Full text data of STXBP2
STXBP2
(UNC18B)
[Confidence: low (only semi-automatic identification from reviews)]
Syntaxin-binding protein 2 (Protein unc-18 homolog 2; Unc18-2; Protein unc-18 homolog B; Unc-18B)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Syntaxin-binding protein 2 (Protein unc-18 homolog 2; Unc18-2; Protein unc-18 homolog B; Unc-18B)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q15833
ID STXB2_HUMAN Reviewed; 593 AA.
AC Q15833; Q9BU65;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Syntaxin-binding protein 2;
DE AltName: Full=Protein unc-18 homolog 2;
DE Short=Unc18-2;
DE AltName: Full=Protein unc-18 homolog B;
DE Short=Unc-18B;
GN Name=STXBP2; Synonyms=UNC18B;
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] (ISOFORM 1), AND VARIANT VAL-526.
RX PubMed=8921365; DOI=10.1006/geno.1996.0515;
RA Ziegler S.F., Mortrud M.T., Swartz A.R., Baker E., Sutherland G.R.,
RA Burmeister M., Mulligan J.T.;
RT "Molecular characterization of a nonneuronal human UNC18 homolog.";
RL Genomics 37:19-23(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lung;
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 [6]
RP FUNCTION, INTERACTION WITH STX11, VARIANTS FHL5 PRO-209; ILE-232 DEL;
RP HIS-292; TRP-405; GLN-405 AND LEU-477, AND CHARACTERIZATION OF
RP VARIANTS FHL5 ILE-232 DEL; HIS-292; TRP-405; GLN-405 AND LEU-477.
RX PubMed=19804848; DOI=10.1016/j.ajhg.2009.09.005;
RA zur Stadt U., Rohr J., Seifert W., Koch F., Grieve S., Pagel J.,
RA Strauss J., Kasper B., Nuernberg G., Becker C., Maul-Pavicic A.,
RA Beutel K., Janka G., Griffiths G., Ehl S., Hennies H.C.;
RT "Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
RT by mutations in Munc18-2 and impaired binding to syntaxin 11.";
RL Am. J. Hum. Genet. 85:482-492(2009).
RN [7]
RP FUNCTION, INTERACTION WITH STX11, AND VARIANT FHL5 LEU-477.
RX PubMed=19884660; DOI=10.1172/JCI40732;
RA Cote M., Menager M.M., Burgess A., Mahlaoui N., Picard C.,
RA Schaffner C., Al-Manjomi F., Al-Harbi M., Alangari A., Le Deist F.,
RA Gennery A.R., Prince N., Cariou A., Nitschke P., Blank U.,
RA El-Ghazali G., Menasche G., Latour S., Fischer A., de Saint Basile G.;
RT "Munc18-2 deficiency causes familial hemophagocytic
RT lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in
RT patient NK cells.";
RL J. Clin. Invest. 119:3765-3773(2009).
RN [8]
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 [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Involved in intracellular vesicle trafficking and
CC vesicle fusion with membranes. Contributes to the granule
CC exocytosis machinery through interaction with soluble N-
CC ethylmaleimide-sensitive factor attachment protein receptor
CC (SNARE) proteins that regulate membrane fusion. Regulates
CC cytotoxic granule exocytosis in natural killer (NK) cells.
CC -!- SUBUNIT: Interacts with STX1A, STX2 and STX3 (By similarity).
CC Interacts with STX11.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15833-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15833-2; Sequence=VSP_040121;
CC -!- TISSUE SPECIFICITY: Placenta, lung, liver, kidney and pancreas, as
CC well as in peripheral blood lymphocytes.
CC -!- DISEASE: Familial hemophagocytic lymphohistiocytosis 5 (FHL5)
CC [MIM:613101]: A rare disorder characterized by immune
CC dysregulation with hypercytokinemia, defective function of natural
CC killer cell, and massive infiltration of several organs by
CC activated lymphocytes and macrophages. The clinical features of
CC the disease include fever, hepatosplenomegaly, cytopenia, and less
CC frequently neurological abnormalities ranging from irritability
CC and hypotonia to seizures, cranial nerve deficits and ataxia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the STXBP/unc-18/SEC1 family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U63533; AAC50762.1; -; mRNA.
DR EMBL; BT006915; AAP35561.1; -; mRNA.
DR EMBL; AC008763; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69018.1; -; Genomic_DNA.
DR EMBL; BC002869; AAH02869.1; -; mRNA.
DR RefSeq; NP_001120868.1; NM_001127396.2.
DR RefSeq; NP_001258963.1; NM_001272034.1.
DR RefSeq; NP_008880.2; NM_006949.3.
DR UniGene; Hs.515104; -.
DR PDB; 4CCA; X-ray; 2.60 A; A=1-593.
DR PDBsum; 4CCA; -.
DR ProteinModelPortal; Q15833; -.
DR SMR; Q15833; 5-590.
DR MINT; MINT-4718353; -.
DR STRING; 9606.ENSP00000221283; -.
DR PhosphoSite; Q15833; -.
DR DMDM; 2501513; -.
DR OGP; Q15833; -.
DR PaxDb; Q15833; -.
DR PRIDE; Q15833; -.
DR DNASU; 6813; -.
DR Ensembl; ENST00000221283; ENSP00000221283; ENSG00000076944.
DR Ensembl; ENST00000414284; ENSP00000409471; ENSG00000076944.
DR GeneID; 6813; -.
DR KEGG; hsa:6813; -.
DR UCSC; uc002mha.5; human.
DR CTD; 6813; -.
DR GeneCards; GC19P007701; -.
DR H-InvDB; HIX0021726; -.
DR HGNC; HGNC:11445; STXBP2.
DR HPA; HPA015564; -.
DR MIM; 601717; gene.
DR MIM; 613101; phenotype.
DR neXtProt; NX_Q15833; -.
DR Orphanet; 540; Familial hemophagocytic lymphohistiocytosis.
DR PharmGKB; PA36242; -.
DR eggNOG; COG5158; -.
DR HOGENOM; HOG000232146; -.
DR HOVERGEN; HBG052710; -.
DR InParanoid; Q15833; -.
DR KO; K15300; -.
DR PhylomeDB; Q15833; -.
DR GeneWiki; Syntaxin_binding_protein_2; -.
DR GenomeRNAi; 6813; -.
DR NextBio; 26589; -.
DR PRO; PR:Q15833; -.
DR ArrayExpress; Q15833; -.
DR Bgee; Q15833; -.
DR CleanEx; HS_STXBP2; -.
DR Genevestigator; Q15833; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0042582; C:azurophil granule; IDA:UniProtKB.
DR GO; GO:0044194; C:cytolytic granule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0042581; C:specific granule; IDA:UniProtKB.
DR GO; GO:0070820; C:tertiary granule; IDA:UniProtKB.
DR GO; GO:0001909; P:leukocyte mediated cytotoxicity; IMP:UniProtKB.
DR GO; GO:0043312; P:neutrophil degranulation; IEP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0043304; P:regulation of mast cell degranulation; ISS:UniProtKB.
DR GO; GO:0006904; P:vesicle docking involved in exocytosis; IEA:InterPro.
DR Gene3D; 3.40.50.1910; -; 2.
DR InterPro; IPR027482; Sec-1-like_dom2.
DR InterPro; IPR001619; Sec1-like.
DR PANTHER; PTHR11679; PTHR11679; 1.
DR Pfam; PF00995; Sec1; 1.
DR PIRSF; PIRSF005715; VPS45_Sec1; 1.
DR SUPFAM; SSF56815; SSF56815; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Disease mutation; Exocytosis; Polymorphism; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 593 Syntaxin-binding protein 2.
FT /FTId=PRO_0000206281.
FT VAR_SEQ 83 85 Missing (in isoform 2).
FT /FTId=VSP_040121.
FT VARIANT 209 209 L -> P (in FHL5).
FT /FTId=VAR_063814.
FT VARIANT 232 232 Missing (in FHL5; leads to a complete
FT loss of the ability to interact with
FT STX11).
FT /FTId=VAR_063815.
FT VARIANT 292 292 R -> H (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063816.
FT VARIANT 405 405 R -> Q (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063817.
FT VARIANT 405 405 R -> W (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063818.
FT VARIANT 477 477 P -> L (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063819.
FT VARIANT 526 526 I -> V (in dbSNP:rs6791).
FT /FTId=VAR_014934.
SQ SEQUENCE 593 AA; 66453 MW; 98E27B55309168A9 CRC64;
MAPSGLKAVV GEKILSGVIR SVKKDGEWKV LIMDHPSMRI LSSCCKMSDI LAEGITIVED
INKRREPIPS LEAIYLLSPT EKSVQALIKD FQGTPTFTYK AAHIFFTDTC PEPLFSELGR
SRLAKVVKTL KEIHLAFLPY EAQVFSLDAP HSTYNLYCPF RAEERTRQLE VLAQQIATLC
ATLQEYPAIR YRKGPEDTAQ LAHAVLAKLN AFKADTPSLG EGPEKTRSQL LIMDRAADPV
SPLLHELTFQ AMAYDLLDIE QDTYRYETTG LSEAREKAVL LDEDDDLWVE LRHMHIADVS
KKVTELLRTF CESKRLTTDK ANIKDLSQIL KKMPQYQKEL NKYSTHLHLA DDCMKHFKGS
VEKLCSVEQD LAMGSDAEGE KIKDSMKLIV PVLLDAAVPA YDKIRVLLLY ILLRNGVSEE
NLAKLIQHAN VQAHSSLIRN LEQLGGTVTN PGGSGTSSRL EPRERMEPTY QLSRWTPVIK
DVMEDAVEDR LDRNLWPFVS DPAPTASSQA AVSARFGHWH KNKAGIEARA GPRLIVYVMG
GVAMSEMRAA YEVTRATEGK WEVLIGSSHI LTPTRFLDDL KALDKKLEDI ALP
//
ID STXB2_HUMAN Reviewed; 593 AA.
AC Q15833; Q9BU65;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-NOV-2010, sequence version 2.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Syntaxin-binding protein 2;
DE AltName: Full=Protein unc-18 homolog 2;
DE Short=Unc18-2;
DE AltName: Full=Protein unc-18 homolog B;
DE Short=Unc-18B;
GN Name=STXBP2; Synonyms=UNC18B;
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] (ISOFORM 1), AND VARIANT VAL-526.
RX PubMed=8921365; DOI=10.1006/geno.1996.0515;
RA Ziegler S.F., Mortrud M.T., Swartz A.R., Baker E., Sutherland G.R.,
RA Burmeister M., Mulligan J.T.;
RT "Molecular characterization of a nonneuronal human UNC18 homolog.";
RL Genomics 37:19-23(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J.,
RA Lamerdin J.E., Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M.,
RA Aerts A., Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E.,
RA Caenepeel S., Carrano A.V., Caoile C., Chan Y.M., Christensen M.,
RA Cleland C.A., Copeland A., Dalin E., Dehal P., Denys M., Detter J.C.,
RA Escobar J., Flowers D., Fotopulos D., Garcia C., Georgescu A.M.,
RA Glavina T., Gomez M., Gonzales E., Groza M., Hammon N., Hawkins T.,
RA Haydu L., Ho I., Huang W., Israni S., Jett J., Kadner K., Kimball H.,
RA Kobayashi A., Larionov V., Leem S.-H., Lopez F., Lou Y., Lowry S.,
RA Malfatti S., Martinez D., McCready P.M., Medina C., Morgan J.,
RA Nelson K., Nolan M., Ovcharenko I., Pitluck S., Pollard M.,
RA Popkie A.P., Predki P., Quan G., Ramirez L., Rash S., Retterer J.,
RA Rodriguez A., Rogers S., Salamov A., Salazar A., She X., Smith D.,
RA Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., Ustaszewska A.,
RA Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., Dubchak I.,
RA Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Lung;
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 [6]
RP FUNCTION, INTERACTION WITH STX11, VARIANTS FHL5 PRO-209; ILE-232 DEL;
RP HIS-292; TRP-405; GLN-405 AND LEU-477, AND CHARACTERIZATION OF
RP VARIANTS FHL5 ILE-232 DEL; HIS-292; TRP-405; GLN-405 AND LEU-477.
RX PubMed=19804848; DOI=10.1016/j.ajhg.2009.09.005;
RA zur Stadt U., Rohr J., Seifert W., Koch F., Grieve S., Pagel J.,
RA Strauss J., Kasper B., Nuernberg G., Becker C., Maul-Pavicic A.,
RA Beutel K., Janka G., Griffiths G., Ehl S., Hennies H.C.;
RT "Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
RT by mutations in Munc18-2 and impaired binding to syntaxin 11.";
RL Am. J. Hum. Genet. 85:482-492(2009).
RN [7]
RP FUNCTION, INTERACTION WITH STX11, AND VARIANT FHL5 LEU-477.
RX PubMed=19884660; DOI=10.1172/JCI40732;
RA Cote M., Menager M.M., Burgess A., Mahlaoui N., Picard C.,
RA Schaffner C., Al-Manjomi F., Al-Harbi M., Alangari A., Le Deist F.,
RA Gennery A.R., Prince N., Cariou A., Nitschke P., Blank U.,
RA El-Ghazali G., Menasche G., Latour S., Fischer A., de Saint Basile G.;
RT "Munc18-2 deficiency causes familial hemophagocytic
RT lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in
RT patient NK cells.";
RL J. Clin. Invest. 119:3765-3773(2009).
RN [8]
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 [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
CC -!- FUNCTION: Involved in intracellular vesicle trafficking and
CC vesicle fusion with membranes. Contributes to the granule
CC exocytosis machinery through interaction with soluble N-
CC ethylmaleimide-sensitive factor attachment protein receptor
CC (SNARE) proteins that regulate membrane fusion. Regulates
CC cytotoxic granule exocytosis in natural killer (NK) cells.
CC -!- SUBUNIT: Interacts with STX1A, STX2 and STX3 (By similarity).
CC Interacts with STX11.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q15833-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q15833-2; Sequence=VSP_040121;
CC -!- TISSUE SPECIFICITY: Placenta, lung, liver, kidney and pancreas, as
CC well as in peripheral blood lymphocytes.
CC -!- DISEASE: Familial hemophagocytic lymphohistiocytosis 5 (FHL5)
CC [MIM:613101]: A rare disorder characterized by immune
CC dysregulation with hypercytokinemia, defective function of natural
CC killer cell, and massive infiltration of several organs by
CC activated lymphocytes and macrophages. The clinical features of
CC the disease include fever, hepatosplenomegaly, cytopenia, and less
CC frequently neurological abnormalities ranging from irritability
CC and hypotonia to seizures, cranial nerve deficits and ataxia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the STXBP/unc-18/SEC1 family.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; U63533; AAC50762.1; -; mRNA.
DR EMBL; BT006915; AAP35561.1; -; mRNA.
DR EMBL; AC008763; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471139; EAW69018.1; -; Genomic_DNA.
DR EMBL; BC002869; AAH02869.1; -; mRNA.
DR RefSeq; NP_001120868.1; NM_001127396.2.
DR RefSeq; NP_001258963.1; NM_001272034.1.
DR RefSeq; NP_008880.2; NM_006949.3.
DR UniGene; Hs.515104; -.
DR PDB; 4CCA; X-ray; 2.60 A; A=1-593.
DR PDBsum; 4CCA; -.
DR ProteinModelPortal; Q15833; -.
DR SMR; Q15833; 5-590.
DR MINT; MINT-4718353; -.
DR STRING; 9606.ENSP00000221283; -.
DR PhosphoSite; Q15833; -.
DR DMDM; 2501513; -.
DR OGP; Q15833; -.
DR PaxDb; Q15833; -.
DR PRIDE; Q15833; -.
DR DNASU; 6813; -.
DR Ensembl; ENST00000221283; ENSP00000221283; ENSG00000076944.
DR Ensembl; ENST00000414284; ENSP00000409471; ENSG00000076944.
DR GeneID; 6813; -.
DR KEGG; hsa:6813; -.
DR UCSC; uc002mha.5; human.
DR CTD; 6813; -.
DR GeneCards; GC19P007701; -.
DR H-InvDB; HIX0021726; -.
DR HGNC; HGNC:11445; STXBP2.
DR HPA; HPA015564; -.
DR MIM; 601717; gene.
DR MIM; 613101; phenotype.
DR neXtProt; NX_Q15833; -.
DR Orphanet; 540; Familial hemophagocytic lymphohistiocytosis.
DR PharmGKB; PA36242; -.
DR eggNOG; COG5158; -.
DR HOGENOM; HOG000232146; -.
DR HOVERGEN; HBG052710; -.
DR InParanoid; Q15833; -.
DR KO; K15300; -.
DR PhylomeDB; Q15833; -.
DR GeneWiki; Syntaxin_binding_protein_2; -.
DR GenomeRNAi; 6813; -.
DR NextBio; 26589; -.
DR PRO; PR:Q15833; -.
DR ArrayExpress; Q15833; -.
DR Bgee; Q15833; -.
DR CleanEx; HS_STXBP2; -.
DR Genevestigator; Q15833; -.
DR GO; GO:0016324; C:apical plasma membrane; IEA:Ensembl.
DR GO; GO:0042582; C:azurophil granule; IDA:UniProtKB.
DR GO; GO:0044194; C:cytolytic granule; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular vesicular exosome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0042581; C:specific granule; IDA:UniProtKB.
DR GO; GO:0070820; C:tertiary granule; IDA:UniProtKB.
DR GO; GO:0001909; P:leukocyte mediated cytotoxicity; IMP:UniProtKB.
DR GO; GO:0043312; P:neutrophil degranulation; IEP:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0043304; P:regulation of mast cell degranulation; ISS:UniProtKB.
DR GO; GO:0006904; P:vesicle docking involved in exocytosis; IEA:InterPro.
DR Gene3D; 3.40.50.1910; -; 2.
DR InterPro; IPR027482; Sec-1-like_dom2.
DR InterPro; IPR001619; Sec1-like.
DR PANTHER; PTHR11679; PTHR11679; 1.
DR Pfam; PF00995; Sec1; 1.
DR PIRSF; PIRSF005715; VPS45_Sec1; 1.
DR SUPFAM; SSF56815; SSF56815; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome;
KW Disease mutation; Exocytosis; Polymorphism; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 593 Syntaxin-binding protein 2.
FT /FTId=PRO_0000206281.
FT VAR_SEQ 83 85 Missing (in isoform 2).
FT /FTId=VSP_040121.
FT VARIANT 209 209 L -> P (in FHL5).
FT /FTId=VAR_063814.
FT VARIANT 232 232 Missing (in FHL5; leads to a complete
FT loss of the ability to interact with
FT STX11).
FT /FTId=VAR_063815.
FT VARIANT 292 292 R -> H (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063816.
FT VARIANT 405 405 R -> Q (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063817.
FT VARIANT 405 405 R -> W (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063818.
FT VARIANT 477 477 P -> L (in FHL5; leads to a complete loss
FT of the ability to interact with STX11).
FT /FTId=VAR_063819.
FT VARIANT 526 526 I -> V (in dbSNP:rs6791).
FT /FTId=VAR_014934.
SQ SEQUENCE 593 AA; 66453 MW; 98E27B55309168A9 CRC64;
MAPSGLKAVV GEKILSGVIR SVKKDGEWKV LIMDHPSMRI LSSCCKMSDI LAEGITIVED
INKRREPIPS LEAIYLLSPT EKSVQALIKD FQGTPTFTYK AAHIFFTDTC PEPLFSELGR
SRLAKVVKTL KEIHLAFLPY EAQVFSLDAP HSTYNLYCPF RAEERTRQLE VLAQQIATLC
ATLQEYPAIR YRKGPEDTAQ LAHAVLAKLN AFKADTPSLG EGPEKTRSQL LIMDRAADPV
SPLLHELTFQ AMAYDLLDIE QDTYRYETTG LSEAREKAVL LDEDDDLWVE LRHMHIADVS
KKVTELLRTF CESKRLTTDK ANIKDLSQIL KKMPQYQKEL NKYSTHLHLA DDCMKHFKGS
VEKLCSVEQD LAMGSDAEGE KIKDSMKLIV PVLLDAAVPA YDKIRVLLLY ILLRNGVSEE
NLAKLIQHAN VQAHSSLIRN LEQLGGTVTN PGGSGTSSRL EPRERMEPTY QLSRWTPVIK
DVMEDAVEDR LDRNLWPFVS DPAPTASSQA AVSARFGHWH KNKAGIEARA GPRLIVYVMG
GVAMSEMRAA YEVTRATEGK WEVLIGSSHI LTPTRFLDDL KALDKKLEDI ALP
//
MIM
601717
*RECORD*
*FIELD* NO
601717
*FIELD* TI
*601717 SYNTAXIN-BINDING PROTEIN 2; STXBP2
;;UNC18, C. ELEGANS, HOMOLOG OF, 2;;
UNC18B;;
read moreMUNC18-2
*FIELD* TX
DESCRIPTION
Several mammalian homologs of the C. elegans gene Unc18 have been
identified, including STXBP2. These genes are conserved across species
from yeast to man and are believed to take part in membrane-fusion
processes. See STXBP1 (602926).
CLONING
Ziegler et al. (1996) identified STXBP2, which they called UNC18B, as
part of a random sequencing of genes from IL2-activated human
natural-killer (NK) cells. Sequence analysis of a full-length cDNA
revealed that it encodes a polypeptide of 593 amino acids, which is most
closely related to mouse Unc18b (95% identical) and less closely related
to Unc18a (64% identical) and Unc18c (48% identical). Ziegler et al.
(1996) found by Northern blot analysis that UNC18B is expressed
predominantly as a 2.4-kb message in placenta, lung, liver, kidney, and
pancreas, as well as in peripheral blood lymphocytes.
GENE STRUCTURE
Zur Stadt et al. (2009) noted that the STXBP2 gene contains 19 exons.
MAPPING
Ziegler et al. (1996) mapped the STXBP2 gene to human chromosome
19p13.3-p13.2 and to the proximal arm of mouse chromosome 8.
GENE FUNCTION
Zur Stadt et al. (2009) demonstrated colocalization of STXBP2 and STX11
(605014) in CD8+ T and NK cells by immunofluorescence analysis.
Stimulation with IL2 (147680) further enhanced colocalization in CD8+
and NK cells. Coimmunoprecipitation analysis demonstrated shared binding
sites between STXBP2 and STX11.
MOLECULAR GENETICS
In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis
(FHL) mapping to chromosome 19p (FHL5; 613101), from 2 Saudi Arabian and
6 Turkish consanguineous families, zur Stadt et al. (2009) sequenced the
candidate gene STXBP2 and identified homozygous mutations in STXBP2 in
all 8 patients (see, e.g., 601717.0001-601717.0003). Sequence analysis
in other patients from nonconsanguineous FHL families revealed
homozygosity or compound heterozygosity for mutations in STXBP2 in 4
additional patients from Germany and the Czech Republic (see, e.g.,
601717.0004-601717.0006), 2 of whom had been previously reported (Beutel
et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous
mutations were found in all available unaffected parents, and none of
the mutations were detected in 210 chromosomes from ethnically matched
controls. Zur Stadt et al. (2009) identified STX11, a mutation in which
causes FHL4 (603552), as an interaction partner of STXBP2, and
demonstrated that this interaction is eliminated by the missense
mutations identified in the FHL5 patients, leading to decreased
stability of both proteins. Activity of NK and cytotoxic T cells was
markedly reduced or absent in FHL5 patients.
In affected members of 6 consanguineous families with FHL mapping to
chromosome 19p13.3-p13.2, Cote et al. (2009) sequenced the STXBP2 gene
and identified homozygosity for the P477L mutation (601717.0001) in 3
Saudi Arabian families and for the IVS14 splice site mutation
(601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian
origin, respectively.
Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in
which mutations in known FHL genes had been excluded by sequence
analysis, and identified homozygosity for 4 different missense mutations
in the STXBP2 gene in 4 (14%) of the 28 families, originating from
Italy, England, Kuwait, and Pakistan, respectively (see, e.g.,
601717.0001 and 601717.0007).
*FIELD* AV
.0001
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, PRO477LEU
In 2 brothers and another proband from unrelated consanguineous Saudi
Arabian families, who had onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) before 1 year of age, zur Stadt et
al. (2009) identified homozygosity for a 1430C-T transition in exon 16
of the STXBP2 gene, resulting in a pro477-to-leu (P477L) substitution at
a conserved residue. Analysis of CD107 degranulation in the 2 brothers
revealed that activity of NK and cytotoxic T cells was markedly reduced
or absent, and immunoblot analysis of cell lysates showed reduced
amounts of STXBP2; markedly decreased levels of syntaxin-11 (STX11;
605014) were also observed in the sibs. Coimmunoprecipitation studies
showed that ability to bind STX11 was absent with the P477L mutant. One
of the brothers underwent mismatched unrelated donor hematopoietic stem
cell transplantation (HSCT) at 12 months of age and had no active
disease at most recent follow-up; the other brother, who had central
nervous system involvement, underwent matched unrelated donor HSCT at 3
months of age but later died of venoocclusive disease.
In affected members of 3 unrelated consanguineous Saudi Arabian families
with FHL5, Cote et al. (2009) identified homozygosity for the P477L
mutation in the STXBP2 gene. No STXBP2 protein was detected in
lymphoblasts from 2 affected female sibs of 1 family. The parents and
unaffected sibs were all heterozygous for the mutated STXBP2 allele,
which was not found in 80 French, 50 Turkish, or 80 Arabic or Iranian
controls. The 5 patients were all diagnosed between 1 and 3.5 months of
age, and 3 of the 5 patients had died between 4 and 16 months of age.
In a Kuwaiti girl who was diagnosed with FHL at 7 months of age and was
still alive at 3.5 years of age after undergoing matched sib donor HSCT,
Cetica et al. (2010) identified homozygosity for the P477L mutation in
the STXBP2 gene.
.0002
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 3-BP DEL, 693GAT
In 2 unrelated Turkish probands from consanguineous families, who had
onset of familial hemophagocytic lymphohistiocytosis (FHL5; 613101) at
1.5 and 2 months of age, respectively, zur Stadt et al. (2009)
identified homozygosity for a 3-bp deletion (693delGAT) in exon 9 of the
STXBP2 gene, resulting in deletion of ile232 at a conserved residue.
Coimmunoprecipitation studies showed that ability to bind STX11 was
absent with the ile232 deletion. Both patients had central nervous
system involvement; one underwent matched sib donor hematopoietic stem
cell transplantation (HSCT) at 4.5 months of age and had no active
disease at approximately 8 years of follow-up, whereas the other patient
did not undergo HSCT and died.
.0003
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, IVS14AS, G-C, -1
In 2 unrelated probands of Turkish and German origin, who had onset of
familial hemophagocytic lymphohistiocytosis (FHL5; 613101) at 28 and 44
months, respectively, zur Stadt et al. (2009) identified homozygosity
for a G-to-C transversion at the splice acceptor site in intron 14 of
the STXBP2 gene (1247-1G-C). Analysis of RNA from the Turkish patient
revealed a deletion of exon 15, resulting in a frameshift and 126 new
codons, in about 95% of clones, as well as 2 minor in-frame and 4
frameshift products. Analysis of CD107 degranulation in this patient
revealed that activity of NK and cytotoxic T cells was markedly reduced
or absent. The German patient underwent matched unrelated donor
hematopoietic stem cell transplantation (HSCT) at 16 years of age but
later died. The Turkish patient, who did not undergo HSCT, had recurrent
reactivations that were responsive to steroids. In another 3 unrelated
FHL patients, all with onset of disease after 1 year of age, the splice
site mutation was found in compound heterozygosity with a missense
mutation (601717.0004) and 2 different 1-bp deletions (601717.0005 and
601717.0006), respectively.
In 3 probands with FHL5 from consanguineous families of Turkish,
Palestinian Arab, and Iranian origin, respectively, Cote et al. (2009)
identified homozygosity for the 1247-1G-C mutation in the STXBP2 gene.
Sequencing of RT-PCR products revealed that rather than leading to a
premature stop codon, the splice mutation resulted in exchange of the
first 17 amino acids of exon 15 for 19 new amino acids from the intronic
sequence, in-frame with the last 20 amino acids of wildtype exon 15. The
parents were all heterozygous for the mutated STXBP2 allele, which was
not found in 80 French, 50 Turkish, or 80 Arabic or Iranian controls.
Lymphoblasts from the Turkish and the Iranian patients showed markedly
decreased STXBP2 protein expression. In the Turkish patient, his
homozygous brother who remained asymptomatic at 2.6 years of age, and
the Iranian patient, cultured NK cells exhibited impaired cytotoxic
granule exocytosis; the defect was overcome by ectopic expression of
wildtype STXBP2. The 3 symptomatic probands were diagnosed between 8
years and 12.5 years of age. The Iranian patient died at 20 years of age
after HSCT and had a sister who died at age 22 months with a
retrospective diagnosis of FHL5.
.0004
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, LEU209PRO
In a German patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 28 months of age, who had central
nervous system involvement and had recurrent reactivations with
spontaneous remissions or response to steroids, zur Stadt et al. (2009)
identified compound heterozygosity for a splice site mutation
(601717.0003) and a 626T-C transition in exon 8 of the STXBP2 gene,
resulting in a leu209-to-pro (L209P) substitution. Analysis of CD107
degranulation in this patient revealed that activity of NK and cytotoxic
T cells was markedly reduced or absent.
.0005
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 1-BP DEL, 260T
In a German patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 15 months of age, who underwent
matched unrelated donor hematopoietic stem cell transplantation at 7
years of age but later died, zur Stadt et al. (2009) identified compound
heterozygosity for a splice site mutation (601717.0003) and a 1-bp
deletion (260delT) in exon 5 of the STXBP2 gene, resulting in a
frameshift and premature termination of the protein.
.0006
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 1-BP DEL, 706G
In a Czech patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 15 months of age, who underwent
mismatched unrelated donor hematopoietic stem cell transplantation at 28
months of age and had no active disease at last follow-up, zur Stadt et
al. (2009) identified compound heterozygosity for a splice site mutation
(601717.0003) and a 1-bp deletion (706delG) in exon 9 of the STXBP2
gene, resulting in a frameshift and premature termination of the
protein.
.0007
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, GLY541SER
In a Caucasian girl from the United Kingdom with FHL, who was still
alive at 2.75 years of age after undergoing matched unrelated donor
HSCT, Cetica et al. (2010) identified homozygosity for a 1621G-A
transition in exon 18 of the STXBP2 gene, resulting in a gly541-to-ser
(G541S) substitution at a highly conserved residue. The mutation was not
found in 120 healthy Caucasian controls. Biochemical analysis revealed
that G541S mutant disrupts association of STXBP2 with STX11 (605014).
Granule release assay using the patient's lymphocytes showed minimal
release in NK cells and completely absent release in CD3(+)CD8 cells;
cytotoxic T-cell lymphocytes from the patient showed a reduced but not
absent cell-killing capacity.
*FIELD* RF
1. Beutel, K.; Gross-Wieltsch, U.; Wiesel, T.; Stadt, U. Z.; Janka,
G.; Wagner, H. J.: Infection of T lymphocytes in Epstein-Barr virus-associated
hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediat.
Blood Cancer 53: 184-190, 2009.
2. Cetica, V.; Santoro, A.; Gilmour, K. C.; Sieni, E.; Beutel, K.;
Pende, D.; Marcenaro, S.; Koch, F.; Grieve, S.; Wheeler, R.; Zhao,
F.; zur Stadt, U.; Griffiths, G. M.; Arico, M.: STXBP2 mutations
in children with familial haemophagocytic lymphohistiocytosis type
5. J. Med. Genet. 47: 595-600, 2010.
3. Cote, M.; Menager, M. M.; Burgess, A.; Mahlaoui, N.; Picard, C.;
Schaffner, C.; Al-Manjomi, F.; Al-Harbi, M.; Alangari, A.; Le Deist,
F.; Gennery, A. R.; Prince, N.; Cariou, A.; Nitschke, P.; Blank, U.;
El-Ghazali, G.; Menasche, G.; Latour, S.; Fischer, A.; de Saint Basile,
G.: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis
type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J.
Clin. Invest. 119: 3765-3773, 2009.
4. Sparber-Sauer, M.; Honig, M.; Schulz, A. S.; Zur Stadt, U.; Schutz,
C.; Debatin, K. M.; Friedrich, W.: Patients with early relapse of
primary hemophagocytic syndromes or with persistent CNS involvement
may benefit from immediate hematopoietic stem cell transplantation. Bone
Marrow Transplant 44: 333-338, 2009.
5. Ziegler, S.F.; Mortrud, M. T.; Swartz, A. R.; Baker, E.; Sutherland,
G. R.; Burmeister, M.; Mulligan, J. T.: Molecular characterization
of a nonneuronal human UNC18 homolog. Genomics 37: 19-23, 1996.
6. zur Stadt, U.; Rohr, J.; Seifert, W.; Koch, F.; Grieve, S.; Pagel,
J.; Strauss, J.; Kasper, B.; Nurnberg, G.; Becker, C.; Maul-Pavicic,
A.; Beutel, K.; Janka, G.; Griffiths, G.; Ehl, S.; Hennies, H. C.
: Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
by mutations in Munc18-2 and impaired binding to syntaxin 11. Am.
J. Hum. Genet. 85: 482-492, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/5/2011
Marla J. F. O'Neill - updated: 6/10/2010
Marla J. F. O'Neill - updated: 10/22/2009
*FIELD* CD
Jennifer P. Macke: 3/24/1997
*FIELD* ED
wwang: 01/10/2011
terry: 1/5/2011
wwang: 6/11/2010
terry: 6/10/2010
wwang: 10/23/2009
terry: 10/22/2009
mgross: 3/8/1999
psherman: 1/21/1999
alopez: 8/4/1998
alopez: 4/2/1997
alopez: 4/1/1997
alopez: 3/24/1997
*RECORD*
*FIELD* NO
601717
*FIELD* TI
*601717 SYNTAXIN-BINDING PROTEIN 2; STXBP2
;;UNC18, C. ELEGANS, HOMOLOG OF, 2;;
UNC18B;;
read moreMUNC18-2
*FIELD* TX
DESCRIPTION
Several mammalian homologs of the C. elegans gene Unc18 have been
identified, including STXBP2. These genes are conserved across species
from yeast to man and are believed to take part in membrane-fusion
processes. See STXBP1 (602926).
CLONING
Ziegler et al. (1996) identified STXBP2, which they called UNC18B, as
part of a random sequencing of genes from IL2-activated human
natural-killer (NK) cells. Sequence analysis of a full-length cDNA
revealed that it encodes a polypeptide of 593 amino acids, which is most
closely related to mouse Unc18b (95% identical) and less closely related
to Unc18a (64% identical) and Unc18c (48% identical). Ziegler et al.
(1996) found by Northern blot analysis that UNC18B is expressed
predominantly as a 2.4-kb message in placenta, lung, liver, kidney, and
pancreas, as well as in peripheral blood lymphocytes.
GENE STRUCTURE
Zur Stadt et al. (2009) noted that the STXBP2 gene contains 19 exons.
MAPPING
Ziegler et al. (1996) mapped the STXBP2 gene to human chromosome
19p13.3-p13.2 and to the proximal arm of mouse chromosome 8.
GENE FUNCTION
Zur Stadt et al. (2009) demonstrated colocalization of STXBP2 and STX11
(605014) in CD8+ T and NK cells by immunofluorescence analysis.
Stimulation with IL2 (147680) further enhanced colocalization in CD8+
and NK cells. Coimmunoprecipitation analysis demonstrated shared binding
sites between STXBP2 and STX11.
MOLECULAR GENETICS
In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis
(FHL) mapping to chromosome 19p (FHL5; 613101), from 2 Saudi Arabian and
6 Turkish consanguineous families, zur Stadt et al. (2009) sequenced the
candidate gene STXBP2 and identified homozygous mutations in STXBP2 in
all 8 patients (see, e.g., 601717.0001-601717.0003). Sequence analysis
in other patients from nonconsanguineous FHL families revealed
homozygosity or compound heterozygosity for mutations in STXBP2 in 4
additional patients from Germany and the Czech Republic (see, e.g.,
601717.0004-601717.0006), 2 of whom had been previously reported (Beutel
et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous
mutations were found in all available unaffected parents, and none of
the mutations were detected in 210 chromosomes from ethnically matched
controls. Zur Stadt et al. (2009) identified STX11, a mutation in which
causes FHL4 (603552), as an interaction partner of STXBP2, and
demonstrated that this interaction is eliminated by the missense
mutations identified in the FHL5 patients, leading to decreased
stability of both proteins. Activity of NK and cytotoxic T cells was
markedly reduced or absent in FHL5 patients.
In affected members of 6 consanguineous families with FHL mapping to
chromosome 19p13.3-p13.2, Cote et al. (2009) sequenced the STXBP2 gene
and identified homozygosity for the P477L mutation (601717.0001) in 3
Saudi Arabian families and for the IVS14 splice site mutation
(601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian
origin, respectively.
Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in
which mutations in known FHL genes had been excluded by sequence
analysis, and identified homozygosity for 4 different missense mutations
in the STXBP2 gene in 4 (14%) of the 28 families, originating from
Italy, England, Kuwait, and Pakistan, respectively (see, e.g.,
601717.0001 and 601717.0007).
*FIELD* AV
.0001
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, PRO477LEU
In 2 brothers and another proband from unrelated consanguineous Saudi
Arabian families, who had onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) before 1 year of age, zur Stadt et
al. (2009) identified homozygosity for a 1430C-T transition in exon 16
of the STXBP2 gene, resulting in a pro477-to-leu (P477L) substitution at
a conserved residue. Analysis of CD107 degranulation in the 2 brothers
revealed that activity of NK and cytotoxic T cells was markedly reduced
or absent, and immunoblot analysis of cell lysates showed reduced
amounts of STXBP2; markedly decreased levels of syntaxin-11 (STX11;
605014) were also observed in the sibs. Coimmunoprecipitation studies
showed that ability to bind STX11 was absent with the P477L mutant. One
of the brothers underwent mismatched unrelated donor hematopoietic stem
cell transplantation (HSCT) at 12 months of age and had no active
disease at most recent follow-up; the other brother, who had central
nervous system involvement, underwent matched unrelated donor HSCT at 3
months of age but later died of venoocclusive disease.
In affected members of 3 unrelated consanguineous Saudi Arabian families
with FHL5, Cote et al. (2009) identified homozygosity for the P477L
mutation in the STXBP2 gene. No STXBP2 protein was detected in
lymphoblasts from 2 affected female sibs of 1 family. The parents and
unaffected sibs were all heterozygous for the mutated STXBP2 allele,
which was not found in 80 French, 50 Turkish, or 80 Arabic or Iranian
controls. The 5 patients were all diagnosed between 1 and 3.5 months of
age, and 3 of the 5 patients had died between 4 and 16 months of age.
In a Kuwaiti girl who was diagnosed with FHL at 7 months of age and was
still alive at 3.5 years of age after undergoing matched sib donor HSCT,
Cetica et al. (2010) identified homozygosity for the P477L mutation in
the STXBP2 gene.
.0002
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 3-BP DEL, 693GAT
In 2 unrelated Turkish probands from consanguineous families, who had
onset of familial hemophagocytic lymphohistiocytosis (FHL5; 613101) at
1.5 and 2 months of age, respectively, zur Stadt et al. (2009)
identified homozygosity for a 3-bp deletion (693delGAT) in exon 9 of the
STXBP2 gene, resulting in deletion of ile232 at a conserved residue.
Coimmunoprecipitation studies showed that ability to bind STX11 was
absent with the ile232 deletion. Both patients had central nervous
system involvement; one underwent matched sib donor hematopoietic stem
cell transplantation (HSCT) at 4.5 months of age and had no active
disease at approximately 8 years of follow-up, whereas the other patient
did not undergo HSCT and died.
.0003
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, IVS14AS, G-C, -1
In 2 unrelated probands of Turkish and German origin, who had onset of
familial hemophagocytic lymphohistiocytosis (FHL5; 613101) at 28 and 44
months, respectively, zur Stadt et al. (2009) identified homozygosity
for a G-to-C transversion at the splice acceptor site in intron 14 of
the STXBP2 gene (1247-1G-C). Analysis of RNA from the Turkish patient
revealed a deletion of exon 15, resulting in a frameshift and 126 new
codons, in about 95% of clones, as well as 2 minor in-frame and 4
frameshift products. Analysis of CD107 degranulation in this patient
revealed that activity of NK and cytotoxic T cells was markedly reduced
or absent. The German patient underwent matched unrelated donor
hematopoietic stem cell transplantation (HSCT) at 16 years of age but
later died. The Turkish patient, who did not undergo HSCT, had recurrent
reactivations that were responsive to steroids. In another 3 unrelated
FHL patients, all with onset of disease after 1 year of age, the splice
site mutation was found in compound heterozygosity with a missense
mutation (601717.0004) and 2 different 1-bp deletions (601717.0005 and
601717.0006), respectively.
In 3 probands with FHL5 from consanguineous families of Turkish,
Palestinian Arab, and Iranian origin, respectively, Cote et al. (2009)
identified homozygosity for the 1247-1G-C mutation in the STXBP2 gene.
Sequencing of RT-PCR products revealed that rather than leading to a
premature stop codon, the splice mutation resulted in exchange of the
first 17 amino acids of exon 15 for 19 new amino acids from the intronic
sequence, in-frame with the last 20 amino acids of wildtype exon 15. The
parents were all heterozygous for the mutated STXBP2 allele, which was
not found in 80 French, 50 Turkish, or 80 Arabic or Iranian controls.
Lymphoblasts from the Turkish and the Iranian patients showed markedly
decreased STXBP2 protein expression. In the Turkish patient, his
homozygous brother who remained asymptomatic at 2.6 years of age, and
the Iranian patient, cultured NK cells exhibited impaired cytotoxic
granule exocytosis; the defect was overcome by ectopic expression of
wildtype STXBP2. The 3 symptomatic probands were diagnosed between 8
years and 12.5 years of age. The Iranian patient died at 20 years of age
after HSCT and had a sister who died at age 22 months with a
retrospective diagnosis of FHL5.
.0004
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, LEU209PRO
In a German patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 28 months of age, who had central
nervous system involvement and had recurrent reactivations with
spontaneous remissions or response to steroids, zur Stadt et al. (2009)
identified compound heterozygosity for a splice site mutation
(601717.0003) and a 626T-C transition in exon 8 of the STXBP2 gene,
resulting in a leu209-to-pro (L209P) substitution. Analysis of CD107
degranulation in this patient revealed that activity of NK and cytotoxic
T cells was markedly reduced or absent.
.0005
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 1-BP DEL, 260T
In a German patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 15 months of age, who underwent
matched unrelated donor hematopoietic stem cell transplantation at 7
years of age but later died, zur Stadt et al. (2009) identified compound
heterozygosity for a splice site mutation (601717.0003) and a 1-bp
deletion (260delT) in exon 5 of the STXBP2 gene, resulting in a
frameshift and premature termination of the protein.
.0006
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, 1-BP DEL, 706G
In a Czech patient with onset of familial hemophagocytic
lymphohistiocytosis (FHL5; 613101) at 15 months of age, who underwent
mismatched unrelated donor hematopoietic stem cell transplantation at 28
months of age and had no active disease at last follow-up, zur Stadt et
al. (2009) identified compound heterozygosity for a splice site mutation
(601717.0003) and a 1-bp deletion (706delG) in exon 9 of the STXBP2
gene, resulting in a frameshift and premature termination of the
protein.
.0007
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL 5
STXBP2, GLY541SER
In a Caucasian girl from the United Kingdom with FHL, who was still
alive at 2.75 years of age after undergoing matched unrelated donor
HSCT, Cetica et al. (2010) identified homozygosity for a 1621G-A
transition in exon 18 of the STXBP2 gene, resulting in a gly541-to-ser
(G541S) substitution at a highly conserved residue. The mutation was not
found in 120 healthy Caucasian controls. Biochemical analysis revealed
that G541S mutant disrupts association of STXBP2 with STX11 (605014).
Granule release assay using the patient's lymphocytes showed minimal
release in NK cells and completely absent release in CD3(+)CD8 cells;
cytotoxic T-cell lymphocytes from the patient showed a reduced but not
absent cell-killing capacity.
*FIELD* RF
1. Beutel, K.; Gross-Wieltsch, U.; Wiesel, T.; Stadt, U. Z.; Janka,
G.; Wagner, H. J.: Infection of T lymphocytes in Epstein-Barr virus-associated
hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediat.
Blood Cancer 53: 184-190, 2009.
2. Cetica, V.; Santoro, A.; Gilmour, K. C.; Sieni, E.; Beutel, K.;
Pende, D.; Marcenaro, S.; Koch, F.; Grieve, S.; Wheeler, R.; Zhao,
F.; zur Stadt, U.; Griffiths, G. M.; Arico, M.: STXBP2 mutations
in children with familial haemophagocytic lymphohistiocytosis type
5. J. Med. Genet. 47: 595-600, 2010.
3. Cote, M.; Menager, M. M.; Burgess, A.; Mahlaoui, N.; Picard, C.;
Schaffner, C.; Al-Manjomi, F.; Al-Harbi, M.; Alangari, A.; Le Deist,
F.; Gennery, A. R.; Prince, N.; Cariou, A.; Nitschke, P.; Blank, U.;
El-Ghazali, G.; Menasche, G.; Latour, S.; Fischer, A.; de Saint Basile,
G.: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis
type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J.
Clin. Invest. 119: 3765-3773, 2009.
4. Sparber-Sauer, M.; Honig, M.; Schulz, A. S.; Zur Stadt, U.; Schutz,
C.; Debatin, K. M.; Friedrich, W.: Patients with early relapse of
primary hemophagocytic syndromes or with persistent CNS involvement
may benefit from immediate hematopoietic stem cell transplantation. Bone
Marrow Transplant 44: 333-338, 2009.
5. Ziegler, S.F.; Mortrud, M. T.; Swartz, A. R.; Baker, E.; Sutherland,
G. R.; Burmeister, M.; Mulligan, J. T.: Molecular characterization
of a nonneuronal human UNC18 homolog. Genomics 37: 19-23, 1996.
6. zur Stadt, U.; Rohr, J.; Seifert, W.; Koch, F.; Grieve, S.; Pagel,
J.; Strauss, J.; Kasper, B.; Nurnberg, G.; Becker, C.; Maul-Pavicic,
A.; Beutel, K.; Janka, G.; Griffiths, G.; Ehl, S.; Hennies, H. C.
: Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
by mutations in Munc18-2 and impaired binding to syntaxin 11. Am.
J. Hum. Genet. 85: 482-492, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/5/2011
Marla J. F. O'Neill - updated: 6/10/2010
Marla J. F. O'Neill - updated: 10/22/2009
*FIELD* CD
Jennifer P. Macke: 3/24/1997
*FIELD* ED
wwang: 01/10/2011
terry: 1/5/2011
wwang: 6/11/2010
terry: 6/10/2010
wwang: 10/23/2009
terry: 10/22/2009
mgross: 3/8/1999
psherman: 1/21/1999
alopez: 8/4/1998
alopez: 4/2/1997
alopez: 4/1/1997
alopez: 3/24/1997
MIM
613101
*RECORD*
*FIELD* NO
613101
*FIELD* TI
#613101 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5; FHL5
*FIELD* TX
A number sign (#) is used with this entry because this form of familial
read morehemophagocytic lymphohistiocytosis is caused by mutation in the
syntaxin-binding protein-2 gene (STXBP2; 601717).
For a phenotypic description and a discussion of genetic heterogeneity
of familial hemophagocytic lymphohistiocytosis (FHL), see 267700.
MAPPING
Zur Stadt et al. (2009) performed genomewide linkage analysis and
homozygosity mapping in 1 Saudi Arabian and 14 unrelated Turkish
probands, all from consanguineous backgrounds, who had familial
hemophagocytic lymphohistiocytosis but did not have mutations in the 3
known FHL genes. A maximum heterogeneity lod (hlod) score of 5.9 was
obtained on chromosome 19p; fine mapping yielded a hlod of 8.3 at dbSNP
rs634968, and detailed genotype analysis revealed an overlapping region
of homozygosity in 7 of the 15 cases, a 1,040-kb interval containing 36
genes. Whole-genome analysis of another consanguineous FHL family from
Saudi Arabia with 2 affected and 3 unaffected sibs revealed 3 homozygous
regions with lod scores greater than 2.0, 1 of which overlapped with the
previously identified interval on chromosome 19p.
In 8 patients from 6 consanguineous families with FHL in which known
causes had been excluded by genetic analysis, Cote et al. (2009)
performed genomewide SNP analysis and found a common region of
homozygosity on chromosome 19p13.2-p13.3; of 40 genes within the
interval, the STXBP2 gene appeared to be the most plausible candidate.
MOLECULAR GENETICS
In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis
mapping to chromosome 19p, from 2 Saudi Arabian and 6 Turkish
consanguineous families, zur Stadt et al. (2009) identified homozygous
mutations in the STXBP2 gene in all 8 patients (see, e.g.,
601717.0001-601717.0003). Sequence analysis in other patients from
nonconsanguineous FHL families revealed homozygosity or compound
heterozygosity for additional mutations in the STXBP2 gene in 4 patients
from Germany and the Czech Republic (see, e.g.,
601717.0004-601717.0006), 2 of whom had previously been reported (Beutel
et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous
mutations were found in all available unaffected parents, and none of
the mutations were detected in 210 chromosomes from ethnically matched
controls. The 7 patients who were homozygous for missense mutations or a
3-bp deletion had early-onset disease, diagnosed before 1 year of age,
whereas the remaining 5 patients, who were homozygous for a splice site
mutation or compound heterozygous for the splice site mutation and
another mutation, had disease that developed after 1 year of age. Zur
Stadt et al. (2009) identified STX11 (605014), mutations in which causes
FHL4 (603552), as an interaction partner of STXBP2, and demonstrated
that this interaction is eliminated by the missense mutations identified
in the FHL5 patients, leading to decreased stability of both proteins.
Analysis of CD107 degranulation in 3 early-onset and 2 late-onset
patients demonstrated marked reduction or absence of natural killer and
cytotoxic T-cell activity.
In affected members of 6 consanguineous families with FHL mapping to
chromosome 19p13.2-p13.3, Cote et al. (2009) sequenced the STXBP2 gene
and identified homozygosity for the P477L mutation (601717.0001) in 3
Saudi Arabian families and for the IVS14 splice site mutation
(601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian
origin, respectively. In all patients with the P477L mutation, FHL was
early in onset and rapidly led to death in 3 of 5 patients, whereas FHL
manifestations occurred several years later in patients with the splice
site mutation, and 1 individual homozygous for the splice site mutation
was asymptomatic at 32 months of age. Cote et al. (2009) confirmed STX11
as the main partner of STXBP2 in lymphocytes, with STXBP2 being required
for its expression.
Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in
which mutations in known FHL genes had been excluded by sequence
analysis, and identified homozygosity for 4 different missense mutations
in the STXBP2 gene in 4 (14%) of the 28 families, originating from
Italy, England, Kuwait, and Pakistan, respectively (see, e.g.,
601717.0001 and 601717.0007). Cetica et al. (2010) noted that the
presenting features of these FHL5 patients appeared largely comparable
to those of other FHL subgroups, in particular FHL2 (603553) and FHL3
(608898).
*FIELD* RF
1. Beutel, K.; Gross-Wieltsch, U.; Wiesel, T.; Stadt, U. Z.; Janka,
G.; Wagner, H. J.: Infection of T lymphocytes in Epstein-Barr virus-associated
hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediat.
Blood Cancer 53: 184-190, 2009.
2. Cetica, V.; Santoro, A.; Gilmour, K. C.; Sieni, E.; Beutel, K.;
Pende, D.; Marcenaro, S.; Koch, F.; Grieve, S.; Wheeler, R.; Zhao,
F.; zur Stadt, U.; Griffiths, G. M.; Arico, M.: STXBP2 mutations
in children with familial haemophagocytic lymphohistiocytosis type
5. J. Med. Genet. 47: 595-600, 2010.
3. Cote, M.; Menager, M. M.; Burgess, A.; Mahlaoui, N.; Picard, C.;
Schaffner, C.; Al-Manjomi, F.; Al-Harbi, M.; Alangari, A.; Le Deist,
F.; Gennery, A. R.; Prince, N.; Cariou, A.; Nitschke, P.; Blank, U.;
El-Ghazali, G.; Menasche, G.; Latour, S.; Fischer, A.; de Saint Basile,
G.: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis
type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J.
Clin. Invest. 119: 3765-3773, 2009.
4. Sparber-Sauer, M.; Honig, M.; Schulz, A. S.; zur Stadt, U.; Schutz,
C.; Debatin, K. M.; Friedrich, W.: Patients with early relapse of
primary hemophagocytic syndromes or with persistent CNS involvement
may benefit from immediate hematopoietic stem cell transplantation. Bone
Marrow Transplant 44: 333-338, 2009.
5. zur Stadt, U.; Rohr, J.; Seifert, W.; Koch, F.; Grieve, S.; Pagel,
J.; Strauss, J.; Kasper, B.; Nurnberg, G.; Becker, C.; Maul-Pavicic,
A.; Beutel, K.; Janka, G.; Griffiths, G.; Ehl, S.; Hennies, H. C.
: Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
by mutations in Munc18-2 and impaired binding to syntaxin 11. Am.
J. Hum. Genet. 85: 482-492, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/5/2011
Marla J. F. O'Neill - updated: 6/10/2010
*FIELD* CD
Marla J. F. O'Neill: 10/22/2009
*FIELD* ED
wwang: 01/10/2011
terry: 1/5/2011
wwang: 6/11/2010
terry: 6/10/2010
carol: 11/18/2009
wwang: 10/23/2009
*RECORD*
*FIELD* NO
613101
*FIELD* TI
#613101 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 5; FHL5
*FIELD* TX
A number sign (#) is used with this entry because this form of familial
read morehemophagocytic lymphohistiocytosis is caused by mutation in the
syntaxin-binding protein-2 gene (STXBP2; 601717).
For a phenotypic description and a discussion of genetic heterogeneity
of familial hemophagocytic lymphohistiocytosis (FHL), see 267700.
MAPPING
Zur Stadt et al. (2009) performed genomewide linkage analysis and
homozygosity mapping in 1 Saudi Arabian and 14 unrelated Turkish
probands, all from consanguineous backgrounds, who had familial
hemophagocytic lymphohistiocytosis but did not have mutations in the 3
known FHL genes. A maximum heterogeneity lod (hlod) score of 5.9 was
obtained on chromosome 19p; fine mapping yielded a hlod of 8.3 at dbSNP
rs634968, and detailed genotype analysis revealed an overlapping region
of homozygosity in 7 of the 15 cases, a 1,040-kb interval containing 36
genes. Whole-genome analysis of another consanguineous FHL family from
Saudi Arabia with 2 affected and 3 unaffected sibs revealed 3 homozygous
regions with lod scores greater than 2.0, 1 of which overlapped with the
previously identified interval on chromosome 19p.
In 8 patients from 6 consanguineous families with FHL in which known
causes had been excluded by genetic analysis, Cote et al. (2009)
performed genomewide SNP analysis and found a common region of
homozygosity on chromosome 19p13.2-p13.3; of 40 genes within the
interval, the STXBP2 gene appeared to be the most plausible candidate.
MOLECULAR GENETICS
In 8 unrelated probands with familial hemophagocytic lymphohistiocytosis
mapping to chromosome 19p, from 2 Saudi Arabian and 6 Turkish
consanguineous families, zur Stadt et al. (2009) identified homozygous
mutations in the STXBP2 gene in all 8 patients (see, e.g.,
601717.0001-601717.0003). Sequence analysis in other patients from
nonconsanguineous FHL families revealed homozygosity or compound
heterozygosity for additional mutations in the STXBP2 gene in 4 patients
from Germany and the Czech Republic (see, e.g.,
601717.0004-601717.0006), 2 of whom had previously been reported (Beutel
et al., 2009; Sparber-Sauer et al., 2009). Corresponding heterozygous
mutations were found in all available unaffected parents, and none of
the mutations were detected in 210 chromosomes from ethnically matched
controls. The 7 patients who were homozygous for missense mutations or a
3-bp deletion had early-onset disease, diagnosed before 1 year of age,
whereas the remaining 5 patients, who were homozygous for a splice site
mutation or compound heterozygous for the splice site mutation and
another mutation, had disease that developed after 1 year of age. Zur
Stadt et al. (2009) identified STX11 (605014), mutations in which causes
FHL4 (603552), as an interaction partner of STXBP2, and demonstrated
that this interaction is eliminated by the missense mutations identified
in the FHL5 patients, leading to decreased stability of both proteins.
Analysis of CD107 degranulation in 3 early-onset and 2 late-onset
patients demonstrated marked reduction or absence of natural killer and
cytotoxic T-cell activity.
In affected members of 6 consanguineous families with FHL mapping to
chromosome 19p13.2-p13.3, Cote et al. (2009) sequenced the STXBP2 gene
and identified homozygosity for the P477L mutation (601717.0001) in 3
Saudi Arabian families and for the IVS14 splice site mutation
(601717.0003) in 3 families of Turkish, Palestinian Arab, and Iranian
origin, respectively. In all patients with the P477L mutation, FHL was
early in onset and rapidly led to death in 3 of 5 patients, whereas FHL
manifestations occurred several years later in patients with the splice
site mutation, and 1 individual homozygous for the splice site mutation
was asymptomatic at 32 months of age. Cote et al. (2009) confirmed STX11
as the main partner of STXBP2 in lymphocytes, with STXBP2 being required
for its expression.
Cetica et al. (2010) analyzed the STXBP2 gene in 28 FHL families in
which mutations in known FHL genes had been excluded by sequence
analysis, and identified homozygosity for 4 different missense mutations
in the STXBP2 gene in 4 (14%) of the 28 families, originating from
Italy, England, Kuwait, and Pakistan, respectively (see, e.g.,
601717.0001 and 601717.0007). Cetica et al. (2010) noted that the
presenting features of these FHL5 patients appeared largely comparable
to those of other FHL subgroups, in particular FHL2 (603553) and FHL3
(608898).
*FIELD* RF
1. Beutel, K.; Gross-Wieltsch, U.; Wiesel, T.; Stadt, U. Z.; Janka,
G.; Wagner, H. J.: Infection of T lymphocytes in Epstein-Barr virus-associated
hemophagocytic lymphohistiocytosis in children of non-Asian origin. Pediat.
Blood Cancer 53: 184-190, 2009.
2. Cetica, V.; Santoro, A.; Gilmour, K. C.; Sieni, E.; Beutel, K.;
Pende, D.; Marcenaro, S.; Koch, F.; Grieve, S.; Wheeler, R.; Zhao,
F.; zur Stadt, U.; Griffiths, G. M.; Arico, M.: STXBP2 mutations
in children with familial haemophagocytic lymphohistiocytosis type
5. J. Med. Genet. 47: 595-600, 2010.
3. Cote, M.; Menager, M. M.; Burgess, A.; Mahlaoui, N.; Picard, C.;
Schaffner, C.; Al-Manjomi, F.; Al-Harbi, M.; Alangari, A.; Le Deist,
F.; Gennery, A. R.; Prince, N.; Cariou, A.; Nitschke, P.; Blank, U.;
El-Ghazali, G.; Menasche, G.; Latour, S.; Fischer, A.; de Saint Basile,
G.: Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis
type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J.
Clin. Invest. 119: 3765-3773, 2009.
4. Sparber-Sauer, M.; Honig, M.; Schulz, A. S.; zur Stadt, U.; Schutz,
C.; Debatin, K. M.; Friedrich, W.: Patients with early relapse of
primary hemophagocytic syndromes or with persistent CNS involvement
may benefit from immediate hematopoietic stem cell transplantation. Bone
Marrow Transplant 44: 333-338, 2009.
5. zur Stadt, U.; Rohr, J.; Seifert, W.; Koch, F.; Grieve, S.; Pagel,
J.; Strauss, J.; Kasper, B.; Nurnberg, G.; Becker, C.; Maul-Pavicic,
A.; Beutel, K.; Janka, G.; Griffiths, G.; Ehl, S.; Hennies, H. C.
: Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused
by mutations in Munc18-2 and impaired binding to syntaxin 11. Am.
J. Hum. Genet. 85: 482-492, 2009.
*FIELD* CN
Marla J. F. O'Neill - updated: 1/5/2011
Marla J. F. O'Neill - updated: 6/10/2010
*FIELD* CD
Marla J. F. O'Neill: 10/22/2009
*FIELD* ED
wwang: 01/10/2011
terry: 1/5/2011
wwang: 6/11/2010
terry: 6/10/2010
carol: 11/18/2009
wwang: 10/23/2009