RBCC

Full text data of STX11

STX11 [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Syntaxin-11

UniProt O75558
ID STX11_HUMAN Reviewed; 287 AA.
AC O75558; E1P598; O75378; O95148; Q5TCL6;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-NOV-1998, sequence version 1.
DT 22-JAN-2014, entry version 119.
DE RecName: Full=Syntaxin-11;
GN Name=STX11;
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].
RX PubMed=9571206; DOI=10.1006/bbrc.1998.8490;
RA Tang B.L., Low D.Y.H., Hong W.;
RT "Syntaxin 11: a member of the syntaxin family without a carboxyl
RT terminal transmembrane domain.";
RL Biochem. Biophys. Res. Commun. 245:627-632(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9553086; DOI=10.1074/jbc.273.17.10317;
RA Advani R.J., Bae H.-R., Bock J.B., Chao D.S., Doung Y.-C.,
RA Prekeris R., Yoo J.-S., Scheller R.H.;
RT "Seven novel mammalian SNARE proteins localize to distinct membrane
RT compartments.";
RL J. Biol. Chem. 273:10317-10324(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=10036234;
RA Valdez A.C., Cabaniols J.-P., Brown M.J., Roche P.A.;
RT "Syntaxin 11 is associated with SNAP-23 on late endosomes and the
RT trans-Golgi network.";
RL J. Cell Sci. 112:845-854(1999).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E.,
RA Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Andrews T.D., Ashwell R.I.S.,
RA Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J.,
RA Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P.,
RA Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E.,
RA Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A.,
RA Frankland J., French L., Garner P., Garnett J., Ghori M.J.,
RA Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M.,
RA Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S.,
RA Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R.,
RA Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E.,
RA Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A.,
RA Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M.,
RA Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K.,
RA McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T.,
RA Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R.,
RA Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W.,
RA Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M.,
RA Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L.,
RA Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J.,
RA Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B.,
RA Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L.,
RA Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W.,
RA Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A.,
RA Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 [7]
RP INVOLVEMENT IN FHL4.
RX PubMed=15703195; DOI=10.1093/hmg/ddi076;
RA zur Stadt U., Schmidt S., Kasper B., Beutel K., Diler A.S.,
RA Henter J.-I., Kabisch H., Schneppenheim R., Nuernberg P., Janka G.,
RA Hennies H.C.;
RT "Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4
RT to chromosome 6q24 and identification of mutations in syntaxin 11.";
RL Hum. Mol. Genet. 14:827-834(2005).
CC -!- FUNCTION: SNARE that acts to regulate protein transport between
CC late endosomes and the trans-Golgi network.
CC -!- SUBUNIT: Interacts with the SNARE proteins SNAP-23 and VAMP.
CC -!- SUBCELLULAR LOCATION: Membrane; Peripheral membrane protein
CC (Potential). Golgi apparatus, trans-Golgi network membrane;
CC Peripheral membrane protein (By similarity).
CC -!- DISEASE: Familial hemophagocytic lymphohistiocytosis 4 (FHL4)
CC [MIM:603552]: 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 syntaxin family.
CC -!- SIMILARITY: Contains 1 t-SNARE coiled-coil homology domain.
CC -!- WEB RESOURCE: Name=STX11base; Note=STX11 mutation db;
CC URL="http://bioinf.uta.fi/STX11base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/STX11";
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DR EMBL; AF038898; AAD02107.1; -; mRNA.
DR EMBL; AF044309; AAC24031.1; -; mRNA.
DR EMBL; AF071504; AAC24004.1; -; mRNA.
DR EMBL; AL135917; CAI22980.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47849.1; -; Genomic_DNA.
DR EMBL; CH471051; EAW47850.1; -; Genomic_DNA.
DR EMBL; BC033519; AAH33519.1; -; mRNA.
DR PIR; JE0094; JE0094.
DR RefSeq; NP_003755.2; NM_003764.3.
DR RefSeq; XP_005267246.1; XM_005267189.1.
DR RefSeq; XP_005267247.1; XM_005267190.1.
DR UniGene; Hs.118958; -.
DR ProteinModelPortal; O75558; -.
DR SMR; O75558; 38-259.
DR IntAct; O75558; 15.
DR MINT; MINT-1398569; -.
DR STRING; 9606.ENSP00000356540; -.
DR PhosphoSite; O75558; -.
DR OGP; O75558; -.
DR PaxDb; O75558; -.
DR PRIDE; O75558; -.
DR DNASU; 8676; -.
DR Ensembl; ENST00000367568; ENSP00000356540; ENSG00000135604.
DR GeneID; 8676; -.
DR KEGG; hsa:8676; -.
DR UCSC; uc003qks.4; human.
DR CTD; 8676; -.
DR GeneCards; GC06P144513; -.
DR HGNC; HGNC:11429; STX11.
DR HPA; HPA007992; -.
DR MIM; 603552; phenotype.
DR MIM; 605014; gene.
DR neXtProt; NX_O75558; -.
DR Orphanet; 540; Familial hemophagocytic lymphohistiocytosis.
DR PharmGKB; PA36229; -.
DR eggNOG; NOG306476; -.
DR HOGENOM; HOG000286023; -.
DR HOVERGEN; HBG099780; -.
DR InParanoid; O75558; -.
DR KO; K08487; -.
DR OMA; PHEDIVF; -.
DR OrthoDB; EOG7X9G7R; -.
DR PhylomeDB; O75558; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_13685; Neuronal System.
DR GeneWiki; STX11; -.
DR GenomeRNAi; 8676; -.
DR NextBio; 32547; -.
DR PRO; PR:O75558; -.
DR Bgee; O75558; -.
DR CleanEx; HS_STX11; -.
DR Genevestigator; O75558; -.
DR GO; GO:0005794; C:Golgi apparatus; IEA:UniProtKB-SubCell.
DR GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005484; F:SNAP receptor activity; TAS:ProtInc.
DR GO; GO:0006886; P:intracellular protein transport; IEA:InterPro.
DR GO; GO:0061025; P:membrane fusion; TAS:ProtInc.
DR GO; GO:0016192; P:vesicle-mediated transport; IEA:InterPro.
DR InterPro; IPR006012; Syntaxin/epimorphin_CS.
DR InterPro; IPR006011; Syntaxin_N.
DR InterPro; IPR010989; t-SNARE.
DR InterPro; IPR000727; T_SNARE_dom.
DR Pfam; PF05739; SNARE; 1.
DR Pfam; PF00804; Syntaxin; 1.
DR SMART; SM00503; SynN; 1.
DR SMART; SM00397; t_SNARE; 1.
DR SUPFAM; SSF47661; SSF47661; 1.
DR PROSITE; PS00914; SYNTAXIN; 1.
DR PROSITE; PS50192; T_SNARE; 1.
PE 2: Evidence at transcript level;
KW Coiled coil; Complete proteome;
KW Familial hemophagocytic lymphohistiocytosis; Golgi apparatus;
KW Membrane; Polymorphism; Protein transport; Reference proteome;
KW Transport.
FT CHAIN 1 287 Syntaxin-11.
FT /FTId=PRO_0000210221.
FT DOMAIN 204 266 t-SNARE coiled-coil homology.
FT COILED 41 71 Potential.
FT VARIANT 31 31 E -> Q (in dbSNP:rs1802414).
FT /FTId=VAR_011995.
FT VARIANT 49 49 R -> Q (in dbSNP:rs17073498).
FT /FTId=VAR_029769.
FT VARIANT 204 204 L -> H (in dbSNP:rs1133248).
FT /FTId=VAR_011996.
FT VARIANT 277 277 T -> A (in dbSNP:rs9496891).
FT /FTId=VAR_029770.
FT CONFLICT 61 61 D -> N (in Ref. 1; AAD02107).
FT CONFLICT 93 94 IK -> FR (in Ref. 2; AAC24031).
FT CONFLICT 96 97 RG -> PP (in Ref. 1; AAD02107).
FT CONFLICT 103 104 KL -> NV (in Ref. 1; AAD02107).
FT CONFLICT 121 126 HSAVAR -> ALGSGG (in Ref. 1; AAD02107).
FT CONFLICT 200 220 ARAALNEIESRHRELLRLESR -> RGPPTTRSRAATANCC
FT AWRAA (in Ref. 2; AAC24031).
FT CONFLICT 200 200 A -> V (in Ref. 1; AAD02107).
FT CONFLICT 215 215 L -> V (in Ref. 1; AAD02107).
FT CONFLICT 220 220 R -> A (in Ref. 1; AAD02107).
SQ SEQUENCE 287 AA; 33196 MW; 18E8B43BA987D891 CRC64;
MKDRLAELLD LSKQYDQQFP DGDDEFDSPH EDIVFETDHI LESLYRDIRD IQDENQLLVA
DVKRLGKQNA RFLTSMRRLS SIKRDTNSIA KAIKARGEVI HCKLRAMKEL SEAAEAQHGP
HSAVARISRA QYNALTLTFQ RAMHDYNQAE MKQRDNCKIR IQRQLEIMGK EVSGDQIEDM
FEQGKWDVFS ENLLADVKGA RAALNEIESR HRELLRLESR IRDVHELFLQ MAVLVEKQAD
TLNVIELNVQ KTVDYTGQAK AQVRKAVQYE EKNPCRTLCC FCCPCLK
//

MIM 603552
*RECORD*
*FIELD* NO
603552
*FIELD* TI
#603552 HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4; FHL4
;;HPLH4;;
HLH4
*FIELD* TX
read moreA number sign (#) is used with this entry because familial
hemophagocytic lymphohistiocytosis-4 (FHL4) is caused by homozygous
mutation in the syntaxin-11 gene (STX11; 605014) on chromosome 6q24.

DESCRIPTION

Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder
clinically diagnosed based on the fulfillment of 5 of 8 criteria,
including fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or
hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK)
cell activity, hyperferritinemia, and high soluble IL2 receptor levels
(IL2R; 147730). The disorder typically presents in infancy or early
childhood. Persistent remission is rarely achieved with chemo- or
immunotherapy; hematopoietic stem cell transplantation is the only cure
(summary by Muller et al., 2014).

For a phenotypic description and a discussion of genetic heterogeneity
of familial hemophagocytic lymphohistiocytosis (FHL), see 267700.

CLINICAL FEATURES

Muller et al. (2014) reported 3 unrelated children, each born of
consanguineous Pakistani parents, with hemophagocytic
lymphohistiocytosis. The patients were diagnosed at ages 2 months, 5
years, and 48 months, respectively. Clinical details for 1 of the
patients was not available; she was lost to follow-up. The other 2
patients had fever, hepatosplenomegaly, and laboratory evidence of a
hyperinflammatory state. Patient NK cells showed defective lysis and
degranulation, which could be partially restored by IL2 (147680)
stimulation.

INHERITANCE

The transmission pattern in the families with FHL4 reported by Muller et
al. (2014) was consistent with autosomal recessive inheritance.

MAPPING

In a large consanguineous family of Kurdish descent with FHL, Zur Stadt
et al. (2005) performed homozygosity mapping and identified a novel FHL
locus on chromosome 6q24, within a 10-cM region defined by markers
D6S1569 and D6S960. They designated this locus FHL4.

MOLECULAR GENETICS

In the Kurdish family in which they mapped the FHL4 locus, Zur Stadt et
al. (2005) identified a 5-bp deletion in the syntaxin-11 gene
(605014.0001). The syntaxin-11 protein was absent in the mononuclear
cell fraction of patients with the deletion. Two additional
consanguineous Turkish/Kurdish FHL kindreds harbored the same mutation,
wheras 1 family displayed a large 19.2-kb genomic deletion spanning the
entire coding region (exon 2) of STX11 (605014.0002), and 2 families
exhibited a nonsense mutation leading to a premature stop codon in the
C-terminal end of the protein (Q268X; 605014.0003). As both STX11 and
UNC13D (608897) are involved in vesicle trafficking and membrane fusion,
the authors concluded that, besides mutations in perforin-1 (170280),
defects in the endocytotic or the exocytotic pathway may be a common
mechanism in FHL.

In a mutation analysis in a group of 63 unrelated patients with FHL of
different geographic origins, Zur Stadt et al. (2006) found 6 mutations
in the STX11 gene, all in patients of Kurdish origin.

Rudd et al. (2006) analyzed the STX11 gene in 34 patients with FHL from
28 unrelated families in whom PRF1 (170280) mutations had been excluded.
They identified homozygosity for the 5-bp deletion in 2 brothers
previously reported by Zur Stadt et al. (2005) and in an unrelated
brother and sister. They identified homozygosity for the Q268X mutation
in a Turkish girl previously reported by Zur Stadt et al. (2005) and in
a unrelated Turkish boy. Three of the children experienced more than 1
year in remission without specific treatment, which the authors stated
was very uncommon in this disease. Two of the children developed severe
psychomotor retardation, one developed acute myelodysplastic syndrome,
and one developed acute myelogenous leukemia. Rudd et al. (2006)
suggested that STX11 mutations may be associated with secondary
malignancies. They noted that a total of 13 individuals from 8 Turkish
families had been shown to carry STX11 mutations.

In 3 unrelated Pakistani children with FHL4, each born of consanguineous
parents, Muller et al. (2014) identified a homozygous missense mutation
in the STX11 gene (L58P; 605014.0004). Peripheral blood cells, including
NK cells, from 1 of the patients showed significantly decreased STX11
protein levels compared to controls. In vitro functional expression
studies in HEK293 cells showed that the mutant L58P protein was
expressed, but did not bind to STXBP2 (601717). In contrast, the
C-terminal Q268X mutant protein (605014.0003) did not show impaired
binding to STXBP2. Muller et al. (2014) suggested that the impaired
binding to STXBP2 may have led to degradation of the mutant L58P STX11
protein.

*FIELD* RF
1. Muller, M.-L.; Chiang, S. C. C.; Meeths, M.; Tesi, B.; Entesarian,
M.; Nilsson, D.; Wood, S. M.; Nordenskjold, M.; Henter, J.-I.; Naqvi,
A.; Bryceson, Y. T.: An N-terminal missense mutation in STX11 causative
of FHL4 abrogates syntaxin-11 binding to Munc18-2. Front. Immun. 4:
515, 2014. Note: Electronic Article.

2. Rudd, E.; Goransdotter Ericson, K.; Zheng, C.; Uysal, Z.; Ozkan,
A.; Gurgey, A.; Fadeel, B.; Nordenskjold, M.; Henter, J.-I.: Spectrum
and clinical implications of syntaxin 11 gene mutations in familial
haemophagocytic lymphohistiocytosis: association with disease-free
remissions and haematopoietic malignancies. J. Med. Genet. 43: e14,
2006.

3. Zur Stadt, U.; Beutel, K.; Kolberg, S.; Schneppenheim, R.; Kabisch,
H.; Janka, G.; Hennies, H. C.: Mutation spectrum in children with
primary hemophagocytic lymphohistiocytosis: molecular and functional
analyses of PRF1, UNC13D, STX11, and RAB27A. Hum. Mutat. 27: 62-68,
2006.

4. Zur Stadt, U.; Schmidt, S.; Kasper, B.; Beutel, K.; Diler, A. S.;
Henter, J. I.; Kabisch, H.; Schneppenheim, R.; Nurnberg, P.; Janka,
G.; Hennies, H. C.: Linkage of familial hemophagocytic lymphohistiocytosis
(FHL) type-4 to chromosome 6q24 and identification of mutations in
syntaxin 11. Hum. Molec. Genet. 14: 827-834, 2005.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/4/2014
Marla J. F. O'Neill - updated: 7/12/2006
George E. Tiller - updated: 3/9/2006

*FIELD* CD
Victor A. McKusick: 2/18/1999

*FIELD* ED
carol: 02/06/2014
mcolton: 2/4/2014
ckniffin: 2/4/2014
wwang: 7/12/2006
alopez: 3/9/2006
mgross: 3/18/2004
terry: 3/21/2003
carol: 2/18/1999

MIM 605014
*RECORD*
*FIELD* NO
605014
*FIELD* TI
*605014 SYNTAXIN 11; STX11
*FIELD* TX

DESCRIPTION

The STX11 gene encodes syntaxin-11, a protein involved in vesicle
read moreexocytosis. Syntaxin-11 contains a C-terminal SNARE domain (summary by
Muller et al., 2014). SNARE proteins play a role in regulating
intracellular protein transport between donor and target membranes. This
docking and fusion process involves the interaction of specific
vesicle-SNAREs (e.g., VAMP, 603177) with specific cognate target-SNAREs
(e.g., SNAP23, 602534) (summary by Valdez et al., 1999).

CLONING

Advani et al. (1998) and Tang et al. (1998) identified human syntaxin-11
by searching EST databases for clones with sequence similarity to other
syntaxin proteins. Both groups found that STX11 encodes a deduced
287-amino acid protein with several predicted coiled-coil domains.
Unlike most membrane-associated proteins, STX11 lacks a hydrophobic
domain but contains a cysteine-rich C terminus. Like SNAP25 (600322),
STX11 may be anchored to membranes by palmitoylated cysteines. By
Northern blot analysis, Tang et al. (1998) identified 2 STX11
transcripts of approximately 0.8 and 1.7 kb that are particularly
abundant in heart and placenta and are detectable at low levels in other
tissues but not in brain.

Using a yeast 2-hybrid system to screen a human B-lymphocyte cDNA
library with SNAP23 as bait, Valdez et al. (1999) cloned STX11. They
determined that STX11 has a molecular mass of 35 kD and is an integral
membrane protein despite the lack of a traditional transmembrane domain.
Both transfected and endogenous STX11 binds to SNAP23 in vitro and in
vivo. STX11 colocalizes with mannose 6-phosphate on late endosomes and
the trans-Golgi network. Immunofluorescence microscopy showed that when
the cysteine cluster at the C terminus of STX11 is deleted, the punctate
intracellular structure does not differ from that of the wildtype
protein, demonstrating that targeting and retention of STX11 on the
intracellular membrane does not depend exclusively on amino acids in the
cysteine-rich domain.

GENE STRUCTURE

The STX11 gene consists of 2 exons and covers a genomic interval of 37
kb (Zur Stadt et al., 2005).

MOLECULAR GENETICS

Familial hemophagocytic lymphohistiocytosis (FHL; 267700) is an
autosomal recessive disease that presents as a severe hyperinflammatory
syndrome with activated macrophages and T lymphocytes. Zur Stadt et al.
(2005) mapped one form of FHL (FHL4; 603552) to chromosome 6q24 by
homozygosity mapping. They identified a 5-bp deletion (605014.0001), a
large genomic deletion (605014.0002), and a nonsense mutation (Q268X;
605014.0003) in the STX11 gene, which maps to the 6q24 region.

In a mutation analysis in a group of 63 unrelated patients with FHL of
different geographic origins, Zur Stadt et al. (2006) found 6 mutations
in the STX11 gene, all in patients of Kurdish origin.

Yamamoto et al. (2005) excluded mutations in the STX11 gene in 30
Japanese patients with FHL.

Rudd et al. (2006) analyzed the STX11 gene in 34 patients with FHL from
28 unrelated families in whom PRF1 (170280) mutations had been excluded,
including 2 families previously reported by Zur Stadt et al. (2005).
They identified homozygosity for the 5-bp deletion and the Q268X
mutation in a Turkish brother and sister and an unrelated Turkish boy,
respectively. They noted that 13 individuals from 8 Turkish families had
been shown to carry STX11 mutations to that date.

In 3 unrelated Pakistani children with FHL4, each born of consanguineous
parents, Muller et al. (2014) identified a homozygous missense mutation
in the STX11 gene (L58P; 605014.0004). Peripheral blood cells, including
NK cells, from 1 of the patients showed significantly decreased STX11
protein levels compared to controls. In vitro functional expression
studies in HEK293 cells showed that the mutant L58P protein was
expressed, but did not bind to STXBP2 (601717). In contrast, the
C-terminal Q268X mutant protein (605014.0003) did not show impaired
binding to STXBP2. Muller et al. (2014) suggested that the impaired
binding to STXBP2 may have led to degradation of the mutant L58P STX11
protein. The patients presented in infancy or early childhood with
clinical and laboratory evidence of a hyperinflammatory state. Resting
patient NK cells showed defective lytic activity and impaired
degranulation.

*FIELD* AV
.0001
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4
STX11, 5-BP DEL

Zur Stadt et al. (2005) identified a homozygous deletion of 5
nucleotides (369_370delAG, 374_376delCGC) in exon 2 of the STX11 gene in
a large family of Kurdish origin in Turkey as the basis of familial
hemophagocytic lymphohistiocytosis (603552). The total deletion of 5
basepairs led to a frameshift and premature termination after 59 altered
residues (val124fsX60). This mutation was identified in 2 additional
families of Kurdish origin. Rudd et al. (2006) noted that 1 of the
brothers from the large Kurdish family developed myelodysplastic
syndrome 6 years after the diagnosis of FHL; both brothers had more than
1 year of remission without specific treatment.

In a Turkish brother and sister with familial hemophagocytic
lymphohistiocytosis, Rudd et al. (2006) identified homozygosity for
369_370delAG and 374_276delCGC mutation. Both children had severe
psychomotor retardation, and the girl died at age 14 months at home with
fever and cough.

.0002
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4
STX11, 19.2-KB DEL

In affected members of a Turkish family of Kurdish origin with familial
hemophagocytic lymphohistiocytosis (603552), Zur Stadt et al. (2005)
identified a deletion of 19,189 basepairs in the STX11 gene, including
part of intron 1 and the entire coding region.

.0003
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4
STX11, GLN268TER

In 2 Turkish families of Kurdish origin with familial hemophagocytic
lymphohistiocytosis (603552), Zur Stadt et al. (2005) identified a
C-to-T transition at nucleotide position 802 of the STX11 gene that
resulted in premature termination at gln268 (Q268X). Rudd et al. (2006)
noted that a girl from 1 of the families reported by Zur Stadt et al.
(2005) had developed acute myelogenous leukemia but was alive and in
remission from AML and FHL at the time of writing.

In a Turkish boy with familial hemophagocytic lymphohistiocytosis, Rudd
et al. (2006) identified homozygosity for the Q268X mutation. The boy
had more than a year in remission without specific treatment, but died
at age 12 years due to hemorrhage.

.0004
HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS, FAMILIAL, 4
STX11, LEU58PRO

In 3 unrelated Pakistani children with FHL4 (603552), each born of
consanguineous parents, Muller et al. (2014) identified a homozygous
c.173T-C transition in the STX11 gene, resulting in a leu58-to-pro
(L58P) substitution in the first alpha-helix of the conserved N-terminal
Habc domain. All of the parents were unaffected and heterozygous for the
mutation. Peripheral blood cells, including NK cells, from 1 of the
patients showed significantly decreased STX11 protein levels compared to
controls. In vitro functional expression studies in HEK293 cells showed
that the mutant L58P protein was expressed, but did not bind to STXBP2
(601717). In contrast, the C-terminal Q268X mutant protein (605014.0003)
did not show impaired binding to STXBP2. Muller et al. (2014) suggested
that the impaired binding to STXBP2 may have led to degradation of the
mutant L58P STX11 protein. The patients presented in infancy or early
childhood with clinical and laboratory evidence of a hyperinflammatory
state. Resting patient NK cells showed defective lytic activity and
impaired degranulation. One of the patients also carried a heterozygous
P271S variant in the UNC13D gene (608897) (frequency of 0.001 among
Caucasians) and a homozygous R928C variant in the UNC13D gene (frequency
of 0.01 among Caucasians); this patient had the earliest onset, at age 2
months. Two of the patients died in childhood, and the third was lost to
follow-up.

*FIELD* RF
1. Advani, R. J.; Bae, H.-R.; Bock, J. B.; Chao, D. S.; Doung, Y.-C.;
Prekeris, R.; Yoo, J.-S.; Scheller, R. H.: Seven novel mammalian
SNARE proteins localize to distinct membrane compartments. J. Biol.
Chem. 273: 10317-10324, 1998.

2. Muller, M.-L.; Chiang, S. C. C.; Meeths, M.; Tesi, B.; Entesarian,
M.; Nilsson, D.; Wood, S. M.; Nordenskjold, M.; Henter, J.-I.; Naqvi,
A.; Bryceson, Y. T.: An N-terminal missense mutation in STX11 causative
of FHL4 abrogates syntaxin-11 binding to Munc18-2. Front. Immun. 4:
515, 2014. Note: Electronic Article.

3. Rudd, E.; Goransdotter Ericson, K.; Zheng, C.; Uysal, Z.; Ozkan,
A.; Gurgey, A.; Fadeel, B.; Nordenskjold, M.; Henter, J.-I.: Spectrum
and clinical implications of syntaxin 11 gene mutations in familial
haemophagocytic lymphohistiocytosis: association with disease-free
remissions and haematopoietic malignancies. J. Med. Genet. 43: e14,
2006.

4. Tang, B. L.; Low, D. Y. H.; Hong, W.: Syntaxin 11: a member of
the syntaxin family without a carboxyl terminal transmembrane domain. Biochem.
Biophys. Res. Commun. 245: 627-632, 1998.

5. Valdez, A. C.; Cabaniois, J.-P.; Brown, M. J.; Roche, P. A.: Syntaxin
11 is associated with SNAP-23 on late endosomes and the trans-Golgi
network. J. Cell Sci. 112: 845-854, 1999.

6. Yamamoto, K.; Ishii, E.; Horiuchi, H.; Ueda, I.; Ohga, S.; Nishi,
M.; Ogata, Y.; Zaitsu, M.; Morimoto, A.; Hara, T.; Imashuku, S.; Sasazuki,
T.; Yasukawa, M.: Mutations of syntaxin 11 and SNAP23 as causes of
familial hemophagocytic lymphohistiocytosis were not found in Japanese
people. J. Hum. Genet. 50: 600-603, 2005.

7. Zur Stadt, U.; Beutel, K.; Kolberg, S.; Schneppenheim, R.; Kabisch,
H.; Janka, G.; Hennies, H. C.: Mutation spectrum in children with
primary hemophagocytic lymphohistiocytosis: molecular and functional
analyses of PRF1, UNC13D, STX11, and RAB27A. Hum. Mutat. 27: 62-68,
2006.

8. Zur Stadt, U.; Schmidt, S.; Kasper, B.; Beutel, K.; Diler, A. S.;
Henter, J. I.; Kabisch, H.; Schneppenheim, R.; Nurnberg, P.; Janka,
G.; Hennies, H. C.: Linkage of familial hemophagocytic lymphohistiocytosis
(FHL) type-4 to chromosome 6q24 and identification of mutations in
syntaxin 11. Hum. Molec. Genet. 14: 827-834, 2005.

*FIELD* CN
Cassandra L. Kniffin - updated: 2/4/2014
Marla J. F. O'Neill - updated: 7/12/2006
Cassandra L. Kniffin - updated: 3/13/2006
George E. Tiller - updated: 3/9/2006
Victor A. McKusick - updated: 1/20/2006

*FIELD* CD
Yen-Pei C. Chang: 5/25/2000

*FIELD* ED
carol: 02/12/2014
carol: 2/6/2014
mcolton: 2/4/2014
ckniffin: 2/4/2014
carol: 3/28/2007
wwang: 8/3/2006
wwang: 7/12/2006
wwang: 5/25/2006
ckniffin: 3/13/2006
alopez: 3/9/2006
terry: 1/20/2006
carol: 6/1/2000
carol: 5/31/2000

RBCC Red Blood Cell Collection

Full text data of STX11