng W., Shi T., Ma D.;
RT "URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB
RT and apoptosis.";
RL Biochem. Biophys. Res. Commun. 368:899-906(2008).
RN [6]
RP INVOLVEMENT IN LAD3.
RX PubMed=18779414; DOI=10.1182/blood-2008-06-163162;
RA Mory A., Feigelson S.W., Yarali N., Kilic S.S., Bayhan G.I.,
RA Gershoni-Baruch R., Etzioni A., Alon R.;
RT "Kindlin-3: a new gene involved in the pathogenesis of LAD-III.";
RL Blood 112:2591-2591(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [8]
RP INVOLVEMENT IN LAD3.
RX PubMed=19617577; DOI=10.1182/blood-2009-04-218636;
RA Manevich-Mendelson E., Feigelson S.W., Pasvolsky R., Aker M.,
RA Grabovsky V., Shulman Z., Kilic S.S., Rosenthal-Allieri M.A.,
RA Ben-Dor S., Mory A., Bernard A., Moser M., Etzioni A., Alon R.;
RT "Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4
RT adhesiveness developed under shear flow conditions.";
RL Blood 114:2344-2353(2009).
RN [9]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19064721; DOI=10.1182/blood-2008-10-182154;
RA Kuijpers T.W., van de Vijver E., Weterman M.A.J., de Boer M.,
RA Tool A.T.J., van den Berg T.K., Moser M., Jakobs M.E., Seeger K.,
RA Sanal O., Uenal S., Cetin M., Roos D., Verhoeven A.J., Baas F.;
RT "LAD-1/variant syndrome is caused by mutations in FERMT3.";
RL Blood 113:4740-4746(2009).
RN [10]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19234463; DOI=10.1038/nm.1931;
RA Svensson L., Howarth K., McDowall A., Patzak I., Evans R., Ussar S.,
RA Moser M., Metin A., Fried M., Tomlinson I., Hogg N.;
RT "Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
RT affecting integrin activation.";
RL Nat. Med. 15:306-312(2009).
RN [11]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19234460; DOI=10.1038/nm.1917;
RA Malinin N.L., Zhang L., Choi J., Ciocea A., Razorenova O., Ma Y.-Q.,
RA Podrez E.A., Tosi M., Lennon D.P., Caplan A.I., Shurin S.B.,
RA Plow E.F., Byzova T.V.;
RT "A point mutation in KINDLIN3 ablates activation of three integrin
RT subfamilies in humans.";
RL Nat. Med. 15:313-318(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11 AND TYR-504, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP STRUCTURE BY NMR OF 349-478.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the PH domain of kindlin-3 from human.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Plays a central role in cell adhesion in hematopoietic
CC cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and
CC ITGB3). Required for integrin-mediated platelet adhesion and
CC leukocyte adhesion to endothelial cells. Required for activation
CC of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes
CC (PMNs) (By similarity).
CC -!- FUNCTION: Isoform 2 may act as a repressor of NF-kappa-B and
CC apoptosis.
CC -!- SUBUNIT: Interacts with ITGB1, ITGB2 and ITGB3 (via cytoplasmic
CC tails) (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell projection, podosome (By similarity).
CC Note=Present in the F-actin surrounding ring structure of
CC podosomes, which are specialized adhesion structures of
CC hematopoietic cells (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long, URP2LF;
CC IsoId=Q86UX7-1; Sequence=Displayed;
CC Name=2; Synonyms=Short, URP2SF;
CC IsoId=Q86UX7-2; Sequence=VSP_009226;
CC -!- TISSUE SPECIFICITY: Highly expressed in lymph node. Expressed in
CC thymus, spleen and leukocytes. Weakly expressed in placenta, small
CC intestine, stomach, testis and lung. Overexpressed in B-cell
CC malignancies.
CC -!- DOMAIN: The FERM domain is not correctly detected by PROSITE or
CC Pfam techniques because it contains the insertion of a PH domain.
CC -!- DISEASE: Leukocyte adhesion deficiency 3 (LAD3) [MIM:612840]: A
CC disorder characterized by recurrent bacterial infections without
CC pus formation, leukocytosis and major bleeding disorders. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the kindlin family.
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- SIMILARITY: Contains 1 PH domain.
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DR EMBL; AY093951; AAM19736.1; -; mRNA.
DR EMBL; AY093952; AAM19737.1; -; mRNA.
DR EMBL; AK093719; BAC04220.1; -; mRNA.
DR EMBL; BC004347; AAH04347.2; -; mRNA.
DR EMBL; BC013366; AAH13366.1; -; mRNA.
DR EMBL; BC015584; AAH15584.1; -; mRNA.
DR RefSeq; NP_113659.3; NM_031471.5.
DR RefSeq; NP_848537.1; NM_178443.2.
DR RefSeq; XP_005274400.1; XM_005274343.1.
DR UniGene; Hs.180535; -.
DR PDB; 2YS3; NMR; -; A=349-478.
DR PDBsum; 2YS3; -.
DR ProteinModelPortal; Q86UX7; -.
DR SMR; Q86UX7; 7-98, 342-480, 488-639.
DR IntAct; Q86UX7; 6.
DR STRING; 9606.ENSP00000279227; -.
DR PhosphoSite; Q86UX7; -.
DR DMDM; 41018464; -.
DR PaxDb; Q86UX7; -.
DR PRIDE; Q86UX7; -.
DR Ensembl; ENST00000279227; ENSP00000279227; ENSG00000149781.
DR Ensembl; ENST00000345728; ENSP00000339950; ENSG00000149781.
DR GeneID; 83706; -.
DR KEGG; hsa:83706; -.
DR UCSC; uc001nyl.2; human.
DR CTD; 83706; -.
DR GeneCards; GC11P063975; -.
DR HGNC; HGNC:23151; FERMT3.
DR MIM; 607901; gene.
DR MIM; 612840; phenotype.
DR neXtProt; NX_Q86UX7; -.
DR Orphanet; 99844; Leukocyte adhesion deficiency type III.
DR PharmGKB; PA162388384; -.
DR eggNOG; NOG277845; -.
DR HOGENOM; HOG000231715; -.
DR HOVERGEN; HBG020688; -.
DR InParanoid; Q86UX7; -.
DR KO; K17084; -.
DR OMA; EMMLFGA; -.
DR OrthoDB; EOG7T7GSC; -.
DR PhylomeDB; Q86UX7; -.
DR EvolutionaryTrace; Q86UX7; -.
DR GeneWiki; FERMT3; -.
DR GenomeRNAi; 83706; -.
DR NextBio; 72692; -.
DR PMAP-CutDB; Q86UX7; -.
DR PRO; PR:Q86UX7; -.
DR ArrayExpress; Q86UX7; -.
DR Bgee; Q86UX7; -.
DR CleanEx; HS_FERMT3; -.
DR Genevestigator; Q86UX7; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0002102; C:podosome; ISS:UniProtKB.
DR GO; GO:0005178; F:integrin binding; ISS:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0033622; P:integrin activation; IMP:UniProtKB.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IMP:UniProtKB.
DR GO; GO:0070527; P:platelet aggregation; ISS:UniProtKB.
DR GO; GO:0033632; P:regulation of cell-cell adhesion mediated by integrin; IMP:UniProtKB.
DR Gene3D; 1.20.80.10; -; 2.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF00169; PH; 1.
DR SMART; SM00295; B41; 1.
DR SMART; SM00233; PH; 1.
DR SUPFAM; SSF47031; SSF47031; 2.
DR PROSITE; PS00660; FERM_1; FALSE_NEG.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; FALSE_NEG.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell junction;
KW Cell projection; Complete proteome; Direct protein sequencing;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 667 Fermitin family homolog 3.
FT /FTId=PRO_0000219454.
FT DOMAIN 229 558 FERM.
FT DOMAIN 354 457 PH.
FT COMPBIAS 147 155 Poly-Lys.
FT MOD_RES 11 11 Phosphotyrosine.
FT MOD_RES 504 504 Phosphotyrosine.
FT VAR_SEQ 360 363 Missing (in isoform 2).
FT /FTId=VSP_009226.
FT CONFLICT 472 472 A -> P (in Ref. 2; BAC04220).
FT CONFLICT 480 480 Q -> R (in Ref. 2; BAC04220).
FT STRAND 370 373
FT STRAND 377 380
FT STRAND 385 390
FT TURN 391 395
FT TURN 404 406
FT STRAND 408 411
FT HELIX 415 417
FT STRAND 419 427
FT STRAND 429 441
FT HELIX 442 456
FT HELIX 465 480
SQ SEQUENCE 667 AA; 75953 MW; 5ACE15EB689B91B5 CRC64;
MAGMKTASGD YIDSSWELRV FVGEEDPEAE SVTLRVTGES HIGGVLLKIV EQINRKQDWS
DHAIWWEQKR QWLLQTHWTL DKYGILADAR LFFGPQHRPV ILRLPNRRAL RLRASFSQPL
FQAVAAICRL LSIRHPEELS LLRAPEKKEK KKKEKEPEEE LYDLSKVVLA GGVAPALFRG
MPAHFSDSAQ TEACYHMLSR PQPPPDPLLL QRLPRPSSLS DKTQLHSRWL DSSRCLMQQG
IKAGDALWLR FKYYSFFDLD PKTDPVRLTQ LYEQARWDLL LEEIDCTEEE MMVFAALQYH
INKLSQSGEV GEPAGTDPGL DDLDVALSNL EVKLEGSAPT DVLDSLTTIP ELKDHLRIFR
IPRRPRKLTL KGYRQHWVVF KETTLSYYKS QDEAPGDPIQ QLNLKGCEVV PDVNVSGQKF
CIKLLVPSPE GMSEIYLRCQ DEQQYARWMA GCRLASKGRT MADSSYTSEV QAILAFLSLQ
RTGSGGPGNH PHGPDASAEG LNPYGLVAPR FQRKFKAKQL TPRILEAHQN VAQLSLAEAQ
LRFIQAWQSL PDFGISYVMV RFKGSRKDEI LGIANNRLIR IDLAVGDVVK TWRFSNMRQW
NVNWDIRQVA IEFDEHINVA FSCVSASCRI VHEYIGGYIF LSTRERARGE ELDEDLFLQL
TGGHEAF
//
ID URP2_HUMAN Reviewed; 667 AA.
AC Q86UX7; Q8IUA1; Q8N207; Q9BT48;
DT 16-JAN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JUN-2003, sequence version 1.
DT 22-JAN-2014, entry version 105.
DE RecName: Full=Fermitin family homolog 3;
DE AltName: Full=Kindlin-3;
DE AltName: Full=MIG2-like protein;
DE AltName: Full=Unc-112-related protein 2;
GN Name=FERMT3; Synonyms=KIND3, MIG2B, URP2;
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] (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RX PubMed=12697302; DOI=10.1016/S0925-4439(03)00035-8;
RA Weinstein E.J., Bourner M., Head R., Zakeri H., Bauer C.,
RA Mazzarella R.;
RT "URP1: a member of a novel family of PH and FERM domain-containing
RT membrane-associated proteins is significantly over-expressed in lung
RT and colon carcinomas.";
RL Biochim. Biophys. Acta 1637:207-216(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Thymus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lung, and Lymph;
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 [4]
RP PROTEIN SEQUENCE OF 20-35; 424-438 AND 569-577, IDENTIFICATION BY MASS
RP SPECTROMETRY, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=12886250; DOI=10.1038/sj.leu.2402993;
RA Boyd R.S., Adam P.J., Patel S., Loader J.A., Berry J., Redpath N.T.,
RA Poyser H.R., Fletcher G.C., Burgess N.A., Stamps A.C., Hudson L.,
RA Smith P., Griffiths M., Willis T.G., Karran E.L., Oscier D.G.,
RA Catovsky D., Terrett J.A., Dyer M.J.S.;
RT "Proteomic analysis of the cell-surface membrane in chronic
RT lymphocytic leukemia: identification of two novel proteins, BCNP1 and
RT MIG2B.";
RL Leukemia 17:1605-1612(2003).
RN [5]
RP POSSIBLE FUNCTION (ISOFORM 2).
RX PubMed=18280249; DOI=10.1016/j.bbrc.2008.02.024;
RA Wang L., Deng W., Shi T., Ma D.;
RT "URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB
RT and apoptosis.";
RL Biochem. Biophys. Res. Commun. 368:899-906(2008).
RN [6]
RP INVOLVEMENT IN LAD3.
RX PubMed=18779414; DOI=10.1182/blood-2008-06-163162;
RA Mory A., Feigelson S.W., Yarali N., Kilic S.S., Bayhan G.I.,
RA Gershoni-Baruch R., Etzioni A., Alon R.;
RT "Kindlin-3: a new gene involved in the pathogenesis of LAD-III.";
RL Blood 112:2591-2591(2008).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [8]
RP INVOLVEMENT IN LAD3.
RX PubMed=19617577; DOI=10.1182/blood-2009-04-218636;
RA Manevich-Mendelson E., Feigelson S.W., Pasvolsky R., Aker M.,
RA Grabovsky V., Shulman Z., Kilic S.S., Rosenthal-Allieri M.A.,
RA Ben-Dor S., Mory A., Bernard A., Moser M., Etzioni A., Alon R.;
RT "Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4
RT adhesiveness developed under shear flow conditions.";
RL Blood 114:2344-2353(2009).
RN [9]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19064721; DOI=10.1182/blood-2008-10-182154;
RA Kuijpers T.W., van de Vijver E., Weterman M.A.J., de Boer M.,
RA Tool A.T.J., van den Berg T.K., Moser M., Jakobs M.E., Seeger K.,
RA Sanal O., Uenal S., Cetin M., Roos D., Verhoeven A.J., Baas F.;
RT "LAD-1/variant syndrome is caused by mutations in FERMT3.";
RL Blood 113:4740-4746(2009).
RN [10]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19234463; DOI=10.1038/nm.1931;
RA Svensson L., Howarth K., McDowall A., Patzak I., Evans R., Ussar S.,
RA Moser M., Metin A., Fried M., Tomlinson I., Hogg N.;
RT "Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
RT affecting integrin activation.";
RL Nat. Med. 15:306-312(2009).
RN [11]
RP INVOLVEMENT IN LAD3, AND FUNCTION.
RX PubMed=19234460; DOI=10.1038/nm.1917;
RA Malinin N.L., Zhang L., Choi J., Ciocea A., Razorenova O., Ma Y.-Q.,
RA Podrez E.A., Tosi M., Lennon D.P., Caplan A.I., Shurin S.B.,
RA Plow E.F., Byzova T.V.;
RT "A point mutation in KINDLIN3 ablates activation of three integrin
RT subfamilies in humans.";
RL Nat. Med. 15:313-318(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-11 AND TYR-504, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP STRUCTURE BY NMR OF 349-478.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of the PH domain of kindlin-3 from human.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Plays a central role in cell adhesion in hematopoietic
CC cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and
CC ITGB3). Required for integrin-mediated platelet adhesion and
CC leukocyte adhesion to endothelial cells. Required for activation
CC of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes
CC (PMNs) (By similarity).
CC -!- FUNCTION: Isoform 2 may act as a repressor of NF-kappa-B and
CC apoptosis.
CC -!- SUBUNIT: Interacts with ITGB1, ITGB2 and ITGB3 (via cytoplasmic
CC tails) (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell projection, podosome (By similarity).
CC Note=Present in the F-actin surrounding ring structure of
CC podosomes, which are specialized adhesion structures of
CC hematopoietic cells (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=Long, URP2LF;
CC IsoId=Q86UX7-1; Sequence=Displayed;
CC Name=2; Synonyms=Short, URP2SF;
CC IsoId=Q86UX7-2; Sequence=VSP_009226;
CC -!- TISSUE SPECIFICITY: Highly expressed in lymph node. Expressed in
CC thymus, spleen and leukocytes. Weakly expressed in placenta, small
CC intestine, stomach, testis and lung. Overexpressed in B-cell
CC malignancies.
CC -!- DOMAIN: The FERM domain is not correctly detected by PROSITE or
CC Pfam techniques because it contains the insertion of a PH domain.
CC -!- DISEASE: Leukocyte adhesion deficiency 3 (LAD3) [MIM:612840]: A
CC disorder characterized by recurrent bacterial infections without
CC pus formation, leukocytosis and major bleeding disorders. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the kindlin family.
CC -!- SIMILARITY: Contains 1 FERM domain.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -----------------------------------------------------------------------
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DR EMBL; AY093951; AAM19736.1; -; mRNA.
DR EMBL; AY093952; AAM19737.1; -; mRNA.
DR EMBL; AK093719; BAC04220.1; -; mRNA.
DR EMBL; BC004347; AAH04347.2; -; mRNA.
DR EMBL; BC013366; AAH13366.1; -; mRNA.
DR EMBL; BC015584; AAH15584.1; -; mRNA.
DR RefSeq; NP_113659.3; NM_031471.5.
DR RefSeq; NP_848537.1; NM_178443.2.
DR RefSeq; XP_005274400.1; XM_005274343.1.
DR UniGene; Hs.180535; -.
DR PDB; 2YS3; NMR; -; A=349-478.
DR PDBsum; 2YS3; -.
DR ProteinModelPortal; Q86UX7; -.
DR SMR; Q86UX7; 7-98, 342-480, 488-639.
DR IntAct; Q86UX7; 6.
DR STRING; 9606.ENSP00000279227; -.
DR PhosphoSite; Q86UX7; -.
DR DMDM; 41018464; -.
DR PaxDb; Q86UX7; -.
DR PRIDE; Q86UX7; -.
DR Ensembl; ENST00000279227; ENSP00000279227; ENSG00000149781.
DR Ensembl; ENST00000345728; ENSP00000339950; ENSG00000149781.
DR GeneID; 83706; -.
DR KEGG; hsa:83706; -.
DR UCSC; uc001nyl.2; human.
DR CTD; 83706; -.
DR GeneCards; GC11P063975; -.
DR HGNC; HGNC:23151; FERMT3.
DR MIM; 607901; gene.
DR MIM; 612840; phenotype.
DR neXtProt; NX_Q86UX7; -.
DR Orphanet; 99844; Leukocyte adhesion deficiency type III.
DR PharmGKB; PA162388384; -.
DR eggNOG; NOG277845; -.
DR HOGENOM; HOG000231715; -.
DR HOVERGEN; HBG020688; -.
DR InParanoid; Q86UX7; -.
DR KO; K17084; -.
DR OMA; EMMLFGA; -.
DR OrthoDB; EOG7T7GSC; -.
DR PhylomeDB; Q86UX7; -.
DR EvolutionaryTrace; Q86UX7; -.
DR GeneWiki; FERMT3; -.
DR GenomeRNAi; 83706; -.
DR NextBio; 72692; -.
DR PMAP-CutDB; Q86UX7; -.
DR PRO; PR:Q86UX7; -.
DR ArrayExpress; Q86UX7; -.
DR Bgee; Q86UX7; -.
DR CleanEx; HS_FERMT3; -.
DR Genevestigator; Q86UX7; -.
DR GO; GO:0030054; C:cell junction; IEA:UniProtKB-KW.
DR GO; GO:0042995; C:cell projection; IEA:UniProtKB-KW.
DR GO; GO:0002102; C:podosome; ISS:UniProtKB.
DR GO; GO:0005178; F:integrin binding; ISS:UniProtKB.
DR GO; GO:0005543; F:phospholipid binding; IEA:InterPro.
DR GO; GO:0033622; P:integrin activation; IMP:UniProtKB.
DR GO; GO:0007159; P:leukocyte cell-cell adhesion; IMP:UniProtKB.
DR GO; GO:0070527; P:platelet aggregation; ISS:UniProtKB.
DR GO; GO:0033632; P:regulation of cell-cell adhesion mediated by integrin; IMP:UniProtKB.
DR Gene3D; 1.20.80.10; -; 2.
DR Gene3D; 2.30.29.30; -; 2.
DR InterPro; IPR019749; Band_41_domain.
DR InterPro; IPR014352; FERM/acyl-CoA-bd_prot_3-hlx.
DR InterPro; IPR019748; FERM_central.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR Pfam; PF00373; FERM_M; 1.
DR Pfam; PF00169; PH; 1.
DR SMART; SM00295; B41; 1.
DR SMART; SM00233; PH; 1.
DR SUPFAM; SSF47031; SSF47031; 2.
DR PROSITE; PS00660; FERM_1; FALSE_NEG.
DR PROSITE; PS00661; FERM_2; 1.
DR PROSITE; PS50057; FERM_3; FALSE_NEG.
DR PROSITE; PS50003; PH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell adhesion; Cell junction;
KW Cell projection; Complete proteome; Direct protein sequencing;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 667 Fermitin family homolog 3.
FT /FTId=PRO_0000219454.
FT DOMAIN 229 558 FERM.
FT DOMAIN 354 457 PH.
FT COMPBIAS 147 155 Poly-Lys.
FT MOD_RES 11 11 Phosphotyrosine.
FT MOD_RES 504 504 Phosphotyrosine.
FT VAR_SEQ 360 363 Missing (in isoform 2).
FT /FTId=VSP_009226.
FT CONFLICT 472 472 A -> P (in Ref. 2; BAC04220).
FT CONFLICT 480 480 Q -> R (in Ref. 2; BAC04220).
FT STRAND 370 373
FT STRAND 377 380
FT STRAND 385 390
FT TURN 391 395
FT TURN 404 406
FT STRAND 408 411
FT HELIX 415 417
FT STRAND 419 427
FT STRAND 429 441
FT HELIX 442 456
FT HELIX 465 480
SQ SEQUENCE 667 AA; 75953 MW; 5ACE15EB689B91B5 CRC64;
MAGMKTASGD YIDSSWELRV FVGEEDPEAE SVTLRVTGES HIGGVLLKIV EQINRKQDWS
DHAIWWEQKR QWLLQTHWTL DKYGILADAR LFFGPQHRPV ILRLPNRRAL RLRASFSQPL
FQAVAAICRL LSIRHPEELS LLRAPEKKEK KKKEKEPEEE LYDLSKVVLA GGVAPALFRG
MPAHFSDSAQ TEACYHMLSR PQPPPDPLLL QRLPRPSSLS DKTQLHSRWL DSSRCLMQQG
IKAGDALWLR FKYYSFFDLD PKTDPVRLTQ LYEQARWDLL LEEIDCTEEE MMVFAALQYH
INKLSQSGEV GEPAGTDPGL DDLDVALSNL EVKLEGSAPT DVLDSLTTIP ELKDHLRIFR
IPRRPRKLTL KGYRQHWVVF KETTLSYYKS QDEAPGDPIQ QLNLKGCEVV PDVNVSGQKF
CIKLLVPSPE GMSEIYLRCQ DEQQYARWMA GCRLASKGRT MADSSYTSEV QAILAFLSLQ
RTGSGGPGNH PHGPDASAEG LNPYGLVAPR FQRKFKAKQL TPRILEAHQN VAQLSLAEAQ
LRFIQAWQSL PDFGISYVMV RFKGSRKDEI LGIANNRLIR IDLAVGDVVK TWRFSNMRQW
NVNWDIRQVA IEFDEHINVA FSCVSASCRI VHEYIGGYIF LSTRERARGE ELDEDLFLQL
TGGHEAF
//
MIM
607901
*RECORD*
*FIELD* NO
607901
*FIELD* TI
*607901 FERMITIN FAMILY (DROSOPHILA) HOMOLOG 3; FERMT3
;;UNC112-RELATED PROTEIN 2; URP2;;
read moreKINDLIN 3; KIND3;;
MIG2B
*FIELD* TX
DESCRIPTION
The FERMT3 gene encodes a protein involved in integrin activation; it is
specifically expressed in hematopoietic cells (Moser et al., 2008). See
also FERMT1 (607900), which is specific to epithelial cells, and FERMT2
(607746), which has more widespread expression.
CLONING
Using microarray analysis of genes showing altered expression in several
tumor tissues, followed by PCR of brain cDNA, Weinstein et al. (2003)
cloned a full-length URP2 cDNA, encoding a protein with significant
homology to the C. elegans protein Unc112. The deduced 663-amino acid
protein has a calculated molecular mass of about 75.4 kD. They also
cloned a variant that contains a 12-bp insertion from a leukocyte cDNA
library. This variant encodes a 667-amino acid protein with a calculated
molecular mass of almost 76 kD. In its C-terminal half, URP2 contains 2
FERM domains flanking a pleckstrin homology domain. URP2 shares 55.4%
identity with MIG2 (607746) and 58.7% identity with URP1 (607900). All 3
proteins share weak but significant homology with talin-1 (186745) and
talin-2 (607349). Northern blot analysis detected strong expression of a
2.7-kb URP2 transcript in thymus, spleen, and leukocytes, weaker
expression in lung and placenta, and little to no expression in other
tissues.
By analyzing membrane proteins expressed in chronic lymphocytic
leukemia, followed by database analysis, Boyd et al. (2003) identified
MIG2B cDNAs. Quantitative RT-PCR showed hemopoietic tissue-specific
MIG2B expression and increased MIG2B expression in B-cell malignancies.
By SDS-PAGE, the apparent molecular mass of MIG2B was 60 kD.
GENE STRUCTURE
Weinstein et al. (2003) determined that the URP2 gene contains 15 exons,
spans about 20 kb, and is oriented in the telomere-to-centromere
direction. The URP2 splice variant utilizes an alternative exon 10
acceptor site.
MAPPING
By genomic sequence analysis, Weinstein et al. (2003) mapped the URP2
gene to chromosome 11q12.
GENE FUNCTION
Using immunoblot analysis, Manevich-Mendelson et al. (2009) showed that
KIND3-negative patients with leukocyte adhesion deficiency-3 (LAD3;
612840) who also lacked expression of CDGI (RAPGEF1; 600303) in resting
T cells (see MOLECULAR GENETICS) acquired CDGI expression after T-cell
activation. Inside-out (i.e., chemokine-mediated) activation with CXCL12
(600835) of normal and KIND3-negative cells resulted in normal CXCR4
(162643) expression but defective conformational activation of LFA1 (see
ITGB2; 600065) and diminished transient and firm adhesiveness during a
range of contact periods. In contrast, the intrinsic adhesiveness of
VLA4 (see ITGA4; 192975) was largely conserved in KIND3-negative cells.
Manevich-Mendelson et al. (2009) concluded that KIND3 is more critical
to LFA1 than to VLA4 adhesiveness in human lymphocytes.
MOLECULAR GENETICS
Integrins, the major adhesion receptors of leukocytes and platelets,
bind poorly to their ligands but become active after 'inside-out'
signaling through other membrane receptors. Hematopoietically derived
cells from individuals with leukocyte adhesion deficiency-3 (LAD3;
612840) express beta-1 (ITGB1; 135630), beta-2 (ITGB2; 600065), and
beta-3 (ITGB3; 173470) integrins, but defective inside-out signaling
results in LAD1 (116920)-like immune deficiency and Glanzmann
thrombasthenia (GT; 273800)-like bleeding problems. Svensson et al.
(2009) noted that Pasvolsky et al. (2007) reported a C-to-A change at a
putative splice acceptor site for exon 16 of the RASGRP2 gene (605577)
as the cause of LAD3 in 2 Turkish patients. Svensson et al. (2009)
identified this RASGRP2 change in 2 additional Turkish LAD3 patients,
but a third Maltese LAD3 patient lacked any changes in the RASGRP2 gene.
Furthermore, Svensson et al. (2009) showed that the C-to-A change had
little or no effect on RASGRP2 mRNA and protein levels, and that RASGRP2
function could not be restored by expression of wildtype RASGRP2.
Instead, Svensson et al. (2009) identified mutations in the KINDLIN3
gene as the cause of LAD3 in the 2 Turkish patients and the Maltese
patient they reported. The Turkish patients were homozygous for an
arg509-to-ter (R509X; 607901.0001) nonsense mutation, and the Maltese
patient was homozygous for an A-to-G transition at the splice acceptor
site of exon 14 (607901.0002). RT-PCR analyses showed that both
mutations destabilized KINDLIN3 mRNA upstream of the mutations. Western
blot analysis showed no expression of KINDLIN3 protein in the patients,
whereas expression was normal in their parents. Interference reflection
microscopy revealed that wildtype KINDLIN3 corrected defective adhesion
to and migration on ICAM1 (147840) by patient B cells. Svensson et al.
(2009) concluded that mutations in KINDLIN3 cause LAD3, and that
wildtype KINDLIN3 can overcome LAD3 defects by generating integrin
adhesive contacts and integrin-mediated migration of LAD3 lymphocytes.
In 9 patients with LAD1V from 7 unrelated consanguineous families
originally from central Turkey, Kuijpers et al. (2009) identified 3
disease-associated variants in genes on chromosome 11q13: a splice site
mutation in RASGRP2, an intronic deletion in NRXN2 (600566), and the
R509X mutation in FERMT3. Two other patients, one from a consanguineous
family from southeastern Turkey and the other from a consanguineous
Arabic family, had novel nonsense mutations in FERMT3, but they lacked
variants in RASGRP2 and NRXN2. The novel FERMT3 mutations were arg573 to
ter (R573X; 607901.0004) in the Turkish patient and trp229 to ter
(W229X; 607901.0005) in the Arabic patient. FERMT3 protein expression
was undetectable in leukocytes and platelets of all patients tested, and
all patients had similar neutrophil and platelet defects. Kuijpers et
al. (2009) concluded that the silent RASGRP1 mutation and the NRXN2
intronic deletion are not disease causing, but are in linkage
disequilibrium with the nonsense mutation in exon 12 of the FERMT3 gene
in the 7 previously reported Turkish families with LAD1V. They noted
that variation in the clinical symptoms of the 11 LAD1V patients
suggests that there is no strict genotype-phenotype relationship in
LAD1V.
In an African American girl with severe LAD3, McDowall et al. (2010)
identified 2 different homozygous mutations in the FERMT3 gene: G308R
(607901.0007) and 1275delT (607901.0008). In vitro studies indicated
that the truncated protein could not restore either leukocyte adhesion
or migration, whereas the G308R-mutant protein affected only migration.
These findings indicated a second activity of FERMT3 essential for
migration, in addition to adhesion.
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome, Robert et al. (2011) identified a homozygous splice-site
mutation in the FERMT3 gene (607901.0009). His parents were heterozygous
carriers. The patient and his unaffected mother were also heterozygous
for a mutation in the ITGA2B gene (607759.0008).
ANIMAL MODEL
Moser et al. (2008) found that Kind3 -/- mice died within a week of
birth with pronounced osteopetrosis and severe hemorrhages in the
gastrointestinal tract, skin, brain, and bladder that were already
apparent during development. Chimeric animals with Kind3 -/- livers also
suffered a pronounced hemostatic defect, suggesting platelet
dysfunction. Platelet counts were normal in Kind3 -/- chimeras, but the
platelets were unable to activate integrins. Activation of integrins
normally occurs after platelets contact a wounded vessel and is mediated
by binding of talin to beta-integrin (see ITGB3; 173470) cytoplasmic
tails. Moser et al. (2008) showed that Kind3 bound to regions of
beta-integrin tails distinct from those bound by talin and triggered
integrin activation. They concluded that KIND3 is an essential element
for platelet integrin activation in hemostasis and thrombosis.
Using immunoprecipitation, immunofluorescence microscopy, and leukocyte
adhesion analysis with neutrophils from Kind3 -/- mice, Moser et al.
(2009) demonstrated that mouse Kind3 bound to Itgb2 and was essential
for neutrophil binding and spreading on Itgb2 ligands, such as Icam1
(147840) and C3b (120700). Kind3 -/- neutrophils lost firm adhesion and
arrest on endothelial cells in vitro and in vivo, whereas selectin (see
173610)-mediated rolling was unaffected. Moser et al. (2009) concluded
that KIND3 is essential for activation of ITGB1, ITGB2, and ITGB3 and
that loss of Kind3 function in mice results in a LAD3-like phenotype.
*FIELD* AV
.0001
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG509TER
In a 4-year old Turkish boy with LAD3 (612840) originally reported by
Kuijpers et al. (2007) and an unrelated Turkish female infant with LAD3,
Svensson et al. (2009) identified a homozygous C-to-T transition at
nucleotide 1525 in exon 12 of the FERMT3 gene, resulting in an
arg509to-ter (R509X) substitution in the FERM F2 subdomain of the
protein.
In 9 children from 7 consanguineous families from central Turkey with
LAD3 originally reported by Kuijpers et al. (2007), Kuijpers et al.
(2009) identified homozygosity for the R509X mutation in the FERMT3
gene. All parents were heterozygous for this mutation.
.0002
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, IVS13AS, A-G, -2
In a Maltese patient with LAD3 (612840) originally reported by McDowall
et al. (2003), Svensson et al. (2009) identified a homozygous A-to-G
transition at the splice acceptor site of exon 14 of the FERMT3 gene.
McDowall et al. (2003) reported that a sister of the patient died with
widespread bleeding hours after birth. The index patient was
successfully treated with a bone marrow transplant.
.0003
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, TRP16TER
In 2 sibs, a boy and a girl, from the United Arab Emirates with symptoms
consistent with a severe form of LAD3 (612840), Malinin et al. (2009)
identified a homozygous G-to-A transition in exon 2 of the FERMT3 gene,
resulting in a trp16-to-ter (W16X) substitution. Both sibs presented
with severe bleeding and recurrent infections from 2 weeks of age,
followed by development of osteopetrosis at about 5 months of age.
Western blot analysis revealed a 56-kD FERMT3 fragment in patient cells,
but no full-length FERMT3. The authors suggested that the FERMT3
fragment in patient cells may have resulted from an alternative
downstream transcription initiation site at codon 181.
.0004
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG573TER
In a 2 year old with LAD3 (612840) and consanguineous parents from
southeastern Turkey, Kuijpers et al. (2009) identified a homozygous
C-to-T transition at nucleotide 1717 in exon 14 of the FERMT3 gene,
resulting in an arg573-to-ter (R573X) substitution in the 2nd FERM
domain of the protein. Both parents were heterozygous for this mutation.
.0005
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, TRP229TER
In a child with LAD3 (612840) and consanguineous Arabic parents,
Kuijpers et al. (2009) identified a homozygous G-to-A transition at
nucleotide 687 in exon 6 of the FERMT3, resulting in a trp229-to-ter
(W229X) substitution. Both parents were heterozygous for this mutation.
The patient died after a hematopoietic stem-cell transplant.
.0006
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG513TER
In 3 Turkish patients with LAD3 (612840), Mory et al. (2008) identified
a homozygous C-to-T transition at nucleotide 1632 of the FERMT3 gene,
resulting in an arg513-to-ter (R513X) substitution. The patients'
parents were all heterozygous carriers of the R513X mutation, which was
not detected in 68 Turkish controls. These patients also had the
putative splice site mutation in RASGRP2 (605577) that Svensson et al.
(2009) and Kuijpers et al. (2009) excluded as a cause of LAD3.
.0007
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, GLY308ARG
In an 11-month-old African American girl with LAD3 (612840), McDowall et
al. (2010) identified 2 homozygous mutations in the FERMT3 gene. One
mutation was a 922G-A transition in exon 8, resulting in a gly308-to-arg
(G308R) substitution in the loop linking the first half of FERM
subdomain 2 and the PH domain. The second homozygous mutation was a 1-bp
deletion (1275delT; 607901.0008). In vitro studies showed that patient T
cells failed to firmly adhere to ICAM1 (147840) and fibronectin (FN1;
135600) when adhesion was stimulated by inside-out signaling agonists.
This defect was rescued by transfection with wildtype FERMT3. Patient T
cells had significantly decreased levels of FERMT3 mRNA and no FERMT3
protein. In vitro functional expression assays showed that B cells
transfected with the G308R-mutant protein had correct FERMT3 membrane
localization and were able to adhere to ICAM1, but were unable to
migrate correctly compared to wildtype. These findings indicated a
second activity of FERMT3 essential for migration, in addition to
adhesion. The patient had a severe disorder, with severe bleeding
tendency, recurrent infections, and osteopetrosis. She was successfully
treated with bone marrow transplantation. The patient's unaffected
mother was heterozygous for both mutations, and showed about half-levels
of FERMT3 mRNA, consistent with the lack of a functional gene on 1
allele.
.0008
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, 1-BP DEL, 1275T
In an 11-month-old African American girl with LAD3 (612840), McDowall et
al. (2010) identified 2 homozygous mutations in the FERMT3 gene. One
mutation was a 1-bp deletion (1275delT) in exon 11, resulting in
premature termination in the PH domain in the loop between the beta-6
and beta-7 strands. The second homozygous mutation was a G308R
substitution (607901.0007). In vitro functional expression assays showed
that B cells transfected with the 1275delT mutant protein had no FERMT3
membrane localization and were unable to adhere to ICAM1. The findings
indicated that the truncated PH domain was no longer capable of membrane
anchoring. The patient's unaffected mother was heterozygous for both
mutations, and showed about half-levels of FERMT3 mRNA, consistent with
the lack of a functional gene on 1 allele.
.0009
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, IVS2AS, A-C, -2
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome (612840), Robert et al. (2011) identified a homozygous
splice-site mutation in intron 2 of the FERMT3 gene. The mutation was an
A-to-C change that affected the acceptor splice site for exon 3
(310-2A-C using the cDNA sequence), resulting in the use of a cryptic
splice site 10 nucleotides after the normal start of exon 3, a
frameshift, and premature termination. The parents were heterozygous
carriers. The mutation resulted in absence of normal FERMT3 protein in
platelets and lymphocytes, failure of integrin activation, and impaired
platelet and leukocyte integrin-dependent function. The patient and his
unaffected mother were also heterozygous for a mutation in the ITGA2B
gene (607759.0008).
*FIELD* RF
1. Boyd, R. S.; Adam, P. J.; Patel, S.; Loader, J. A.; Berry, J.;
Redpath, N. T.; Poyser, H. R.; Fletcher, G. C.; Burgess, N. A.; Stamps,
A. C.; Hudson, L.; Smith, P.; Griffiths, M.; Willis, T. G.; Karran,
E. L.; Oscier, D. G.; Catovsky, D.; Terrett, J. A.; Dyer, M. J. S.
: Proteomic analysis of the cell-surface membrane in chronic lymphocytic
leukemia: identification of two novel proteins, BCNP1 and MIG2B. Leukemia 17:
1605-1612, 2003.
2. Kuijpers, T. W.; van Bruggen, R.; Kamerbeek, N.; Tool, A. T. J.;
Hicsonmez, G.; Gurgey, A.; Karow, A.; Verhoeven, A. J.; Seeger, K.;
Sanal, O.; Niemeyer, C.; Roos, D.: Natural history and early diagnosis
of LAD-1/variant syndrome. Blood 109: 3529-3537, 2007.
3. Kuijpers, T. W.; van de Vijver, E.; Weterman, M. A. J.; de Boer,
M.; Tool, A. T. J.; van den Berg, T. K.; Moser, M.; Jakobs, M. E.;
Seeger, K.; Sanal, O.; Unal, S.; Cetin, M.; Roos, D.; Verhoeven, A.
J.; Baas, F.: LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113:
4740-4746, 2009.
4. Malinin, N. L.; Zhang, L.; Choi, J.; Ciocea, A.; Razorenova, O.;
Ma, Y.-Q.; Podrez, E. A.; Tosi, M.; Lennon, D. P.; Caplan, A. I.;
Shurin, S. B.; Plow, E. F.; Byzova, T. V.: A point mutation in KINDLIN3
ablates activation of three integrin subfamilies in humans. Nature
Med. 15: 313-318, 2009.
5. Manevich-Mendelson, E.; Feigelson, S. W.; Pasvolsky, R.; Aker,
M.; Grabovsky, V.; Shulman, Z.; Kilic, S. S.; Rosenthal-Allieri, M.
A.; Ben-Dor, S.; Mory, A.; Bernard, A.; Moser, M.; Etzioni, A.; Alon,
R.: Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness
developed under shear flow conditions. Blood 114: 2344-2353, 2009.
6. 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.
7. McDowall, A.; Svensson, L.; Stanley, P.; Patzak, I.; Chakravarty,
P.; Howarth, K.; Sabnis, H.; Briones, M.; Hogg, N.: Two mutations
in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient
reveal distinct effects on leukocyte function in vitro. Blood 115:
4834-4842, 2010.
8. Mory, A.; Feigelson, S. W.; Yarali, N.; Kilic, S. S.; Bayhan, G.
I.; Gershoni-Baruch, R.; Etzioni, A.; Alon, R.: Kindlin-3: a new
gene involved in the pathogenesis of LAD-III. (Letter) Blood 112:
2591 only, 2008.
9. Moser, M.; Bauer, M.; Schmid, S.; Ruppert, R.; Schmidt, S.; Sixt,
M.; Wang, H.-V.; Sperandio, M.; Fassler, R.: Kindlin-3 is required
for beta-2 integrin-mediated leukocyte adhesion to endothelial cells. Nature
Med. 15: 300-305, 2009.
10. Moser, M.; Nieswandt, B.; Ussar, S.; Pozgajova, M.; Fassler, R.
: Kindlin-3 is essential for integrin activation and platelet aggregation. Nature
Med. 14: 325-330, 2008.
11. Pasvolsky, R.; Feigelson, S. W.; Kilic, S. S.; Simon, A. J.; Tal-Lapidot,
G.; Grabovsky, V.; Crittenden, J. R.; Amariglio, N.; Safran, M.; Graybiel,
A. M.; Rechavi, G.; Ben-Dor, S.; Etzioni, A.; Alon, R.: A LAD-III
syndrome is associated with defective expression of the Rap-1 activator
CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J. Exp. Med. 204:
1571-1582, 2007.
12. Robert, P.; Canault, M.; Farnarier, C.; Nurden, A.; Grosdidier,
C.; Barlogis, V.; Bongrand, P.; Pierres, A.; Chambost, H.; Alessi,
M.-C.: A novel leukocyte adhesion deficiency III variant: kindlin-3
deficiency results in integrin- and nonintegrin-related defects in
different steps of leukocyte adhesion. J. Immun. 186: 5273-5283,
2011.
13. Svensson, L.; Howarth, K.; McDowall, A.; Patzak, I.; Evans, R.;
Ussar, S.; Moser, M.; Metin, A.; Fried, M.; Tomlinson, I.; Hogg, N.
: Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
affecting integrin activation. Nature Med. 15: 306-312, 2009.
14. Weinstein, E. J.; Bourner, M.; Head, R.; Zakeri, H.; Bauer, C.;
Mazzarella, R.: URP1: a member of a novel family of PH and FERM domain-containing
membrane-associated proteins is significantly over-expressed in lung
and colon carcinomas. Biochim. Biophys. Acta 1637: 207-216, 2003.
*FIELD* CN
Paul J. Converse - updated: 3/22/2012
Paul J. Converse - updated: 12/7/2011
Cassandra L. Kniffin - updated: 5/11/2011
Paul J. Converse - updated: 6/5/2009
Patricia A. Hartz - updated: 5/28/2008
Patricia A. Hartz - updated: 3/16/2006
*FIELD* CD
Patricia A. Hartz: 6/19/2003
*FIELD* ED
carol: 09/19/2013
carol: 9/19/2013
mgross: 5/7/2012
terry: 3/22/2012
mgross: 1/19/2012
terry: 12/7/2011
wwang: 5/24/2011
ckniffin: 5/11/2011
carol: 7/30/2010
carol: 11/5/2009
mgross: 6/5/2009
mgross: 6/3/2008
terry: 5/28/2008
carol: 3/26/2008
mgross: 3/16/2006
terry: 3/16/2006
carol: 7/16/2003
tkritzer: 7/14/2003
mgross: 6/19/2003
*RECORD*
*FIELD* NO
607901
*FIELD* TI
*607901 FERMITIN FAMILY (DROSOPHILA) HOMOLOG 3; FERMT3
;;UNC112-RELATED PROTEIN 2; URP2;;
read moreKINDLIN 3; KIND3;;
MIG2B
*FIELD* TX
DESCRIPTION
The FERMT3 gene encodes a protein involved in integrin activation; it is
specifically expressed in hematopoietic cells (Moser et al., 2008). See
also FERMT1 (607900), which is specific to epithelial cells, and FERMT2
(607746), which has more widespread expression.
CLONING
Using microarray analysis of genes showing altered expression in several
tumor tissues, followed by PCR of brain cDNA, Weinstein et al. (2003)
cloned a full-length URP2 cDNA, encoding a protein with significant
homology to the C. elegans protein Unc112. The deduced 663-amino acid
protein has a calculated molecular mass of about 75.4 kD. They also
cloned a variant that contains a 12-bp insertion from a leukocyte cDNA
library. This variant encodes a 667-amino acid protein with a calculated
molecular mass of almost 76 kD. In its C-terminal half, URP2 contains 2
FERM domains flanking a pleckstrin homology domain. URP2 shares 55.4%
identity with MIG2 (607746) and 58.7% identity with URP1 (607900). All 3
proteins share weak but significant homology with talin-1 (186745) and
talin-2 (607349). Northern blot analysis detected strong expression of a
2.7-kb URP2 transcript in thymus, spleen, and leukocytes, weaker
expression in lung and placenta, and little to no expression in other
tissues.
By analyzing membrane proteins expressed in chronic lymphocytic
leukemia, followed by database analysis, Boyd et al. (2003) identified
MIG2B cDNAs. Quantitative RT-PCR showed hemopoietic tissue-specific
MIG2B expression and increased MIG2B expression in B-cell malignancies.
By SDS-PAGE, the apparent molecular mass of MIG2B was 60 kD.
GENE STRUCTURE
Weinstein et al. (2003) determined that the URP2 gene contains 15 exons,
spans about 20 kb, and is oriented in the telomere-to-centromere
direction. The URP2 splice variant utilizes an alternative exon 10
acceptor site.
MAPPING
By genomic sequence analysis, Weinstein et al. (2003) mapped the URP2
gene to chromosome 11q12.
GENE FUNCTION
Using immunoblot analysis, Manevich-Mendelson et al. (2009) showed that
KIND3-negative patients with leukocyte adhesion deficiency-3 (LAD3;
612840) who also lacked expression of CDGI (RAPGEF1; 600303) in resting
T cells (see MOLECULAR GENETICS) acquired CDGI expression after T-cell
activation. Inside-out (i.e., chemokine-mediated) activation with CXCL12
(600835) of normal and KIND3-negative cells resulted in normal CXCR4
(162643) expression but defective conformational activation of LFA1 (see
ITGB2; 600065) and diminished transient and firm adhesiveness during a
range of contact periods. In contrast, the intrinsic adhesiveness of
VLA4 (see ITGA4; 192975) was largely conserved in KIND3-negative cells.
Manevich-Mendelson et al. (2009) concluded that KIND3 is more critical
to LFA1 than to VLA4 adhesiveness in human lymphocytes.
MOLECULAR GENETICS
Integrins, the major adhesion receptors of leukocytes and platelets,
bind poorly to their ligands but become active after 'inside-out'
signaling through other membrane receptors. Hematopoietically derived
cells from individuals with leukocyte adhesion deficiency-3 (LAD3;
612840) express beta-1 (ITGB1; 135630), beta-2 (ITGB2; 600065), and
beta-3 (ITGB3; 173470) integrins, but defective inside-out signaling
results in LAD1 (116920)-like immune deficiency and Glanzmann
thrombasthenia (GT; 273800)-like bleeding problems. Svensson et al.
(2009) noted that Pasvolsky et al. (2007) reported a C-to-A change at a
putative splice acceptor site for exon 16 of the RASGRP2 gene (605577)
as the cause of LAD3 in 2 Turkish patients. Svensson et al. (2009)
identified this RASGRP2 change in 2 additional Turkish LAD3 patients,
but a third Maltese LAD3 patient lacked any changes in the RASGRP2 gene.
Furthermore, Svensson et al. (2009) showed that the C-to-A change had
little or no effect on RASGRP2 mRNA and protein levels, and that RASGRP2
function could not be restored by expression of wildtype RASGRP2.
Instead, Svensson et al. (2009) identified mutations in the KINDLIN3
gene as the cause of LAD3 in the 2 Turkish patients and the Maltese
patient they reported. The Turkish patients were homozygous for an
arg509-to-ter (R509X; 607901.0001) nonsense mutation, and the Maltese
patient was homozygous for an A-to-G transition at the splice acceptor
site of exon 14 (607901.0002). RT-PCR analyses showed that both
mutations destabilized KINDLIN3 mRNA upstream of the mutations. Western
blot analysis showed no expression of KINDLIN3 protein in the patients,
whereas expression was normal in their parents. Interference reflection
microscopy revealed that wildtype KINDLIN3 corrected defective adhesion
to and migration on ICAM1 (147840) by patient B cells. Svensson et al.
(2009) concluded that mutations in KINDLIN3 cause LAD3, and that
wildtype KINDLIN3 can overcome LAD3 defects by generating integrin
adhesive contacts and integrin-mediated migration of LAD3 lymphocytes.
In 9 patients with LAD1V from 7 unrelated consanguineous families
originally from central Turkey, Kuijpers et al. (2009) identified 3
disease-associated variants in genes on chromosome 11q13: a splice site
mutation in RASGRP2, an intronic deletion in NRXN2 (600566), and the
R509X mutation in FERMT3. Two other patients, one from a consanguineous
family from southeastern Turkey and the other from a consanguineous
Arabic family, had novel nonsense mutations in FERMT3, but they lacked
variants in RASGRP2 and NRXN2. The novel FERMT3 mutations were arg573 to
ter (R573X; 607901.0004) in the Turkish patient and trp229 to ter
(W229X; 607901.0005) in the Arabic patient. FERMT3 protein expression
was undetectable in leukocytes and platelets of all patients tested, and
all patients had similar neutrophil and platelet defects. Kuijpers et
al. (2009) concluded that the silent RASGRP1 mutation and the NRXN2
intronic deletion are not disease causing, but are in linkage
disequilibrium with the nonsense mutation in exon 12 of the FERMT3 gene
in the 7 previously reported Turkish families with LAD1V. They noted
that variation in the clinical symptoms of the 11 LAD1V patients
suggests that there is no strict genotype-phenotype relationship in
LAD1V.
In an African American girl with severe LAD3, McDowall et al. (2010)
identified 2 different homozygous mutations in the FERMT3 gene: G308R
(607901.0007) and 1275delT (607901.0008). In vitro studies indicated
that the truncated protein could not restore either leukocyte adhesion
or migration, whereas the G308R-mutant protein affected only migration.
These findings indicated a second activity of FERMT3 essential for
migration, in addition to adhesion.
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome, Robert et al. (2011) identified a homozygous splice-site
mutation in the FERMT3 gene (607901.0009). His parents were heterozygous
carriers. The patient and his unaffected mother were also heterozygous
for a mutation in the ITGA2B gene (607759.0008).
ANIMAL MODEL
Moser et al. (2008) found that Kind3 -/- mice died within a week of
birth with pronounced osteopetrosis and severe hemorrhages in the
gastrointestinal tract, skin, brain, and bladder that were already
apparent during development. Chimeric animals with Kind3 -/- livers also
suffered a pronounced hemostatic defect, suggesting platelet
dysfunction. Platelet counts were normal in Kind3 -/- chimeras, but the
platelets were unable to activate integrins. Activation of integrins
normally occurs after platelets contact a wounded vessel and is mediated
by binding of talin to beta-integrin (see ITGB3; 173470) cytoplasmic
tails. Moser et al. (2008) showed that Kind3 bound to regions of
beta-integrin tails distinct from those bound by talin and triggered
integrin activation. They concluded that KIND3 is an essential element
for platelet integrin activation in hemostasis and thrombosis.
Using immunoprecipitation, immunofluorescence microscopy, and leukocyte
adhesion analysis with neutrophils from Kind3 -/- mice, Moser et al.
(2009) demonstrated that mouse Kind3 bound to Itgb2 and was essential
for neutrophil binding and spreading on Itgb2 ligands, such as Icam1
(147840) and C3b (120700). Kind3 -/- neutrophils lost firm adhesion and
arrest on endothelial cells in vitro and in vivo, whereas selectin (see
173610)-mediated rolling was unaffected. Moser et al. (2009) concluded
that KIND3 is essential for activation of ITGB1, ITGB2, and ITGB3 and
that loss of Kind3 function in mice results in a LAD3-like phenotype.
*FIELD* AV
.0001
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG509TER
In a 4-year old Turkish boy with LAD3 (612840) originally reported by
Kuijpers et al. (2007) and an unrelated Turkish female infant with LAD3,
Svensson et al. (2009) identified a homozygous C-to-T transition at
nucleotide 1525 in exon 12 of the FERMT3 gene, resulting in an
arg509to-ter (R509X) substitution in the FERM F2 subdomain of the
protein.
In 9 children from 7 consanguineous families from central Turkey with
LAD3 originally reported by Kuijpers et al. (2007), Kuijpers et al.
(2009) identified homozygosity for the R509X mutation in the FERMT3
gene. All parents were heterozygous for this mutation.
.0002
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, IVS13AS, A-G, -2
In a Maltese patient with LAD3 (612840) originally reported by McDowall
et al. (2003), Svensson et al. (2009) identified a homozygous A-to-G
transition at the splice acceptor site of exon 14 of the FERMT3 gene.
McDowall et al. (2003) reported that a sister of the patient died with
widespread bleeding hours after birth. The index patient was
successfully treated with a bone marrow transplant.
.0003
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, TRP16TER
In 2 sibs, a boy and a girl, from the United Arab Emirates with symptoms
consistent with a severe form of LAD3 (612840), Malinin et al. (2009)
identified a homozygous G-to-A transition in exon 2 of the FERMT3 gene,
resulting in a trp16-to-ter (W16X) substitution. Both sibs presented
with severe bleeding and recurrent infections from 2 weeks of age,
followed by development of osteopetrosis at about 5 months of age.
Western blot analysis revealed a 56-kD FERMT3 fragment in patient cells,
but no full-length FERMT3. The authors suggested that the FERMT3
fragment in patient cells may have resulted from an alternative
downstream transcription initiation site at codon 181.
.0004
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG573TER
In a 2 year old with LAD3 (612840) and consanguineous parents from
southeastern Turkey, Kuijpers et al. (2009) identified a homozygous
C-to-T transition at nucleotide 1717 in exon 14 of the FERMT3 gene,
resulting in an arg573-to-ter (R573X) substitution in the 2nd FERM
domain of the protein. Both parents were heterozygous for this mutation.
.0005
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, TRP229TER
In a child with LAD3 (612840) and consanguineous Arabic parents,
Kuijpers et al. (2009) identified a homozygous G-to-A transition at
nucleotide 687 in exon 6 of the FERMT3, resulting in a trp229-to-ter
(W229X) substitution. Both parents were heterozygous for this mutation.
The patient died after a hematopoietic stem-cell transplant.
.0006
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, ARG513TER
In 3 Turkish patients with LAD3 (612840), Mory et al. (2008) identified
a homozygous C-to-T transition at nucleotide 1632 of the FERMT3 gene,
resulting in an arg513-to-ter (R513X) substitution. The patients'
parents were all heterozygous carriers of the R513X mutation, which was
not detected in 68 Turkish controls. These patients also had the
putative splice site mutation in RASGRP2 (605577) that Svensson et al.
(2009) and Kuijpers et al. (2009) excluded as a cause of LAD3.
.0007
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, GLY308ARG
In an 11-month-old African American girl with LAD3 (612840), McDowall et
al. (2010) identified 2 homozygous mutations in the FERMT3 gene. One
mutation was a 922G-A transition in exon 8, resulting in a gly308-to-arg
(G308R) substitution in the loop linking the first half of FERM
subdomain 2 and the PH domain. The second homozygous mutation was a 1-bp
deletion (1275delT; 607901.0008). In vitro studies showed that patient T
cells failed to firmly adhere to ICAM1 (147840) and fibronectin (FN1;
135600) when adhesion was stimulated by inside-out signaling agonists.
This defect was rescued by transfection with wildtype FERMT3. Patient T
cells had significantly decreased levels of FERMT3 mRNA and no FERMT3
protein. In vitro functional expression assays showed that B cells
transfected with the G308R-mutant protein had correct FERMT3 membrane
localization and were able to adhere to ICAM1, but were unable to
migrate correctly compared to wildtype. These findings indicated a
second activity of FERMT3 essential for migration, in addition to
adhesion. The patient had a severe disorder, with severe bleeding
tendency, recurrent infections, and osteopetrosis. She was successfully
treated with bone marrow transplantation. The patient's unaffected
mother was heterozygous for both mutations, and showed about half-levels
of FERMT3 mRNA, consistent with the lack of a functional gene on 1
allele.
.0008
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, 1-BP DEL, 1275T
In an 11-month-old African American girl with LAD3 (612840), McDowall et
al. (2010) identified 2 homozygous mutations in the FERMT3 gene. One
mutation was a 1-bp deletion (1275delT) in exon 11, resulting in
premature termination in the PH domain in the loop between the beta-6
and beta-7 strands. The second homozygous mutation was a G308R
substitution (607901.0007). In vitro functional expression assays showed
that B cells transfected with the 1275delT mutant protein had no FERMT3
membrane localization and were unable to adhere to ICAM1. The findings
indicated that the truncated PH domain was no longer capable of membrane
anchoring. The patient's unaffected mother was heterozygous for both
mutations, and showed about half-levels of FERMT3 mRNA, consistent with
the lack of a functional gene on 1 allele.
.0009
LEUKOCYTE ADHESION DEFICIENCY, TYPE III
FERMT3, IVS2AS, A-C, -2
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome (612840), Robert et al. (2011) identified a homozygous
splice-site mutation in intron 2 of the FERMT3 gene. The mutation was an
A-to-C change that affected the acceptor splice site for exon 3
(310-2A-C using the cDNA sequence), resulting in the use of a cryptic
splice site 10 nucleotides after the normal start of exon 3, a
frameshift, and premature termination. The parents were heterozygous
carriers. The mutation resulted in absence of normal FERMT3 protein in
platelets and lymphocytes, failure of integrin activation, and impaired
platelet and leukocyte integrin-dependent function. The patient and his
unaffected mother were also heterozygous for a mutation in the ITGA2B
gene (607759.0008).
*FIELD* RF
1. Boyd, R. S.; Adam, P. J.; Patel, S.; Loader, J. A.; Berry, J.;
Redpath, N. T.; Poyser, H. R.; Fletcher, G. C.; Burgess, N. A.; Stamps,
A. C.; Hudson, L.; Smith, P.; Griffiths, M.; Willis, T. G.; Karran,
E. L.; Oscier, D. G.; Catovsky, D.; Terrett, J. A.; Dyer, M. J. S.
: Proteomic analysis of the cell-surface membrane in chronic lymphocytic
leukemia: identification of two novel proteins, BCNP1 and MIG2B. Leukemia 17:
1605-1612, 2003.
2. Kuijpers, T. W.; van Bruggen, R.; Kamerbeek, N.; Tool, A. T. J.;
Hicsonmez, G.; Gurgey, A.; Karow, A.; Verhoeven, A. J.; Seeger, K.;
Sanal, O.; Niemeyer, C.; Roos, D.: Natural history and early diagnosis
of LAD-1/variant syndrome. Blood 109: 3529-3537, 2007.
3. Kuijpers, T. W.; van de Vijver, E.; Weterman, M. A. J.; de Boer,
M.; Tool, A. T. J.; van den Berg, T. K.; Moser, M.; Jakobs, M. E.;
Seeger, K.; Sanal, O.; Unal, S.; Cetin, M.; Roos, D.; Verhoeven, A.
J.; Baas, F.: LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113:
4740-4746, 2009.
4. Malinin, N. L.; Zhang, L.; Choi, J.; Ciocea, A.; Razorenova, O.;
Ma, Y.-Q.; Podrez, E. A.; Tosi, M.; Lennon, D. P.; Caplan, A. I.;
Shurin, S. B.; Plow, E. F.; Byzova, T. V.: A point mutation in KINDLIN3
ablates activation of three integrin subfamilies in humans. Nature
Med. 15: 313-318, 2009.
5. Manevich-Mendelson, E.; Feigelson, S. W.; Pasvolsky, R.; Aker,
M.; Grabovsky, V.; Shulman, Z.; Kilic, S. S.; Rosenthal-Allieri, M.
A.; Ben-Dor, S.; Mory, A.; Bernard, A.; Moser, M.; Etzioni, A.; Alon,
R.: Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness
developed under shear flow conditions. Blood 114: 2344-2353, 2009.
6. 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.
7. McDowall, A.; Svensson, L.; Stanley, P.; Patzak, I.; Chakravarty,
P.; Howarth, K.; Sabnis, H.; Briones, M.; Hogg, N.: Two mutations
in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient
reveal distinct effects on leukocyte function in vitro. Blood 115:
4834-4842, 2010.
8. Mory, A.; Feigelson, S. W.; Yarali, N.; Kilic, S. S.; Bayhan, G.
I.; Gershoni-Baruch, R.; Etzioni, A.; Alon, R.: Kindlin-3: a new
gene involved in the pathogenesis of LAD-III. (Letter) Blood 112:
2591 only, 2008.
9. Moser, M.; Bauer, M.; Schmid, S.; Ruppert, R.; Schmidt, S.; Sixt,
M.; Wang, H.-V.; Sperandio, M.; Fassler, R.: Kindlin-3 is required
for beta-2 integrin-mediated leukocyte adhesion to endothelial cells. Nature
Med. 15: 300-305, 2009.
10. Moser, M.; Nieswandt, B.; Ussar, S.; Pozgajova, M.; Fassler, R.
: Kindlin-3 is essential for integrin activation and platelet aggregation. Nature
Med. 14: 325-330, 2008.
11. Pasvolsky, R.; Feigelson, S. W.; Kilic, S. S.; Simon, A. J.; Tal-Lapidot,
G.; Grabovsky, V.; Crittenden, J. R.; Amariglio, N.; Safran, M.; Graybiel,
A. M.; Rechavi, G.; Ben-Dor, S.; Etzioni, A.; Alon, R.: A LAD-III
syndrome is associated with defective expression of the Rap-1 activator
CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J. Exp. Med. 204:
1571-1582, 2007.
12. Robert, P.; Canault, M.; Farnarier, C.; Nurden, A.; Grosdidier,
C.; Barlogis, V.; Bongrand, P.; Pierres, A.; Chambost, H.; Alessi,
M.-C.: A novel leukocyte adhesion deficiency III variant: kindlin-3
deficiency results in integrin- and nonintegrin-related defects in
different steps of leukocyte adhesion. J. Immun. 186: 5273-5283,
2011.
13. Svensson, L.; Howarth, K.; McDowall, A.; Patzak, I.; Evans, R.;
Ussar, S.; Moser, M.; Metin, A.; Fried, M.; Tomlinson, I.; Hogg, N.
: Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
affecting integrin activation. Nature Med. 15: 306-312, 2009.
14. Weinstein, E. J.; Bourner, M.; Head, R.; Zakeri, H.; Bauer, C.;
Mazzarella, R.: URP1: a member of a novel family of PH and FERM domain-containing
membrane-associated proteins is significantly over-expressed in lung
and colon carcinomas. Biochim. Biophys. Acta 1637: 207-216, 2003.
*FIELD* CN
Paul J. Converse - updated: 3/22/2012
Paul J. Converse - updated: 12/7/2011
Cassandra L. Kniffin - updated: 5/11/2011
Paul J. Converse - updated: 6/5/2009
Patricia A. Hartz - updated: 5/28/2008
Patricia A. Hartz - updated: 3/16/2006
*FIELD* CD
Patricia A. Hartz: 6/19/2003
*FIELD* ED
carol: 09/19/2013
carol: 9/19/2013
mgross: 5/7/2012
terry: 3/22/2012
mgross: 1/19/2012
terry: 12/7/2011
wwang: 5/24/2011
ckniffin: 5/11/2011
carol: 7/30/2010
carol: 11/5/2009
mgross: 6/5/2009
mgross: 6/3/2008
terry: 5/28/2008
carol: 3/26/2008
mgross: 3/16/2006
terry: 3/16/2006
carol: 7/16/2003
tkritzer: 7/14/2003
mgross: 6/19/2003
MIM
612840
*RECORD*
*FIELD* NO
612840
*FIELD* TI
#612840 LEUKOCYTE ADHESION DEFICIENCY, TYPE III; LAD3
;;LEUKOCYTE ADHESION DEFICIENCY 3;;
read moreLEUKOCYTE ADHESION DEFICIENCY 1 VARIANT; LAD1V;;
INTEGRIN ACTIVATION DEFICIENCY DISEASE; IADD
*FIELD* TX
A number sign (#) is used with this entry because LAD3 can be caused by
homozygous mutation in the FERMT3 gene (607901) on chromosome 11q12.
DESCRIPTION
Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant
(LAD1V), is an autosomal recessive disorder characterized by LAD1
(116920)-like immune deficiency and Glanzmann thrombasthenia (GT;
273800)-like bleeding problems. LAD3 results from mutations in FERMT3,
or KINDLIN3, which encodes an intracellular protein that interacts with
beta-integrins in hematopoietic cells. In LAD3, the adhesive functions
of integrins on both leukocytes and platelets are disrupted, most likely
due to defects in activation-dependent alterations of surface integrins
that enable high-avidity binding to ligands on target cells, a process
termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009).
CLINICAL FEATURES
Kuijpers et al. (1997) reported a male infant, born of consanguineous
Turkish parents, who developed recurrent bouts of nonpussing
inflammatory lesions and bacterial infections. Wound healing was
delayed, and the umbilical cord detached spontaneously at 5 weeks. By
age 2 years, he developed a bleeding tendency in the presence of normal
platelet numbers. Laboratory studies showed defective neutrophil
activation and adhesion with normal expression of CD11 (see 153370)/CD18
(ITGB2; 600065), thus excluding a diagnosis of LAD1. However, the
patient's leukocytes were deficient in beta-2-mediated adhesion ligand
binding upon stimulation.
Alon et al. (2003) reported an Arab child, born of consanguineous
parents, who developed periumbilical cellulitis and Staphylococcal
septicemia at age 5 days. The umbilical cord was shed at 4 weeks.
Initial laboratory tests showed low hemoglobin, slightly reduced
platelet count, and leukocytosis. During the subsequent months, he
developed severe mucosal bleeding that necessitated blood and platelet
transfusions, as well as recurrent nonsuppurating skin infections.
Platelet aggregation studies demonstrated a grossly abnormal response to
agonists. He died at age 6 years from a disseminated fungal infection
after a mismatched bone marrow transplantation. A younger brother who
presented with the same clinical and hematologic phenotypes at birth
died at 1 week of age from sepsis. Laboratory studies showed an impaired
ability of neutrophil and lymphocyte beta-1 (ITGB1; 135630) and beta-2
integrins to generate high avidity to their endothelial ligands and
arrest cells on vascular endothelium in response to endothelial
chemoattractant signals, despite normal expression and intrinsic
function of integrins and chemokine receptors. The findings suggested a
primary defect in integrin rearrangement at ligand-bearing contacts.
In a patient with features of Glanzmann thrombasthenia and LAD1,
McDowall et al. (2003) identified a form of integrin dysfunction
involving ITGB1, 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.
Kuijpers et al. (2007) reported 9 patients with LAD1V from 7 unrelated
consanguineous families from central Turkey, including the patient
reported by Kuijpers et al. (1997). Patients presented in infancy with
recurrent infections and/or bleeding, including skin infections,
omphalitis, sepsis, petechiae, nose bleeds, anemia, and mucosal
bleeding. Perianal abscesses were common. Infections were mainly
bacterial and fungal. Wound healing was poor, and there was a moderate
to severe bleeding tendency necessitating multiple red blood cell and
platelet transfusions. Most patients also had hepatosplenomegaly.
Laboratory studies indicated defective neutrophil adhesion, chemotaxis,
and NADPH oxidase activity.
Malinin et al. (2009) described 2 sibs, a boy and a girl, from the
United Arab Emirates who developed severe bleeding and recurrent
infections at 2 weeks of age, in spite of having normal platelet counts,
hemoglobin levels, and peripheral blood cell morphology. An older
brother and other family members lacked any history of recurrent
bleeding or infections. Both patients also developed osteopetrosis at
about 5 months of age. Malinin et al. (2009) noted that the symptoms
were consistent with, but more severe, than those of patients previously
reported with LAD3. Immortalized lymphocyte cell lines isolated from the
2 patients showed integrin activation defects. Bone marrow
transplantation successfully resolved the clinical problems of both
patients. Malinin et al. (2009) proposed the designation 'integrin
activation deficiency disease' to reflect the defect underlying the
symptoms.
McDowall et al. (2010) reported an 11-month-old African American girl
with a severe bleeding tendency from birth, recurrent bacterial
infections, and osteopetrosis. Laboratory studies of patient cells
showed normal expression of major T-cell integrins, but T cells failed
to firmly adhere to ICAM1 (147840) and fibronectin (FN1; 135600) when
adhesion was stimulated by inside-out signaling agonists. Activation of
integrins from outside the cell showed that the integrins from patient T
cells were capable of normal adhesion. The T cells from the mother
adhered to and spread on ICAM1 normally, but patient T cells were unable
to spread. The girl was successfully treated with bone marrow
transplantation.
Robert et al. (2011) described a 33-month-old first son of
consanguineous Gypsy parents with LAD3 syndrome characterized by a
serious bleeding defect and immune deficiency. The boy's height and
neuropsychologic development were normal, and he was homozygous for a
splice-site mutation in the FERMT3 gene (607901.0009). Analysis of
leukocyte adhesion defects in the patient showed that initial bond
formation was readily stimulated when neutrophils were exposed to
bacterial fMLF or when neutrophils or lymphocytes were stimulated with a
phorbol ester (PMA) or Mn(2+). However, attachment strengthening was
defective in lymphocytes treated with PMA or Mn(2+) and in neutrophils
stimulated with fMLF, whereas neutrophils responded normally to PMA or
Mn(2+). The patient's T cells displayed defective integrin-mediated
spreading and moderately decreased spreading on anti-CD3-coated
surfaces. Integrin-mediated spreading in neutrophils was severely
defective after incubation with fMLF or PMA, but not Mn(2+). Robert et
al. (2011) concluded that the consequences of FERMT3 deficiency on
beta-2 integrin function depend on both cell type and the stimulus used
for integrin activation.
MAPPING
LAD3 is caused by mutations in the FERMT3 gene, which maps to chromosome
11q13 (Svensson et al., 2009).
MOLECULAR GENETICS
Svensson et al. (2009) noted that Pasvolsky et al. (2007) reported a
C-to-A change at a putative splice acceptor site for exon 16 of the
RASGRP2 gene (605577) as the cause of LAD3 in 2 Turkish patients.
Svensson et al. (2009) identified this RASGRP2 change in 2 additional
Turkish LAD3 patients, but a third Maltese LAD3 patient lacked any
changes in the RASGRP2 gene. Furthermore, Svensson et al. (2009) showed
that the C-to-A change had little or no effect on RASGRP2 mRNA and
protein levels, and that RASGRP2 function could not be restored by
expression of wildtype RASGRP2. Instead, Svensson et al. (2009)
identified mutations in the KINDLIN3 gene as the cause of LAD3 in the 2
Turkish patients and the Maltese patient they reported. The Turkish
patients were homozygous for an arg509-to-ter (R509X; 607901.0001)
nonsense mutation, and the Maltese patient was homozygous for an A-to-G
transition at the splice acceptor site of exon 14 (607901.0002). RT-PCR
analyses showed that both mutations destabilized KINDLIN3 mRNA upstream
of the mutations. Western blot analysis showed no expression of KINDLIN3
protein in the patients, whereas expression was normal in their parents.
Interference reflection microscopy revealed that wildtype KINDLIN3
corrected defective adhesion to and migration on ICAM1 (147840) by
patient B cells. Svensson et al. (2009) concluded that mutations in
KINDLIN3 cause LAD3, and that wildtype KINDLIN3 can overcome LAD3
defects by generating integrin adhesive contacts and integrin-mediated
migration of LAD3 lymphocytes.
In the 2 sibs they reported with symptoms consistent with a severe form
of LAD3, Malinin et al. (2009) identified a trp16-to-ter (W16X;
607901.0003) nonsense mutation in the KINDLIN3 gene.
In 9 patients with LAD1V from 7 unrelated consanguineous families from
central Turkey reported by Kuijpers et al. (2007), Kuijpers et al.
(2009) identified 3 disease-associated variants in genes on chromosome
11q13: a splice site mutation in RASGRP2, an intronic deletion in NRXN2
(600566), and the R509X mutation in FERMT3. Two other patients, one from
a consanguineous family from southeastern Turkey and the other from a
consanguineous Arabic family, had novel nonsense mutations in FERMT3,
but they lacked variants in RASGRP2 and NRXN2. The novel FERMT3
mutations were arg573 to ter (R573X; 607901.0004) in the Turkish patient
and trp229 to ter (W229X; 607901.0005) in the Arabic patient. FERMT3
protein expression was undetectable in leukocytes and platelets of all
patients tested, and all patients had similar neutrophil and platelet
defects. Kuijpers et al. (2009) concluded that the silent RASGRP1
mutation a fnd the NRXN2 intronic deletion are not disease causing, but
are in linkage disequilibrium with the nonsense mutation in exon 12 of
the FERMT3 gene in the 7 previously reported Turkish families with
LAD1V. They noted that variation in the clinical symptoms of the 11
LAD1V patients suggests that there is no strict genotype-phenotype
relationship in LAD1V.
In an African American girl with severe LAD3, McDowall et al. (2010)
identified 2 different homozygous mutations in the FERMT3 gene: G308R
(607901.0007) and 1275delT (607901.0008). In vitro studies indicated
that the truncated protein could not restore either leukocyte adhesion
or migration, whereas the G308R-mutant protein affected only migration.
The patient's unaffected mother was heterozygous for both mutations, and
showed about half-levels of FERMT3 mRNA, consistent with the lack of a
functional gene on 1 allele.
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome, Robert et al. (2011) identified a homozygous splice-site
mutation in the FERMT3 gene (607901.0009). His parents were heterozygous
carriers. The patient and his unaffected mother were also heterozygous
for a mutation in the ITGA2B gene (607759.0008).
ANIMAL MODEL
Moser et al. (2008) found that Kind3 -/- mice died within a week of
birth with pronounced osteopetrosis and severe hemorrhages in the
gastrointestinal tract, skin, brain, and bladder that were already
apparent during development. Chimeric animals with Kind3 -/- livers also
suffered a pronounced hemostatic defect, suggesting platelet
dysfunction. Platelet counts were normal in Kind3 -/- chimeras, but the
platelets were unable to activate integrins.
Using Kind3 -/- mouse neutrophils, Moser et al. (2009) showed that KIND3
was essential for activation of Itgb1, Itgb2, and Itgb3. They concluded
that loss of Kind3 function in mice results in a LAD3-like phenotype.
*FIELD* RF
1. Alon, R.; Aker, M.; Feigelson, S.; Sokolovsky-Eisenberg, M.; Staunton,
D. E.; Cinamon, G.; Grabovsky, V.; Shamri, R.; Etzioni, A.: A novel
genetic leukocyte adhesion deficiency in subsecond triggering of integrin
avidity by endothelial chemokines results in impaired leukocyte arrest
on vascular endothelium under shear flow. Blood 101: 4437-4445,
2003.
2. Kuijpers, T. W.; van Bruggen, R.; Kamerbeek, N.; Tool, A. T. J.;
Hicsonmez, G.; Gurgey, A.; Karow, A.; Verhoeven, A. J.; Seeger, K.;
Sanal, O.; Niemeyer, C.; Roos, D.: Natural history and early diagnosis
of LAD-1/variant syndrome. Blood 109: 3529-3537, 2007.
3. Kuijpers, T. W.; van de Vijver, E.; Weterman, M. A. J.; de Boer,
M.; Tool, A. T. J.; van den Berg, T. K.; Moser, M.; Jakobs, M. E.;
Seeger, K.; Sanal, O.; Unal, S.; Cetin, M.; Roos, D.; Verhoeven, A.
J.; Baas, F.: LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113:
4740-4746, 2009.
4. Kuijpers, T. W.; van Lier, R. A. W.; Hamann, D.; de Boer, M.; Thung,
L. Y.; Weening, R. S.; Verhoeven, A. J.; Roos, D.: Leukocyte adhesion
deficiency type 1 (LAD-1)/variant: a novel immunodeficiency syndrome
characterized by dysfunctional beta-2 integrins. J. Clin. Invest. 100:
1725-1733, 1997.
5. Malinin, N. L.; Zhang, L.; Choi, J.; Ciocea, A.; Razorenova, O.;
Ma, Y.-Q.; Podrez, E. A.; Tosi, M.; Lennon, D. P.; Caplan, A. I.;
Shurin, S. B.; Plow, E. F.; Byzova, T. V.: A point mutation in KINDLIN3
ablates activation of three integrin subfamilies in humans. Nature
Med. 15: 313-318, 2009.
6. 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.
7. McDowall, A.; Svensson, L.; Stanley, P.; Patzak, I.; Chakravarty,
P.; Howarth, K.; Sabnis, H.; Briones, M.; Hogg, N.: Two mutations
in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient
reveal distinct effects on leukocyte function in vitro. Blood 115:
4834-4842, 2010.
8. Moser, M.; Bauer, M.; Schmid, S.; Ruppert, R.; Schmidt, S.; Sixt,
M.; Wang, H.-V.; Sperandio, M.; Fassler, R.: Kindlin-3 is required
for beta-2 integrin-mediated leukocyte adhesion to endothelial cells. Nature
Med. 15: 300-305, 2009.
9. Moser, M.; Nieswandt, B.; Ussar, S.; Pozgajova, M.; Fassler, R.
: Kindlin-3 is essential for integrin activation and platelet aggregation. Nature
Med. 14: 325-330, 2008.
10. Pasvolsky, R.; Feigelson, S. W.; Kilic, S. S.; Simon, A. J.; Tal-Lapidot,
G.; Grabovsky, V.; Crittenden, J. R.; Amariglio, N.; Safran, M.; Graybiel,
A. M.; Rechavi, G.; Ben-Dor, S.; Etzioni, A.; Alon, R.: A LAD-III
syndrome is associated with defective expression of the Rap-1 activator
CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J. Exp. Med. 204:
1571-1582, 2007.
11. Robert, P.; Canault, M.; Farnarier, C.; Nurden, A.; Grosdidier,
C.; Barlogis, V.; Bongrand, P.; Pierres, A.; Chambost, H.; Alessi,
M.-C.: A novel leukocyte adhesion deficiency III variant: kindlin-3
deficiency results in integrin- and nonintegrin-related defects in
different steps of leukocyte adhesion. J. Immun. 186: 5273-5283,
2011.
12. Svensson, L.; Howarth, K.; McDowall, A.; Patzak, I.; Evans, R.;
Ussar, S.; Moser, M.; Metin, A.; Fried, M.; Tomlinson, I.; Hogg, N.
: Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
affecting integrin activation. Nature Med. 15: 306-312, 2009.
13. Zimmerman, G. A.: LAD syndromes: FERMT3 kindles the signal. Blood 113:
4485-4486, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Nose];
Epistaxis
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Mucosal bleeding
SKELETAL:
Osteopetrosis (in severe cases)
SKIN, NAILS, HAIR:
[Skin];
Petechiae
HEMATOLOGY:
Bleeding tendency;
Anemia;
Defective platelet adhesion with normal platelet count
IMMUNOLOGY:
Leukocytosis;
Recurrent bacterial infections;
Fungal infections;
Defective neutrophil adhesion to endothelial cells
MISCELLANEOUS:
Onset in infancy;
Delayed wound healing;
Delayed separation of umbilical cord;
Can be treated by bone marrow transplantation
MOLECULAR BASIS:
Caused by mutation in the fermitin family (Drosophila) homolog 3 gene
(FERMT3, 607901.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/11/2011
*FIELD* CD
Cassandra L. Kniffin: 6/8/2009
*FIELD* ED
joanna: 06/05/2012
ckniffin: 5/11/2011
ckniffin: 6/8/2009
*FIELD* CN
Paul J. Converse - updated: 3/22/2012
Cassandra L. Kniffin - updated: 5/11/2011
*FIELD* CD
Paul J. Converse: 6/5/2009
*FIELD* ED
carol: 09/19/2013
terry: 5/22/2012
mgross: 5/7/2012
terry: 3/22/2012
wwang: 5/24/2011
ckniffin: 5/11/2011
carol: 7/30/2010
mgross: 6/8/2009
ckniffin: 6/8/2009
mgross: 6/5/2009
*RECORD*
*FIELD* NO
612840
*FIELD* TI
#612840 LEUKOCYTE ADHESION DEFICIENCY, TYPE III; LAD3
;;LEUKOCYTE ADHESION DEFICIENCY 3;;
read moreLEUKOCYTE ADHESION DEFICIENCY 1 VARIANT; LAD1V;;
INTEGRIN ACTIVATION DEFICIENCY DISEASE; IADD
*FIELD* TX
A number sign (#) is used with this entry because LAD3 can be caused by
homozygous mutation in the FERMT3 gene (607901) on chromosome 11q12.
DESCRIPTION
Leukocyte adhesion deficiency-3 (LAD3), also known as LAD1 variant
(LAD1V), is an autosomal recessive disorder characterized by LAD1
(116920)-like immune deficiency and Glanzmann thrombasthenia (GT;
273800)-like bleeding problems. LAD3 results from mutations in FERMT3,
or KINDLIN3, which encodes an intracellular protein that interacts with
beta-integrins in hematopoietic cells. In LAD3, the adhesive functions
of integrins on both leukocytes and platelets are disrupted, most likely
due to defects in activation-dependent alterations of surface integrins
that enable high-avidity binding to ligands on target cells, a process
termed 'inside-out signaling' (Svensson et al., 2009; Zimmerman, 2009).
CLINICAL FEATURES
Kuijpers et al. (1997) reported a male infant, born of consanguineous
Turkish parents, who developed recurrent bouts of nonpussing
inflammatory lesions and bacterial infections. Wound healing was
delayed, and the umbilical cord detached spontaneously at 5 weeks. By
age 2 years, he developed a bleeding tendency in the presence of normal
platelet numbers. Laboratory studies showed defective neutrophil
activation and adhesion with normal expression of CD11 (see 153370)/CD18
(ITGB2; 600065), thus excluding a diagnosis of LAD1. However, the
patient's leukocytes were deficient in beta-2-mediated adhesion ligand
binding upon stimulation.
Alon et al. (2003) reported an Arab child, born of consanguineous
parents, who developed periumbilical cellulitis and Staphylococcal
septicemia at age 5 days. The umbilical cord was shed at 4 weeks.
Initial laboratory tests showed low hemoglobin, slightly reduced
platelet count, and leukocytosis. During the subsequent months, he
developed severe mucosal bleeding that necessitated blood and platelet
transfusions, as well as recurrent nonsuppurating skin infections.
Platelet aggregation studies demonstrated a grossly abnormal response to
agonists. He died at age 6 years from a disseminated fungal infection
after a mismatched bone marrow transplantation. A younger brother who
presented with the same clinical and hematologic phenotypes at birth
died at 1 week of age from sepsis. Laboratory studies showed an impaired
ability of neutrophil and lymphocyte beta-1 (ITGB1; 135630) and beta-2
integrins to generate high avidity to their endothelial ligands and
arrest cells on vascular endothelium in response to endothelial
chemoattractant signals, despite normal expression and intrinsic
function of integrins and chemokine receptors. The findings suggested a
primary defect in integrin rearrangement at ligand-bearing contacts.
In a patient with features of Glanzmann thrombasthenia and LAD1,
McDowall et al. (2003) identified a form of integrin dysfunction
involving ITGB1, 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.
Kuijpers et al. (2007) reported 9 patients with LAD1V from 7 unrelated
consanguineous families from central Turkey, including the patient
reported by Kuijpers et al. (1997). Patients presented in infancy with
recurrent infections and/or bleeding, including skin infections,
omphalitis, sepsis, petechiae, nose bleeds, anemia, and mucosal
bleeding. Perianal abscesses were common. Infections were mainly
bacterial and fungal. Wound healing was poor, and there was a moderate
to severe bleeding tendency necessitating multiple red blood cell and
platelet transfusions. Most patients also had hepatosplenomegaly.
Laboratory studies indicated defective neutrophil adhesion, chemotaxis,
and NADPH oxidase activity.
Malinin et al. (2009) described 2 sibs, a boy and a girl, from the
United Arab Emirates who developed severe bleeding and recurrent
infections at 2 weeks of age, in spite of having normal platelet counts,
hemoglobin levels, and peripheral blood cell morphology. An older
brother and other family members lacked any history of recurrent
bleeding or infections. Both patients also developed osteopetrosis at
about 5 months of age. Malinin et al. (2009) noted that the symptoms
were consistent with, but more severe, than those of patients previously
reported with LAD3. Immortalized lymphocyte cell lines isolated from the
2 patients showed integrin activation defects. Bone marrow
transplantation successfully resolved the clinical problems of both
patients. Malinin et al. (2009) proposed the designation 'integrin
activation deficiency disease' to reflect the defect underlying the
symptoms.
McDowall et al. (2010) reported an 11-month-old African American girl
with a severe bleeding tendency from birth, recurrent bacterial
infections, and osteopetrosis. Laboratory studies of patient cells
showed normal expression of major T-cell integrins, but T cells failed
to firmly adhere to ICAM1 (147840) and fibronectin (FN1; 135600) when
adhesion was stimulated by inside-out signaling agonists. Activation of
integrins from outside the cell showed that the integrins from patient T
cells were capable of normal adhesion. The T cells from the mother
adhered to and spread on ICAM1 normally, but patient T cells were unable
to spread. The girl was successfully treated with bone marrow
transplantation.
Robert et al. (2011) described a 33-month-old first son of
consanguineous Gypsy parents with LAD3 syndrome characterized by a
serious bleeding defect and immune deficiency. The boy's height and
neuropsychologic development were normal, and he was homozygous for a
splice-site mutation in the FERMT3 gene (607901.0009). Analysis of
leukocyte adhesion defects in the patient showed that initial bond
formation was readily stimulated when neutrophils were exposed to
bacterial fMLF or when neutrophils or lymphocytes were stimulated with a
phorbol ester (PMA) or Mn(2+). However, attachment strengthening was
defective in lymphocytes treated with PMA or Mn(2+) and in neutrophils
stimulated with fMLF, whereas neutrophils responded normally to PMA or
Mn(2+). The patient's T cells displayed defective integrin-mediated
spreading and moderately decreased spreading on anti-CD3-coated
surfaces. Integrin-mediated spreading in neutrophils was severely
defective after incubation with fMLF or PMA, but not Mn(2+). Robert et
al. (2011) concluded that the consequences of FERMT3 deficiency on
beta-2 integrin function depend on both cell type and the stimulus used
for integrin activation.
MAPPING
LAD3 is caused by mutations in the FERMT3 gene, which maps to chromosome
11q13 (Svensson et al., 2009).
MOLECULAR GENETICS
Svensson et al. (2009) noted that Pasvolsky et al. (2007) reported a
C-to-A change at a putative splice acceptor site for exon 16 of the
RASGRP2 gene (605577) as the cause of LAD3 in 2 Turkish patients.
Svensson et al. (2009) identified this RASGRP2 change in 2 additional
Turkish LAD3 patients, but a third Maltese LAD3 patient lacked any
changes in the RASGRP2 gene. Furthermore, Svensson et al. (2009) showed
that the C-to-A change had little or no effect on RASGRP2 mRNA and
protein levels, and that RASGRP2 function could not be restored by
expression of wildtype RASGRP2. Instead, Svensson et al. (2009)
identified mutations in the KINDLIN3 gene as the cause of LAD3 in the 2
Turkish patients and the Maltese patient they reported. The Turkish
patients were homozygous for an arg509-to-ter (R509X; 607901.0001)
nonsense mutation, and the Maltese patient was homozygous for an A-to-G
transition at the splice acceptor site of exon 14 (607901.0002). RT-PCR
analyses showed that both mutations destabilized KINDLIN3 mRNA upstream
of the mutations. Western blot analysis showed no expression of KINDLIN3
protein in the patients, whereas expression was normal in their parents.
Interference reflection microscopy revealed that wildtype KINDLIN3
corrected defective adhesion to and migration on ICAM1 (147840) by
patient B cells. Svensson et al. (2009) concluded that mutations in
KINDLIN3 cause LAD3, and that wildtype KINDLIN3 can overcome LAD3
defects by generating integrin adhesive contacts and integrin-mediated
migration of LAD3 lymphocytes.
In the 2 sibs they reported with symptoms consistent with a severe form
of LAD3, Malinin et al. (2009) identified a trp16-to-ter (W16X;
607901.0003) nonsense mutation in the KINDLIN3 gene.
In 9 patients with LAD1V from 7 unrelated consanguineous families from
central Turkey reported by Kuijpers et al. (2007), Kuijpers et al.
(2009) identified 3 disease-associated variants in genes on chromosome
11q13: a splice site mutation in RASGRP2, an intronic deletion in NRXN2
(600566), and the R509X mutation in FERMT3. Two other patients, one from
a consanguineous family from southeastern Turkey and the other from a
consanguineous Arabic family, had novel nonsense mutations in FERMT3,
but they lacked variants in RASGRP2 and NRXN2. The novel FERMT3
mutations were arg573 to ter (R573X; 607901.0004) in the Turkish patient
and trp229 to ter (W229X; 607901.0005) in the Arabic patient. FERMT3
protein expression was undetectable in leukocytes and platelets of all
patients tested, and all patients had similar neutrophil and platelet
defects. Kuijpers et al. (2009) concluded that the silent RASGRP1
mutation a fnd the NRXN2 intronic deletion are not disease causing, but
are in linkage disequilibrium with the nonsense mutation in exon 12 of
the FERMT3 gene in the 7 previously reported Turkish families with
LAD1V. They noted that variation in the clinical symptoms of the 11
LAD1V patients suggests that there is no strict genotype-phenotype
relationship in LAD1V.
In an African American girl with severe LAD3, McDowall et al. (2010)
identified 2 different homozygous mutations in the FERMT3 gene: G308R
(607901.0007) and 1275delT (607901.0008). In vitro studies indicated
that the truncated protein could not restore either leukocyte adhesion
or migration, whereas the G308R-mutant protein affected only migration.
The patient's unaffected mother was heterozygous for both mutations, and
showed about half-levels of FERMT3 mRNA, consistent with the lack of a
functional gene on 1 allele.
In a 33-month-old first son of consanguineous Gypsy parents with LAD3
syndrome, Robert et al. (2011) identified a homozygous splice-site
mutation in the FERMT3 gene (607901.0009). His parents were heterozygous
carriers. The patient and his unaffected mother were also heterozygous
for a mutation in the ITGA2B gene (607759.0008).
ANIMAL MODEL
Moser et al. (2008) found that Kind3 -/- mice died within a week of
birth with pronounced osteopetrosis and severe hemorrhages in the
gastrointestinal tract, skin, brain, and bladder that were already
apparent during development. Chimeric animals with Kind3 -/- livers also
suffered a pronounced hemostatic defect, suggesting platelet
dysfunction. Platelet counts were normal in Kind3 -/- chimeras, but the
platelets were unable to activate integrins.
Using Kind3 -/- mouse neutrophils, Moser et al. (2009) showed that KIND3
was essential for activation of Itgb1, Itgb2, and Itgb3. They concluded
that loss of Kind3 function in mice results in a LAD3-like phenotype.
*FIELD* RF
1. Alon, R.; Aker, M.; Feigelson, S.; Sokolovsky-Eisenberg, M.; Staunton,
D. E.; Cinamon, G.; Grabovsky, V.; Shamri, R.; Etzioni, A.: A novel
genetic leukocyte adhesion deficiency in subsecond triggering of integrin
avidity by endothelial chemokines results in impaired leukocyte arrest
on vascular endothelium under shear flow. Blood 101: 4437-4445,
2003.
2. Kuijpers, T. W.; van Bruggen, R.; Kamerbeek, N.; Tool, A. T. J.;
Hicsonmez, G.; Gurgey, A.; Karow, A.; Verhoeven, A. J.; Seeger, K.;
Sanal, O.; Niemeyer, C.; Roos, D.: Natural history and early diagnosis
of LAD-1/variant syndrome. Blood 109: 3529-3537, 2007.
3. Kuijpers, T. W.; van de Vijver, E.; Weterman, M. A. J.; de Boer,
M.; Tool, A. T. J.; van den Berg, T. K.; Moser, M.; Jakobs, M. E.;
Seeger, K.; Sanal, O.; Unal, S.; Cetin, M.; Roos, D.; Verhoeven, A.
J.; Baas, F.: LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 113:
4740-4746, 2009.
4. Kuijpers, T. W.; van Lier, R. A. W.; Hamann, D.; de Boer, M.; Thung,
L. Y.; Weening, R. S.; Verhoeven, A. J.; Roos, D.: Leukocyte adhesion
deficiency type 1 (LAD-1)/variant: a novel immunodeficiency syndrome
characterized by dysfunctional beta-2 integrins. J. Clin. Invest. 100:
1725-1733, 1997.
5. Malinin, N. L.; Zhang, L.; Choi, J.; Ciocea, A.; Razorenova, O.;
Ma, Y.-Q.; Podrez, E. A.; Tosi, M.; Lennon, D. P.; Caplan, A. I.;
Shurin, S. B.; Plow, E. F.; Byzova, T. V.: A point mutation in KINDLIN3
ablates activation of three integrin subfamilies in humans. Nature
Med. 15: 313-318, 2009.
6. 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.
7. McDowall, A.; Svensson, L.; Stanley, P.; Patzak, I.; Chakravarty,
P.; Howarth, K.; Sabnis, H.; Briones, M.; Hogg, N.: Two mutations
in the KINDLIN3 gene of a new leukocyte adhesion deficiency III patient
reveal distinct effects on leukocyte function in vitro. Blood 115:
4834-4842, 2010.
8. Moser, M.; Bauer, M.; Schmid, S.; Ruppert, R.; Schmidt, S.; Sixt,
M.; Wang, H.-V.; Sperandio, M.; Fassler, R.: Kindlin-3 is required
for beta-2 integrin-mediated leukocyte adhesion to endothelial cells. Nature
Med. 15: 300-305, 2009.
9. Moser, M.; Nieswandt, B.; Ussar, S.; Pozgajova, M.; Fassler, R.
: Kindlin-3 is essential for integrin activation and platelet aggregation. Nature
Med. 14: 325-330, 2008.
10. Pasvolsky, R.; Feigelson, S. W.; Kilic, S. S.; Simon, A. J.; Tal-Lapidot,
G.; Grabovsky, V.; Crittenden, J. R.; Amariglio, N.; Safran, M.; Graybiel,
A. M.; Rechavi, G.; Ben-Dor, S.; Etzioni, A.; Alon, R.: A LAD-III
syndrome is associated with defective expression of the Rap-1 activator
CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J. Exp. Med. 204:
1571-1582, 2007.
11. Robert, P.; Canault, M.; Farnarier, C.; Nurden, A.; Grosdidier,
C.; Barlogis, V.; Bongrand, P.; Pierres, A.; Chambost, H.; Alessi,
M.-C.: A novel leukocyte adhesion deficiency III variant: kindlin-3
deficiency results in integrin- and nonintegrin-related defects in
different steps of leukocyte adhesion. J. Immun. 186: 5273-5283,
2011.
12. Svensson, L.; Howarth, K.; McDowall, A.; Patzak, I.; Evans, R.;
Ussar, S.; Moser, M.; Metin, A.; Fried, M.; Tomlinson, I.; Hogg, N.
: Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3
affecting integrin activation. Nature Med. 15: 306-312, 2009.
13. Zimmerman, G. A.: LAD syndromes: FERMT3 kindles the signal. Blood 113:
4485-4486, 2009.
*FIELD* CS
INHERITANCE:
Autosomal recessive
HEAD AND NECK:
[Nose];
Epistaxis
ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly;
[Gastrointestinal];
Mucosal bleeding
SKELETAL:
Osteopetrosis (in severe cases)
SKIN, NAILS, HAIR:
[Skin];
Petechiae
HEMATOLOGY:
Bleeding tendency;
Anemia;
Defective platelet adhesion with normal platelet count
IMMUNOLOGY:
Leukocytosis;
Recurrent bacterial infections;
Fungal infections;
Defective neutrophil adhesion to endothelial cells
MISCELLANEOUS:
Onset in infancy;
Delayed wound healing;
Delayed separation of umbilical cord;
Can be treated by bone marrow transplantation
MOLECULAR BASIS:
Caused by mutation in the fermitin family (Drosophila) homolog 3 gene
(FERMT3, 607901.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 5/11/2011
*FIELD* CD
Cassandra L. Kniffin: 6/8/2009
*FIELD* ED
joanna: 06/05/2012
ckniffin: 5/11/2011
ckniffin: 6/8/2009
*FIELD* CN
Paul J. Converse - updated: 3/22/2012
Cassandra L. Kniffin - updated: 5/11/2011
*FIELD* CD
Paul J. Converse: 6/5/2009
*FIELD* ED
carol: 09/19/2013
terry: 5/22/2012
mgross: 5/7/2012
terry: 3/22/2012
wwang: 5/24/2011
ckniffin: 5/11/2011
carol: 7/30/2010
mgross: 6/8/2009
ckniffin: 6/8/2009
mgross: 6/5/2009