Full text data of STXBP1
STXBP1
(UNC18A)
[Confidence: low (only semi-automatic identification from reviews)]
Syntaxin-binding protein 1 (MUNC18-1; N-Sec1; Protein unc-18 homolog 1; Unc18-1; Protein unc-18 homolog A; Unc-18A; p67)
Syntaxin-binding protein 1 (MUNC18-1; N-Sec1; Protein unc-18 homolog 1; Unc18-1; Protein unc-18 homolog A; Unc-18A; p67)
UniProt
P61764
ID STXB1_HUMAN Reviewed; 594 AA.
AC P61764; B1AM97; Q28208; Q62759; Q64320; Q96TG8;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUN-2004, sequence version 1.
DT 22-JAN-2014, entry version 100.
DE RecName: Full=Syntaxin-binding protein 1;
DE AltName: Full=MUNC18-1;
DE AltName: Full=N-Sec1;
DE AltName: Full=Protein unc-18 homolog 1;
DE Short=Unc18-1;
DE AltName: Full=Protein unc-18 homolog A;
DE Short=Unc-18A;
DE AltName: Full=p67;
GN Name=STXBP1; Synonyms=UNC18A;
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).
RC TISSUE=Fetal brain;
RX PubMed=8824310;
RA Gengyo-Ando K., Kitayama H., Mukaida M., Ikawa Y.;
RT "A murine neural-specific homolog corrects cholinergic defects in
RT Caenorhabditis elegans unc-18 mutants.";
RL J. Neurosci. 16:6695-6702(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9545644; DOI=10.1006/geno.1997.5202;
RA Swanson D.A., Steel J.M., Valle D.;
RT "Identification and characterization of the human ortholog of rat
RT STXBP1, a protein implicated in vesicle trafficking and
RT neurotransmitter release.";
RL Genomics 48:373-376(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 INTERACTION WITH STX1A.
RX PubMed=12730201; DOI=10.1074/jbc.M300492200;
RA Tian J.H., Das S., Sheng Z.H.;
RT "Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated
RT protein (DAP) kinase regulates its interaction with Munc18.";
RL J. Biol. Chem. 278:26265-26274(2003).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
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 VARIANTS EIEE4 ASP-84; TYR-180; ARG-443 AND ASP-544, AND
RP CHARACTERIZATION OF VARIANTS EIEE4 ASP-84; TYR-180; ARG-443 AND
RP ASP-544.
RX PubMed=18469812; DOI=10.1038/ng.150;
RA Saitsu H., Kato M., Mizuguchi T., Hamada K., Osaka H., Tohyama J.,
RA Uruno K., Kumada S., Nishiyama K., Nishimura A., Okada I.,
RA Yoshimura Y., Hirai S., Kumada T., Hayasaka K., Fukuda A., Ogata K.,
RA Matsumoto N.;
RT "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early
RT infantile epileptic encephalopathy.";
RL Nat. Genet. 40:782-788(2008).
CC -!- FUNCTION: May participate in the regulation of synaptic vesicle
CC docking and fusion, possibly through interaction with GTP-binding
CC proteins. Essential for neurotransmission and binds syntaxin, a
CC component of the synaptic vesicle fusion machinery probably in a
CC 1:1 ratio. Can interact with syntaxins 1, 2, and 3 but not
CC syntaxin 4. May play a role in determining the specificity of
CC intracellular fusion reactions.
CC -!- SUBUNIT: Binds SYTL4 (By similarity). Interacts with STX1A.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=A;
CC IsoId=P61764-1, Q64320-1;
CC Sequence=Displayed;
CC Name=2; Synonyms=BE, HUNC18b;
CC IsoId=P61764-2, Q64320-2;
CC Sequence=VSP_006713;
CC -!- TISSUE SPECIFICITY: Brain and spinal cord. Highly enriched in
CC axons.
CC -!- DISEASE: Epileptic encephalopathy, early infantile, 4 (EIEE4)
CC [MIM:612164]: A severe form of epilepsy characterized by frequent
CC tonic seizures or spasms beginning in infancy with a specific EEG
CC finding of suppression-burst patterns, characterized by high-
CC voltage bursts alternating with almost flat suppression phases.
CC Affected individuals have neonatal or infantile onset of seizures,
CC profound mental retardation, and MRI evidence of brain
CC hypomyelination. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the STXBP/unc-18/SEC1 family.
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DR EMBL; D63851; BAA19483.1; -; mRNA.
DR EMBL; AF004562; AAC39688.1; -; mRNA.
DR EMBL; AF004563; AAC39689.1; -; mRNA.
DR EMBL; AL162426; CAI41180.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87681.1; -; Genomic_DNA.
DR EMBL; BC015749; AAH15749.1; -; mRNA.
DR RefSeq; NP_001027392.1; NM_001032221.3.
DR RefSeq; NP_003156.1; NM_003165.3.
DR UniGene; Hs.288229; -.
DR ProteinModelPortal; P61764; -.
DR SMR; P61764; 4-592.
DR IntAct; P61764; 4.
DR MINT; MINT-125987; -.
DR STRING; 9606.ENSP00000362399; -.
DR PhosphoSite; P61764; -.
DR DMDM; 50403646; -.
DR PaxDb; P61764; -.
DR PRIDE; P61764; -.
DR DNASU; 6812; -.
DR Ensembl; ENST00000373299; ENSP00000362396; ENSG00000136854.
DR Ensembl; ENST00000373302; ENSP00000362399; ENSG00000136854.
DR GeneID; 6812; -.
DR KEGG; hsa:6812; -.
DR UCSC; uc004brl.2; human.
DR CTD; 6812; -.
DR GeneCards; GC09P130374; -.
DR HGNC; HGNC:11444; STXBP1.
DR HPA; CAB034434; -.
DR HPA; HPA008209; -.
DR HPA; HPA023483; -.
DR MIM; 602926; gene.
DR MIM; 612164; phenotype.
DR neXtProt; NX_P61764; -.
DR Orphanet; 1934; Early infantile epileptic encephalopathy.
DR PharmGKB; PA36241; -.
DR eggNOG; COG5158; -.
DR HOGENOM; HOG000232146; -.
DR HOVERGEN; HBG052710; -.
DR KO; K15292; -.
DR OMA; GVDKLCK; -.
DR OrthoDB; EOG78PV8M; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; STXBP1; human.
DR GeneWiki; STXBP1; -.
DR GenomeRNAi; 6812; -.
DR NextBio; 26583; -.
DR PRO; PR:P61764; -.
DR ArrayExpress; P61764; -.
DR Bgee; P61764; -.
DR CleanEx; HS_STXBP1; -.
DR Genevestigator; P61764; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0031091; C:platelet alpha granule; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0017075; F:syntaxin-1 binding; ISS:UniProtKB.
DR GO; GO:0007412; P:axon target recognition; ISS:UniProtKB.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0014047; P:glutamate secretion; TAS:Reactome.
DR GO; GO:0060292; P:long term synaptic depression; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0032229; P:negative regulation of synaptic transmission, GABAergic; ISS:UniProtKB.
DR GO; GO:0007274; P:neuromuscular synaptic transmission; IEA:Ensembl.
DR GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome.
DR GO; GO:0070527; P:platelet aggregation; IMP:UniProtKB.
DR GO; GO:0002576; P:platelet degranulation; IMP:UniProtKB.
DR GO; GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IEA:Ensembl.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0010807; P:regulation of synaptic vesicle priming; ISS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0016188; P:synaptic vesicle maturation; ISS:UniProtKB.
DR GO; GO:0006904; P:vesicle docking involved in exocytosis; IEA:Ensembl.
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 Alternative splicing; Complete proteome; Cytoplasm; Disease mutation;
KW Epilepsy; Membrane; Mental retardation; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 594 Syntaxin-binding protein 1.
FT /FTId=PRO_0000206277.
FT VAR_SEQ 576 594 QKLLDTLKKLNKTDEEISS -> TKFLMDLRHPDFRESSRV
FT SFEDQAPTME (in isoform 2).
FT /FTId=VSP_006713.
FT VARIANT 84 84 V -> D (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046205.
FT VARIANT 180 180 C -> Y (in EIEE4; reduced
FT thermostability; decreased binding to
FT STX1A).
FT /FTId=VAR_046206.
FT VARIANT 443 443 M -> R (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046207.
FT VARIANT 544 544 G -> D (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046208.
SQ SEQUENCE 594 AA; 67569 MW; 2DD0715F875CE0F3 CRC64;
MAPIGLKAVV GEKIMHDVIK KVKKKGEWKV LVVDQLSMRM LSSCCKMTDI MTEGITIVED
INKRREPLPS LEAVYLITPS EKSVHSLISD FKDPPTAKYR AAHVFFTDSC PDALFNELVK
SRAAKVIKTL TEINIAFLPY ESQVYSLDSA DSFQSFYSPH KAQMKNPILE RLAEQIATLC
ATLKEYPAVR YRGEYKDNAL LAQLIQDKLD AYKADDPTMG EGPDKARSQL LILDRGFDPS
SPVLHELTFQ AMSYDLLPIE NDVYKYETSG IGEARVKEVL LDEDDDLWIA LRHKHIAEVS
QEVTRSLKDF SSSKRMNTGE KTTMRDLSQM LKKMPQYQKE LSKYSTHLHL AEDCMKHYQG
TVDKLCRVEQ DLAMGTDAEG EKIKDPMRAI VPILLDANVS TYDKIRIILL YIFLKNGITE
ENLNKLIQHA QIPPEDSEII TNMAHLGVPI VTDSTLRRRS KPERKERISE QTYQLSRWTP
IIKDIMEDTI EDKLDTKHYP YISTRSSASF STTAVSARYG HWHKNKAPGE YRSGPRLIIF
ILGGVSLNEM RCAYEVTQAN GKWEVLIGST HILTPQKLLD TLKKLNKTDE EISS
//
ID STXB1_HUMAN Reviewed; 594 AA.
AC P61764; B1AM97; Q28208; Q62759; Q64320; Q96TG8;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 07-JUN-2004, sequence version 1.
DT 22-JAN-2014, entry version 100.
DE RecName: Full=Syntaxin-binding protein 1;
DE AltName: Full=MUNC18-1;
DE AltName: Full=N-Sec1;
DE AltName: Full=Protein unc-18 homolog 1;
DE Short=Unc18-1;
DE AltName: Full=Protein unc-18 homolog A;
DE Short=Unc-18A;
DE AltName: Full=p67;
GN Name=STXBP1; Synonyms=UNC18A;
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).
RC TISSUE=Fetal brain;
RX PubMed=8824310;
RA Gengyo-Ando K., Kitayama H., Mukaida M., Ikawa Y.;
RT "A murine neural-specific homolog corrects cholinergic defects in
RT Caenorhabditis elegans unc-18 mutants.";
RL J. Neurosci. 16:6695-6702(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RX PubMed=9545644; DOI=10.1006/geno.1997.5202;
RA Swanson D.A., Steel J.M., Valle D.;
RT "Identification and characterization of the human ortholog of rat
RT STXBP1, a protein implicated in vesicle trafficking and
RT neurotransmitter release.";
RL Genomics 48:373-376(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Skin;
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 INTERACTION WITH STX1A.
RX PubMed=12730201; DOI=10.1074/jbc.M300492200;
RA Tian J.H., Das S., Sheng Z.H.;
RT "Ca2+-dependent phosphorylation of syntaxin-1A by the death-associated
RT protein (DAP) kinase regulates its interaction with Munc18.";
RL J. Biol. Chem. 278:26265-26274(2003).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
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 VARIANTS EIEE4 ASP-84; TYR-180; ARG-443 AND ASP-544, AND
RP CHARACTERIZATION OF VARIANTS EIEE4 ASP-84; TYR-180; ARG-443 AND
RP ASP-544.
RX PubMed=18469812; DOI=10.1038/ng.150;
RA Saitsu H., Kato M., Mizuguchi T., Hamada K., Osaka H., Tohyama J.,
RA Uruno K., Kumada S., Nishiyama K., Nishimura A., Okada I.,
RA Yoshimura Y., Hirai S., Kumada T., Hayasaka K., Fukuda A., Ogata K.,
RA Matsumoto N.;
RT "De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early
RT infantile epileptic encephalopathy.";
RL Nat. Genet. 40:782-788(2008).
CC -!- FUNCTION: May participate in the regulation of synaptic vesicle
CC docking and fusion, possibly through interaction with GTP-binding
CC proteins. Essential for neurotransmission and binds syntaxin, a
CC component of the synaptic vesicle fusion machinery probably in a
CC 1:1 ratio. Can interact with syntaxins 1, 2, and 3 but not
CC syntaxin 4. May play a role in determining the specificity of
CC intracellular fusion reactions.
CC -!- SUBUNIT: Binds SYTL4 (By similarity). Interacts with STX1A.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane
CC protein.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=A;
CC IsoId=P61764-1, Q64320-1;
CC Sequence=Displayed;
CC Name=2; Synonyms=BE, HUNC18b;
CC IsoId=P61764-2, Q64320-2;
CC Sequence=VSP_006713;
CC -!- TISSUE SPECIFICITY: Brain and spinal cord. Highly enriched in
CC axons.
CC -!- DISEASE: Epileptic encephalopathy, early infantile, 4 (EIEE4)
CC [MIM:612164]: A severe form of epilepsy characterized by frequent
CC tonic seizures or spasms beginning in infancy with a specific EEG
CC finding of suppression-burst patterns, characterized by high-
CC voltage bursts alternating with almost flat suppression phases.
CC Affected individuals have neonatal or infantile onset of seizures,
CC profound mental retardation, and MRI evidence of brain
CC hypomyelination. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the STXBP/unc-18/SEC1 family.
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DR EMBL; D63851; BAA19483.1; -; mRNA.
DR EMBL; AF004562; AAC39688.1; -; mRNA.
DR EMBL; AF004563; AAC39689.1; -; mRNA.
DR EMBL; AL162426; CAI41180.1; -; Genomic_DNA.
DR EMBL; CH471090; EAW87681.1; -; Genomic_DNA.
DR EMBL; BC015749; AAH15749.1; -; mRNA.
DR RefSeq; NP_001027392.1; NM_001032221.3.
DR RefSeq; NP_003156.1; NM_003165.3.
DR UniGene; Hs.288229; -.
DR ProteinModelPortal; P61764; -.
DR SMR; P61764; 4-592.
DR IntAct; P61764; 4.
DR MINT; MINT-125987; -.
DR STRING; 9606.ENSP00000362399; -.
DR PhosphoSite; P61764; -.
DR DMDM; 50403646; -.
DR PaxDb; P61764; -.
DR PRIDE; P61764; -.
DR DNASU; 6812; -.
DR Ensembl; ENST00000373299; ENSP00000362396; ENSG00000136854.
DR Ensembl; ENST00000373302; ENSP00000362399; ENSG00000136854.
DR GeneID; 6812; -.
DR KEGG; hsa:6812; -.
DR UCSC; uc004brl.2; human.
DR CTD; 6812; -.
DR GeneCards; GC09P130374; -.
DR HGNC; HGNC:11444; STXBP1.
DR HPA; CAB034434; -.
DR HPA; HPA008209; -.
DR HPA; HPA023483; -.
DR MIM; 602926; gene.
DR MIM; 612164; phenotype.
DR neXtProt; NX_P61764; -.
DR Orphanet; 1934; Early infantile epileptic encephalopathy.
DR PharmGKB; PA36241; -.
DR eggNOG; COG5158; -.
DR HOGENOM; HOG000232146; -.
DR HOVERGEN; HBG052710; -.
DR KO; K15292; -.
DR OMA; GVDKLCK; -.
DR OrthoDB; EOG78PV8M; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; STXBP1; human.
DR GeneWiki; STXBP1; -.
DR GenomeRNAi; 6812; -.
DR NextBio; 26583; -.
DR PRO; PR:P61764; -.
DR ArrayExpress; P61764; -.
DR Bgee; P61764; -.
DR CleanEx; HS_STXBP1; -.
DR Genevestigator; P61764; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0031091; C:platelet alpha granule; IDA:UniProtKB.
DR GO; GO:0043234; C:protein complex; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISS:UniProtKB.
DR GO; GO:0017075; F:syntaxin-1 binding; ISS:UniProtKB.
DR GO; GO:0007412; P:axon target recognition; ISS:UniProtKB.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0014047; P:glutamate secretion; TAS:Reactome.
DR GO; GO:0060292; P:long term synaptic depression; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0032229; P:negative regulation of synaptic transmission, GABAergic; ISS:UniProtKB.
DR GO; GO:0007274; P:neuromuscular synaptic transmission; IEA:Ensembl.
DR GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome.
DR GO; GO:0070527; P:platelet aggregation; IMP:UniProtKB.
DR GO; GO:0002576; P:platelet degranulation; IMP:UniProtKB.
DR GO; GO:0045956; P:positive regulation of calcium ion-dependent exocytosis; IEA:Ensembl.
DR GO; GO:0050821; P:protein stabilization; IEA:Ensembl.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0050796; P:regulation of insulin secretion; TAS:Reactome.
DR GO; GO:0010807; P:regulation of synaptic vesicle priming; ISS:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0016188; P:synaptic vesicle maturation; ISS:UniProtKB.
DR GO; GO:0006904; P:vesicle docking involved in exocytosis; IEA:Ensembl.
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 Alternative splicing; Complete proteome; Cytoplasm; Disease mutation;
KW Epilepsy; Membrane; Mental retardation; Protein transport;
KW Reference proteome; Transport.
FT CHAIN 1 594 Syntaxin-binding protein 1.
FT /FTId=PRO_0000206277.
FT VAR_SEQ 576 594 QKLLDTLKKLNKTDEEISS -> TKFLMDLRHPDFRESSRV
FT SFEDQAPTME (in isoform 2).
FT /FTId=VSP_006713.
FT VARIANT 84 84 V -> D (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046205.
FT VARIANT 180 180 C -> Y (in EIEE4; reduced
FT thermostability; decreased binding to
FT STX1A).
FT /FTId=VAR_046206.
FT VARIANT 443 443 M -> R (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046207.
FT VARIANT 544 544 G -> D (in EIEE4; may alter protein
FT structure).
FT /FTId=VAR_046208.
SQ SEQUENCE 594 AA; 67569 MW; 2DD0715F875CE0F3 CRC64;
MAPIGLKAVV GEKIMHDVIK KVKKKGEWKV LVVDQLSMRM LSSCCKMTDI MTEGITIVED
INKRREPLPS LEAVYLITPS EKSVHSLISD FKDPPTAKYR AAHVFFTDSC PDALFNELVK
SRAAKVIKTL TEINIAFLPY ESQVYSLDSA DSFQSFYSPH KAQMKNPILE RLAEQIATLC
ATLKEYPAVR YRGEYKDNAL LAQLIQDKLD AYKADDPTMG EGPDKARSQL LILDRGFDPS
SPVLHELTFQ AMSYDLLPIE NDVYKYETSG IGEARVKEVL LDEDDDLWIA LRHKHIAEVS
QEVTRSLKDF SSSKRMNTGE KTTMRDLSQM LKKMPQYQKE LSKYSTHLHL AEDCMKHYQG
TVDKLCRVEQ DLAMGTDAEG EKIKDPMRAI VPILLDANVS TYDKIRIILL YIFLKNGITE
ENLNKLIQHA QIPPEDSEII TNMAHLGVPI VTDSTLRRRS KPERKERISE QTYQLSRWTP
IIKDIMEDTI EDKLDTKHYP YISTRSSASF STTAVSARYG HWHKNKAPGE YRSGPRLIIF
ILGGVSLNEM RCAYEVTQAN GKWEVLIGST HILTPQKLLD TLKKLNKTDE EISS
//
MIM
602926
*RECORD*
*FIELD* NO
602926
*FIELD* TI
*602926 SYNTAXIN-BINDING PROTEIN 1; STXBP1
;;UNC18, C. ELEGANS, HOMOLOG OF, 1;;
MUNC18-1
read more*FIELD* TX
CLONING
Within the secretory pathway, proteins and other cargo are transferred
from one compartment to another by vesicular traffic. Transport vesicles
bud from donor membranes and dock to specific acceptor compartments. The
S. cerevisiae protein Sec1 participates in the constitutive secretory
pathway between the Golgi apparatus and the plasma membrane. Pevsner et
al. (1994) identified rat Stxbp1, which they called n-Sec1. The
predicted 68-kD n-Sec1 protein shares 27% identity with S. cerevisiae
Sec1 and 59% identity with C. elegans Unc18. RNA blot analysis showed
that n-Sec1 mRNA expression was neural-specific.
Since Unc18 mutation leads to severe paralysis and presynaptic
acetylcholine accumulation, Unc18 has been implicated in
neurotransmitter release. Gengyo-Ando et al. (1996) identified cDNAs
encoding 2 mouse Unc18 homologs, a neural-specific protein called
Munc18-1 and a ubiquitous protein called Munc18-3. They used the murine
cDNAs to isolate human Munc18-1 cDNAs from a fetal brain cDNA library.
The sequences of the predicted 594-amino acid mouse and human Munc18-1
proteins are identical. Gengyo-Ando et al. (1996) found that Munc18-1
complemented the locomotion and cholinergic defects in Unc18 mutant
animals.
By Northern blot analysis of human tissues, Swanson et al. (1998)
determined that STXBP1 is expressed as a 4-kb transcript in various
tissues. The highest levels of expression were observed in retina and
cerebellum. RT-PCR analysis revealed an additional, alternatively
spliced form of STXBP1 in retina and cerebellum. This mRNA contains an
additional exon and encodes a predicted 603-amino acid protein. Two
alternatively spliced forms of STXBP1 are also found in rat, and the
predicted proteins are identical to their human counterparts.
GENE STRUCTURE
Hamdan et al. (2009) stated that the STXBP1 gene contains 20 exons and
that alternative splicing results in 2 isoforms with and without exon
19.
MAPPING
By fluorescence in situ hybridization, Swanson et al. (1998) mapped the
STXBP1 gene to chromosome 9q34.1.
GENE FUNCTION
Pevsner et al. (1994) found that rat n-Sec1 is a neural-specific,
syntaxin (see 186590)-binding protein that may participate in the
regulation of synaptic vesicle docking and fusion.
Yang et al. (2000) identified high titer autoantibodies against Munc18
in the serum and CSF of a single patient with Rasmussen encephalitis, a
rare disorder characterized by progressive degeneration of a single
cerebral hemisphere and intractable seizures. The patient had previously
been reported by Rogers et al. (1994) who identified autoantibodies
against GLUR3 (GRIA3; 305915) in serum and CSF. Weak immunoreactivity to
Munc18 was found in 3 of 14 additional patients with Rasmussen
encephalitis, but often only on prolonged exposure or multiple
experiments. As Munc18 is a cytosolic protein, Yang et al. (2000)
hypothesized that humoral attack on GluR3 would first damage neurons,
thus exposing Munc18 and leading to expanded immune attack. Both
proteins are involved in synaptic transmission; immune attack on these
proteins may have acted synergistically to produce a severe neurologic
phenotype.
In adrenal chromaffin cells, Fisher et al. (2001) expressed a Munc18
mutant with reduced affinity for syntaxin, which specifically modified
the kinetics of single-granule exocytotic release events, consistent
with an acceleration of fusion pore expansion. This observation
demonstrated that Munc18 functions in a late stage in the intracellular
membrane fusion process, where its dissociation from syntaxin determines
the kinetics of postfusion events.
In a study of synaptic vesicle exocytosis in C. elegans unc18 mutants,
Weimer et al. (2003) found a reduction in docked vesicles at the plasma
membrane active zone, suggesting that unc18 functions, either directly
or indirectly, as a facilitator of vesicle docking.
Toonen et al. (2006) found that synapses from Munc18-1 +/- mice
displayed increased depression during intense stimulation at
glutamatergic, GABAergic, and neuromuscular synapses. This depression
was due to a smaller readily releasable pool (RRP) of synaptic vesicles.
Conversely, overexpression of Munc18-1 made these synapses recover
faster, which was due to a larger RRP and enhanced activity-dependent
RRP replenishment.
SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein
receptor) proteins comprise the core fusion machinery in which cognate
vesicle-associated (v-) and target membrane-associated (t-) SNAREs
assemble into SNAREpins to bring 2 membranes into close apposition and
fuse. Using a reconstituted lipid bilayer system with mammalian SNARE
components, Shen et al. (2007) showed that rat Munc18-1 accelerated the
fusion reaction through direct contact with both t- and v-SNAREs.
During synaptic vesicle fusion, the SNARE protein syntaxin-1 (186590)
exhibits 2 conformations that both bind to Munc18-1: a 'closed'
conformation outside the SNARE complex and an 'open' conformation in the
SNARE complex. Gerber et al. (2008) generated knockin/knockout mice that
expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but
succumbed to generalized seizures at 2 to 3 months of age. Binding of
Munc18-1 to syntaxin-1B was impaired in syntaxin-1B(Open) synapses, and
the size of the readily releasable vesicle pool was decreased; however,
the rate of synaptic vesicle fusion was dramatically enhanced. Thus,
Gerber et al. (2008) concluded that the closed conformation of
syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction,
which is then mediated by SNARE complex/Munc18-1 assemblies.
Wierda et al. (2007) stated that MUNC18-1 is essential for presynaptic
vesicle release and is rapidly phosphorylated by protein kinase C (PKC:
176960) upon depolarization. They found that diacylglycerol (DAG)- and
phorbol ester-induced potentiation of excitatory postsynaptic currents
in mouse neurons depended on both direct activation of Munc13 (UNC13B;
605836) and PKC-mediated phosphorylation of Munc18-1. Wierda et al.
(2007) hypothesized that the 2 pathways may operate separately during
different steps in the synaptic vesicle cycle or may converge and
cooperate at a single step in the cycle.
Ma et al. (2013) found that Munc18-1 could displace SNAP25 (600322) from
syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with
synaptobrevin (see 185880) liposomes required Munc13, in addition to
SNAP25 and synaptotagmin-1 (185605)-Ca(2+). Moreover, when starting with
syntaxin-1-SNAP25 liposomes, NSF (N-ethylmaleimide-sensitive
factor)-alpha-SNAP disassembled the syntaxin-1-SNAP25 heterodimers and
abrogated fusion, which then required Munc18-1 and Munc13. Ma et al.
(2013) proposed that fusion does not proceed through syntaxin-1-SNAP25
heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1
and Munc13 then orchestrate membrane fusion together with the SNAREs and
synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner.
MOLECULAR GENETICS
In a Japanese girl with early infantile epileptic encephalopathy-4
(EIEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous
microdeletion at chromosome 9q33.3-q34.11 that included the STXBP1 gene.
Screening of this gene in 13 additional unrelated patients with a
similar phenotype identified 4 different heterozygous mutations in the
STXBP1 gene (602926.0001-602926.0004) in 4 patients. All mutations
occurred in the hydrophobic core of the protein and were predicted to
result in destabilization and disruption of protein structure. In vitro
studies of the mutant proteins suggested a tendency for aggregation. The
phenotype included infantile onset of tonic-clonic or tonic seizures,
suppression-burst pattern on EEG, profound mental retardation, and MRI
evidence of hypomyelination. Other features included hypsarrhythmia and
spastic di- or quadriplegia. Saitsu et al. (2008) concluded that
haploinsufficiency of STXBP1 results in impaired synaptic vesicle
release and the phenotype of EIEE.
In 2 unrelated French Canadian patients with severe mental retardation
and epilepsy, Hamdan et al. (2009) identified respective de novo
heterozygous truncating mutations in the STXBP1 gene (602926.0005 and
602926.0006). The patients were ascertained from a larger group of 95
patients with idiopathic mental retardation.
ANIMAL MODEL
Verhage et al. (2000) abolished Munc18-1 in mice by homologous
recombination. This resulted in a completely paralyzed organism. Null
mutant embryos were alive until birth but died immediately after birth,
probably because they could not breathe. Despite the general, complete,
and permanent loss of synaptic transmission in knockout mice, their
brains were assembled correctly. Neuronal proliferation, migration, and
differentiation into specific brain areas were unaffected. By embryonic
day 12, brains from null mutant and control littermates were
morphologically indistinguishable. At birth, late-forming brain areas
such as the neocortex appeared identical in null mutant and control
littermates. After initial brain assembly, extensive cell death of
mature neurons was observed in null mutants, occurring first in lower
brain areas that mature and form synapses relatively early. The
degeneration in the mutant brains exhibited all characteristics of
apoptosis. Ablation of Munc18-1 renders the brain synaptically silent,
identifying Munc18-1 as the currently most upstream essential protein in
neurotransmitter release. Verhage et al. (2000) concluded that synaptic
connectivity does not depend on neurotransmitter secretion, but its
maintenance does. Neurotransmitter secretion probably functions to
validate already established synaptic connections.
*FIELD* AV
.0001
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, GLY544ASP
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 1631G-A
transition in the STXBP1 gene, resulting in a gly544-to-asp (G544D)
substitution. He developed seizures by age 10 days with a
suppression-burst pattern on EEG. He had profound mental retardation and
spastic paraplegia at age 37 years. The mutation was not found in 500
control chromosomes.
.0002
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, CYS180TYR
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 539G-A
transition in the STXBP1 gene, resulting in a cys180-to-tyr (C180Y)
substitution. He had infantile onset of tonic and myoclonic seizures
with suppression-burst pattern and hypsarrhythmia, delayed brain
myelination, and spastic quadriplegia. In vitro studies showed that the
mutant protein had impaired structural stability, lower thermostability,
and decreased binding to several functional synaptic proteins. Saitsu et
al. (2008) concluded that this patient had impaired release of synaptic
vesicles.
.0003
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, MET443ARG
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 1328T-G
transversion in the STXBP1 gene, resulting in a met443-to-arg (M443R)
substitution. She developed tonic seizures at age 6 weeks and later had
profoundly delayed development. Brain MRI showed delayed myelination.
.0004
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, VAL84ASP
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 251T-A
transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D)
substitution. He developed tonic seizures at age 2 months with
suppression-burst pattern and hypsarrhythmia, and later showed profound
mental retardation.
.0005
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, ARG388TER
In a French Canadian patient with EIEE4 (612164), Hamdan et al. (2009)
identified a de novo heterozygous 1162C-T transition in exon 14 of the
STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution,
predicted to truncate the domain-3 region, which together with domain-1
provides a binding surface for syntaxin-1 (186590). The patient had
severe mental retardation, with hypotonia, abnormal gait, tremor, and
seizures.
.0006
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, IVS3DS, G-A, +1
In a French Canadian patient with EIEE4 (612164), Hamdan et al. (2009)
identified a de novo heterozygous G-to-A transition in intron 3 of the
STXBP1 gene, resulting in the creation of a stop codon downstream of
exon 3. The mutation truncated the domain-1 region, which is implicated
in binding to syntaxin-1. The patient had severe mental retardation,
with hypotonia, abnormal gait, tremor, and seizures.
.0007
VARIANT OF UNKNOWN SIGNIFICANCE
STXBP1, 1-BP DEL, 1206T
This variant is classified as a variant of unknown significance because
its contribution to nonsyndromic mental retardation has not been
confirmed.
By targeted sequencing of the STXBP1 gene in 50 patients with
nonsyndromic mental retardation, Hamdan et al. (2011) identified 1
patient of French Canadian origin with a de novo heterozygous 1-bp
deletion (1206delT) in domain 3 of the gene, resulting in a frameshift
and premature termination (Y402X). The variation was not found in 190
French Canadian controls. The patient was a 21-year-old man who showed
global developmental delay and severe mental retardation with limited
speech. He had no history of seizures, but did have diffuse tremor of
the extremities and an abnormal gait. EEG showed intermittent slow
dysfunction in the temporal area; brain CT was normal. Hamdan et al.
(2011) suggested that this variant may be pathogenic because truncation
of the C. elegans ortholog downstream of Y402 results in defects in
synaptic vesicle docking (Weimer et al., 2003) and Stxbp1
haploinsufficiency causes impaired neurotransmission in mice (Toonen et
al., 2006).
*FIELD* RF
1. Fisher, R. J.; Pevsner, J.; Burgoyne, R. D.: Control of fusion
pore dynamics during exocytosis by Munc18. Science 291: 875-878,
2001.
2. Gengyo-Ando, K.; Kitayama, H.; Mukaida, M.; Ikawa, Y.: A murine
neural-specific homolog corrects cholinergic defects in Caenorhabditis
elegans unc-18 mutants. J. Neurosci. 16: 6695-6702, 1996.
3. Gerber, S. H.; Rah, J.-C.; Min, S.-W.; Liu, X.; de Wit, H.; Dulubova,
I.; Meyer, A. C.; Rizo, J.; Arancillo, M.; Hammer, R. E.; Verhage,
M.; Rosenmund, C.; Sudhof, T. C.: Conformational switch of syntaxin-1
controls synaptic vesicle fusion. Science 321: 1507-1510, 2008.
4. Hamdan, F. F.; Gauthier, J.; Dobrzeniecka, S.; Lortie, A.; Mottron,
L.; Vanasse, M.; D'Anjou, G.; Lacaille, J. C.; Rouleau, G. A.; Michaud,
J. L.: Intellectual disability without epilepsy associated with STXBP1
disruption. Europ. J. Hum. Genet. 19: 607-609, 2011.
5. Hamdan, F. F.; Piton, A.; Gauthier, J.; Lortie, A.; Dubeau, F.;
Dobrzeniecka, S.; Spiegelman, D.; Noreau, A.; Pellerin, S.; Cote,
M.; Henrion, E.; Fombonne, E.; Mottron, L.; Marineau, C.; Drapeau,
P.; Lafreniere, R. G.; Lacaille, J. C.; Rouleau, G. A.; Michaud, J.
L.: De novo STXBP1 mutations in mental retardation and nonsyndromic
epilepsy. Ann. Neurol. 65: 748-753, 2009.
6. Ma, C.; Su, L.; Seven, A. B.; Xu, Y.; Rizo, J.: Reconstitution
of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339:
421-425, 2013.
7. Pevsner, J.; Hsu, S.-C.; Scheller, R. H.: n-Sec1: a neural-specific
syntaxin-binding protein. Proc. Nat. Acad. Sci. 91: 1445-1449, 1994.
8. Rogers, S. W.; Andrews, P. I.; Gahring, L. C.; Whisenand, T.; Cauley,
K.; Crain, B.; Hughes, T. E.; Heinemann, S. F.; McNamara, J. O.:
Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265:
648-651, 1994.
9. Saitsu, H.; Kato, M.; Mizuguchi, T.; Hamada, K.; Osaka, H.; Tohyama,
J.; Uruno, K.; Kumada, S.; Nishiyama, K.; Nishimura, A.; Okada, I.;
Yoshimura, Y.; Hirai, S.; Kumada, T.; Hayasaka, K.; Fukuda, A.; Ogata,
K.; Matsumoto, N.: De novo mutations in the gene encoding STXBP1
(MUNC18-1) cause early infantile epileptic encephalopathy. Nature
Genet. 40: 782-788, 2008.
10. Shen, J.; Tareste, D. C.; Paumet, F.; Rothman, J. E.; Melia, T.
J.: Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell 128:
183-195, 2007.
11. Swanson, D. A.; Steel, J. M.; Valle, D.: Identification and characterization
of the human ortholog of rat STXBP1, a protein implicated in vesicle
trafficking and neurotransmitter release. Genomics 48: 373-376,
1998.
12. Toonen, R. F. G.; Wierda, K.; Sons, M. S.; de Wit, H.; Cornelisse,
L. N.; Brussaard, A.; Plomp, J. J.; Verhage, M.: Munc18-1 expression
levels control synapse recovery by regulating readily releasable pool
size. Proc. Nat. Acad. Sci. 103: 18332-18337, 2006.
13. Verhage, M.; Mala, A. S.; Plomp, J. J.; Brussaard, A. B.; Heeroma,
J. H.; Vermeer, H.; Toonen, R. F.; Hammer, R. E.; van den Berg, T.
K.; Missler, M.; Geuze, H. J.; Sudhof, T. C.: Synaptic assembly of
the brain in the absence of neurotransmitter secretion. Science 287:
864-869, 2000.
14. Weimer, R. M.; Richmond, J. E.; Davis, W. S.; Hadwiger, G.; Nonet,
M. L.; Jorgensen, E. M.: Defects in synaptic vesicle docking in unc-18
mutants. Nature Neurosci. 6: 1023-1030, 2003.
15. Wierda, K. D. B.; Toonen, R. F. G.; de Wit, H.; Brussaard, A.
B.; Verhage, M.: Interdependence of PKC-dependent and PKC-independent
pathways for presynaptic plasticity. Neuron 54: 275-290, 2007.
16. Yang, R.; Puranam, R. S.; Butler, L. S.; Qian, W.-H.; He, X.-P.;
Moyer, M. B.; Blackburn, K.; Andrews, P. I.; McNamara, J. O.: Autoimmunity
to Munc-18 in Rasmussen's encephalitis. Neuron 28: 375-383, 2000.
*FIELD* CN
Ada Hamosh - updated: 2/21/2013
Cassandra L. Kniffin - updated: 1/2/2013
Patricia A. Hartz - updated: 2/11/2011
Cassandra L. Kniffin - updated: 11/5/2009
Ada Hamosh - updated: 9/29/2008
Cassandra L. Kniffin - updated: 7/10/2008
Patricia A. Hartz - updated: 1/4/2008
Patricia A. Hartz - updated: 2/8/2007
Cassandra L. Kniffin - updated: 8/26/2005
Cassandra L. Kniffin - updated: 9/12/2003
Ada Hamosh - updated: 2/5/2001
Ada Hamosh - updated: 2/2/2000
*FIELD* CD
Rebekah S. Rasooly: 8/4/1998
*FIELD* ED
carol: 09/26/2013
alopez: 2/25/2013
terry: 2/21/2013
carol: 1/10/2013
ckniffin: 1/2/2013
mgross: 2/16/2011
terry: 2/11/2011
wwang: 11/18/2009
ckniffin: 11/5/2009
alopez: 9/30/2008
terry: 9/29/2008
alopez: 7/18/2008
ckniffin: 7/10/2008
mgross: 1/16/2008
terry: 1/4/2008
alopez: 2/8/2007
wwang: 9/6/2005
ckniffin: 8/26/2005
alopez: 10/16/2003
carol: 9/16/2003
ckniffin: 9/12/2003
alopez: 2/7/2001
terry: 2/5/2001
alopez: 2/3/2000
terry: 2/2/2000
mgross: 3/8/1999
psherman: 1/21/1999
alopez: 8/4/1998
*RECORD*
*FIELD* NO
602926
*FIELD* TI
*602926 SYNTAXIN-BINDING PROTEIN 1; STXBP1
;;UNC18, C. ELEGANS, HOMOLOG OF, 1;;
MUNC18-1
read more*FIELD* TX
CLONING
Within the secretory pathway, proteins and other cargo are transferred
from one compartment to another by vesicular traffic. Transport vesicles
bud from donor membranes and dock to specific acceptor compartments. The
S. cerevisiae protein Sec1 participates in the constitutive secretory
pathway between the Golgi apparatus and the plasma membrane. Pevsner et
al. (1994) identified rat Stxbp1, which they called n-Sec1. The
predicted 68-kD n-Sec1 protein shares 27% identity with S. cerevisiae
Sec1 and 59% identity with C. elegans Unc18. RNA blot analysis showed
that n-Sec1 mRNA expression was neural-specific.
Since Unc18 mutation leads to severe paralysis and presynaptic
acetylcholine accumulation, Unc18 has been implicated in
neurotransmitter release. Gengyo-Ando et al. (1996) identified cDNAs
encoding 2 mouse Unc18 homologs, a neural-specific protein called
Munc18-1 and a ubiquitous protein called Munc18-3. They used the murine
cDNAs to isolate human Munc18-1 cDNAs from a fetal brain cDNA library.
The sequences of the predicted 594-amino acid mouse and human Munc18-1
proteins are identical. Gengyo-Ando et al. (1996) found that Munc18-1
complemented the locomotion and cholinergic defects in Unc18 mutant
animals.
By Northern blot analysis of human tissues, Swanson et al. (1998)
determined that STXBP1 is expressed as a 4-kb transcript in various
tissues. The highest levels of expression were observed in retina and
cerebellum. RT-PCR analysis revealed an additional, alternatively
spliced form of STXBP1 in retina and cerebellum. This mRNA contains an
additional exon and encodes a predicted 603-amino acid protein. Two
alternatively spliced forms of STXBP1 are also found in rat, and the
predicted proteins are identical to their human counterparts.
GENE STRUCTURE
Hamdan et al. (2009) stated that the STXBP1 gene contains 20 exons and
that alternative splicing results in 2 isoforms with and without exon
19.
MAPPING
By fluorescence in situ hybridization, Swanson et al. (1998) mapped the
STXBP1 gene to chromosome 9q34.1.
GENE FUNCTION
Pevsner et al. (1994) found that rat n-Sec1 is a neural-specific,
syntaxin (see 186590)-binding protein that may participate in the
regulation of synaptic vesicle docking and fusion.
Yang et al. (2000) identified high titer autoantibodies against Munc18
in the serum and CSF of a single patient with Rasmussen encephalitis, a
rare disorder characterized by progressive degeneration of a single
cerebral hemisphere and intractable seizures. The patient had previously
been reported by Rogers et al. (1994) who identified autoantibodies
against GLUR3 (GRIA3; 305915) in serum and CSF. Weak immunoreactivity to
Munc18 was found in 3 of 14 additional patients with Rasmussen
encephalitis, but often only on prolonged exposure or multiple
experiments. As Munc18 is a cytosolic protein, Yang et al. (2000)
hypothesized that humoral attack on GluR3 would first damage neurons,
thus exposing Munc18 and leading to expanded immune attack. Both
proteins are involved in synaptic transmission; immune attack on these
proteins may have acted synergistically to produce a severe neurologic
phenotype.
In adrenal chromaffin cells, Fisher et al. (2001) expressed a Munc18
mutant with reduced affinity for syntaxin, which specifically modified
the kinetics of single-granule exocytotic release events, consistent
with an acceleration of fusion pore expansion. This observation
demonstrated that Munc18 functions in a late stage in the intracellular
membrane fusion process, where its dissociation from syntaxin determines
the kinetics of postfusion events.
In a study of synaptic vesicle exocytosis in C. elegans unc18 mutants,
Weimer et al. (2003) found a reduction in docked vesicles at the plasma
membrane active zone, suggesting that unc18 functions, either directly
or indirectly, as a facilitator of vesicle docking.
Toonen et al. (2006) found that synapses from Munc18-1 +/- mice
displayed increased depression during intense stimulation at
glutamatergic, GABAergic, and neuromuscular synapses. This depression
was due to a smaller readily releasable pool (RRP) of synaptic vesicles.
Conversely, overexpression of Munc18-1 made these synapses recover
faster, which was due to a larger RRP and enhanced activity-dependent
RRP replenishment.
SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein
receptor) proteins comprise the core fusion machinery in which cognate
vesicle-associated (v-) and target membrane-associated (t-) SNAREs
assemble into SNAREpins to bring 2 membranes into close apposition and
fuse. Using a reconstituted lipid bilayer system with mammalian SNARE
components, Shen et al. (2007) showed that rat Munc18-1 accelerated the
fusion reaction through direct contact with both t- and v-SNAREs.
During synaptic vesicle fusion, the SNARE protein syntaxin-1 (186590)
exhibits 2 conformations that both bind to Munc18-1: a 'closed'
conformation outside the SNARE complex and an 'open' conformation in the
SNARE complex. Gerber et al. (2008) generated knockin/knockout mice that
expressed only open syntaxin-1B. Syntaxin-1B(Open) mice were viable but
succumbed to generalized seizures at 2 to 3 months of age. Binding of
Munc18-1 to syntaxin-1B was impaired in syntaxin-1B(Open) synapses, and
the size of the readily releasable vesicle pool was decreased; however,
the rate of synaptic vesicle fusion was dramatically enhanced. Thus,
Gerber et al. (2008) concluded that the closed conformation of
syntaxin-1 gates the initiation of the synaptic vesicle fusion reaction,
which is then mediated by SNARE complex/Munc18-1 assemblies.
Wierda et al. (2007) stated that MUNC18-1 is essential for presynaptic
vesicle release and is rapidly phosphorylated by protein kinase C (PKC:
176960) upon depolarization. They found that diacylglycerol (DAG)- and
phorbol ester-induced potentiation of excitatory postsynaptic currents
in mouse neurons depended on both direct activation of Munc13 (UNC13B;
605836) and PKC-mediated phosphorylation of Munc18-1. Wierda et al.
(2007) hypothesized that the 2 pathways may operate separately during
different steps in the synaptic vesicle cycle or may converge and
cooperate at a single step in the cycle.
Ma et al. (2013) found that Munc18-1 could displace SNAP25 (600322) from
syntaxin-1 and that fusion of syntaxin-1-Munc18-1 liposomes with
synaptobrevin (see 185880) liposomes required Munc13, in addition to
SNAP25 and synaptotagmin-1 (185605)-Ca(2+). Moreover, when starting with
syntaxin-1-SNAP25 liposomes, NSF (N-ethylmaleimide-sensitive
factor)-alpha-SNAP disassembled the syntaxin-1-SNAP25 heterodimers and
abrogated fusion, which then required Munc18-1 and Munc13. Ma et al.
(2013) proposed that fusion does not proceed through syntaxin-1-SNAP25
heterodimers but starts with the syntaxin-1-Munc18-1 complex; Munc18-1
and Munc13 then orchestrate membrane fusion together with the SNAREs and
synaptotagmin-1-Ca(2+) in an NSF- and SNAP-resistant manner.
MOLECULAR GENETICS
In a Japanese girl with early infantile epileptic encephalopathy-4
(EIEE4; 612164), Saitsu et al. (2008) identified a de novo heterozygous
microdeletion at chromosome 9q33.3-q34.11 that included the STXBP1 gene.
Screening of this gene in 13 additional unrelated patients with a
similar phenotype identified 4 different heterozygous mutations in the
STXBP1 gene (602926.0001-602926.0004) in 4 patients. All mutations
occurred in the hydrophobic core of the protein and were predicted to
result in destabilization and disruption of protein structure. In vitro
studies of the mutant proteins suggested a tendency for aggregation. The
phenotype included infantile onset of tonic-clonic or tonic seizures,
suppression-burst pattern on EEG, profound mental retardation, and MRI
evidence of hypomyelination. Other features included hypsarrhythmia and
spastic di- or quadriplegia. Saitsu et al. (2008) concluded that
haploinsufficiency of STXBP1 results in impaired synaptic vesicle
release and the phenotype of EIEE.
In 2 unrelated French Canadian patients with severe mental retardation
and epilepsy, Hamdan et al. (2009) identified respective de novo
heterozygous truncating mutations in the STXBP1 gene (602926.0005 and
602926.0006). The patients were ascertained from a larger group of 95
patients with idiopathic mental retardation.
ANIMAL MODEL
Verhage et al. (2000) abolished Munc18-1 in mice by homologous
recombination. This resulted in a completely paralyzed organism. Null
mutant embryos were alive until birth but died immediately after birth,
probably because they could not breathe. Despite the general, complete,
and permanent loss of synaptic transmission in knockout mice, their
brains were assembled correctly. Neuronal proliferation, migration, and
differentiation into specific brain areas were unaffected. By embryonic
day 12, brains from null mutant and control littermates were
morphologically indistinguishable. At birth, late-forming brain areas
such as the neocortex appeared identical in null mutant and control
littermates. After initial brain assembly, extensive cell death of
mature neurons was observed in null mutants, occurring first in lower
brain areas that mature and form synapses relatively early. The
degeneration in the mutant brains exhibited all characteristics of
apoptosis. Ablation of Munc18-1 renders the brain synaptically silent,
identifying Munc18-1 as the currently most upstream essential protein in
neurotransmitter release. Verhage et al. (2000) concluded that synaptic
connectivity does not depend on neurotransmitter secretion, but its
maintenance does. Neurotransmitter secretion probably functions to
validate already established synaptic connections.
*FIELD* AV
.0001
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, GLY544ASP
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 1631G-A
transition in the STXBP1 gene, resulting in a gly544-to-asp (G544D)
substitution. He developed seizures by age 10 days with a
suppression-burst pattern on EEG. He had profound mental retardation and
spastic paraplegia at age 37 years. The mutation was not found in 500
control chromosomes.
.0002
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, CYS180TYR
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 539G-A
transition in the STXBP1 gene, resulting in a cys180-to-tyr (C180Y)
substitution. He had infantile onset of tonic and myoclonic seizures
with suppression-burst pattern and hypsarrhythmia, delayed brain
myelination, and spastic quadriplegia. In vitro studies showed that the
mutant protein had impaired structural stability, lower thermostability,
and decreased binding to several functional synaptic proteins. Saitsu et
al. (2008) concluded that this patient had impaired release of synaptic
vesicles.
.0003
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, MET443ARG
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 1328T-G
transversion in the STXBP1 gene, resulting in a met443-to-arg (M443R)
substitution. She developed tonic seizures at age 6 weeks and later had
profoundly delayed development. Brain MRI showed delayed myelination.
.0004
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, VAL84ASP
In a Japanese patient with early infantile epileptic encephalopathy-4
(612164), Saitsu et al. (2008) identified a heterozygous 251T-A
transversion in the STXBP1 gene, resulting in a val84-to-asp (V84D)
substitution. He developed tonic seizures at age 2 months with
suppression-burst pattern and hypsarrhythmia, and later showed profound
mental retardation.
.0005
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, ARG388TER
In a French Canadian patient with EIEE4 (612164), Hamdan et al. (2009)
identified a de novo heterozygous 1162C-T transition in exon 14 of the
STXBP1 gene, resulting in an arg388-to-ter (R388X) substitution,
predicted to truncate the domain-3 region, which together with domain-1
provides a binding surface for syntaxin-1 (186590). The patient had
severe mental retardation, with hypotonia, abnormal gait, tremor, and
seizures.
.0006
EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4
STXBP1, IVS3DS, G-A, +1
In a French Canadian patient with EIEE4 (612164), Hamdan et al. (2009)
identified a de novo heterozygous G-to-A transition in intron 3 of the
STXBP1 gene, resulting in the creation of a stop codon downstream of
exon 3. The mutation truncated the domain-1 region, which is implicated
in binding to syntaxin-1. The patient had severe mental retardation,
with hypotonia, abnormal gait, tremor, and seizures.
.0007
VARIANT OF UNKNOWN SIGNIFICANCE
STXBP1, 1-BP DEL, 1206T
This variant is classified as a variant of unknown significance because
its contribution to nonsyndromic mental retardation has not been
confirmed.
By targeted sequencing of the STXBP1 gene in 50 patients with
nonsyndromic mental retardation, Hamdan et al. (2011) identified 1
patient of French Canadian origin with a de novo heterozygous 1-bp
deletion (1206delT) in domain 3 of the gene, resulting in a frameshift
and premature termination (Y402X). The variation was not found in 190
French Canadian controls. The patient was a 21-year-old man who showed
global developmental delay and severe mental retardation with limited
speech. He had no history of seizures, but did have diffuse tremor of
the extremities and an abnormal gait. EEG showed intermittent slow
dysfunction in the temporal area; brain CT was normal. Hamdan et al.
(2011) suggested that this variant may be pathogenic because truncation
of the C. elegans ortholog downstream of Y402 results in defects in
synaptic vesicle docking (Weimer et al., 2003) and Stxbp1
haploinsufficiency causes impaired neurotransmission in mice (Toonen et
al., 2006).
*FIELD* RF
1. Fisher, R. J.; Pevsner, J.; Burgoyne, R. D.: Control of fusion
pore dynamics during exocytosis by Munc18. Science 291: 875-878,
2001.
2. Gengyo-Ando, K.; Kitayama, H.; Mukaida, M.; Ikawa, Y.: A murine
neural-specific homolog corrects cholinergic defects in Caenorhabditis
elegans unc-18 mutants. J. Neurosci. 16: 6695-6702, 1996.
3. Gerber, S. H.; Rah, J.-C.; Min, S.-W.; Liu, X.; de Wit, H.; Dulubova,
I.; Meyer, A. C.; Rizo, J.; Arancillo, M.; Hammer, R. E.; Verhage,
M.; Rosenmund, C.; Sudhof, T. C.: Conformational switch of syntaxin-1
controls synaptic vesicle fusion. Science 321: 1507-1510, 2008.
4. Hamdan, F. F.; Gauthier, J.; Dobrzeniecka, S.; Lortie, A.; Mottron,
L.; Vanasse, M.; D'Anjou, G.; Lacaille, J. C.; Rouleau, G. A.; Michaud,
J. L.: Intellectual disability without epilepsy associated with STXBP1
disruption. Europ. J. Hum. Genet. 19: 607-609, 2011.
5. Hamdan, F. F.; Piton, A.; Gauthier, J.; Lortie, A.; Dubeau, F.;
Dobrzeniecka, S.; Spiegelman, D.; Noreau, A.; Pellerin, S.; Cote,
M.; Henrion, E.; Fombonne, E.; Mottron, L.; Marineau, C.; Drapeau,
P.; Lafreniere, R. G.; Lacaille, J. C.; Rouleau, G. A.; Michaud, J.
L.: De novo STXBP1 mutations in mental retardation and nonsyndromic
epilepsy. Ann. Neurol. 65: 748-753, 2009.
6. Ma, C.; Su, L.; Seven, A. B.; Xu, Y.; Rizo, J.: Reconstitution
of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science 339:
421-425, 2013.
7. Pevsner, J.; Hsu, S.-C.; Scheller, R. H.: n-Sec1: a neural-specific
syntaxin-binding protein. Proc. Nat. Acad. Sci. 91: 1445-1449, 1994.
8. Rogers, S. W.; Andrews, P. I.; Gahring, L. C.; Whisenand, T.; Cauley,
K.; Crain, B.; Hughes, T. E.; Heinemann, S. F.; McNamara, J. O.:
Autoantibodies to glutamate receptor GluR3 in Rasmussen's encephalitis. Science 265:
648-651, 1994.
9. Saitsu, H.; Kato, M.; Mizuguchi, T.; Hamada, K.; Osaka, H.; Tohyama,
J.; Uruno, K.; Kumada, S.; Nishiyama, K.; Nishimura, A.; Okada, I.;
Yoshimura, Y.; Hirai, S.; Kumada, T.; Hayasaka, K.; Fukuda, A.; Ogata,
K.; Matsumoto, N.: De novo mutations in the gene encoding STXBP1
(MUNC18-1) cause early infantile epileptic encephalopathy. Nature
Genet. 40: 782-788, 2008.
10. Shen, J.; Tareste, D. C.; Paumet, F.; Rothman, J. E.; Melia, T.
J.: Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell 128:
183-195, 2007.
11. Swanson, D. A.; Steel, J. M.; Valle, D.: Identification and characterization
of the human ortholog of rat STXBP1, a protein implicated in vesicle
trafficking and neurotransmitter release. Genomics 48: 373-376,
1998.
12. Toonen, R. F. G.; Wierda, K.; Sons, M. S.; de Wit, H.; Cornelisse,
L. N.; Brussaard, A.; Plomp, J. J.; Verhage, M.: Munc18-1 expression
levels control synapse recovery by regulating readily releasable pool
size. Proc. Nat. Acad. Sci. 103: 18332-18337, 2006.
13. Verhage, M.; Mala, A. S.; Plomp, J. J.; Brussaard, A. B.; Heeroma,
J. H.; Vermeer, H.; Toonen, R. F.; Hammer, R. E.; van den Berg, T.
K.; Missler, M.; Geuze, H. J.; Sudhof, T. C.: Synaptic assembly of
the brain in the absence of neurotransmitter secretion. Science 287:
864-869, 2000.
14. Weimer, R. M.; Richmond, J. E.; Davis, W. S.; Hadwiger, G.; Nonet,
M. L.; Jorgensen, E. M.: Defects in synaptic vesicle docking in unc-18
mutants. Nature Neurosci. 6: 1023-1030, 2003.
15. Wierda, K. D. B.; Toonen, R. F. G.; de Wit, H.; Brussaard, A.
B.; Verhage, M.: Interdependence of PKC-dependent and PKC-independent
pathways for presynaptic plasticity. Neuron 54: 275-290, 2007.
16. Yang, R.; Puranam, R. S.; Butler, L. S.; Qian, W.-H.; He, X.-P.;
Moyer, M. B.; Blackburn, K.; Andrews, P. I.; McNamara, J. O.: Autoimmunity
to Munc-18 in Rasmussen's encephalitis. Neuron 28: 375-383, 2000.
*FIELD* CN
Ada Hamosh - updated: 2/21/2013
Cassandra L. Kniffin - updated: 1/2/2013
Patricia A. Hartz - updated: 2/11/2011
Cassandra L. Kniffin - updated: 11/5/2009
Ada Hamosh - updated: 9/29/2008
Cassandra L. Kniffin - updated: 7/10/2008
Patricia A. Hartz - updated: 1/4/2008
Patricia A. Hartz - updated: 2/8/2007
Cassandra L. Kniffin - updated: 8/26/2005
Cassandra L. Kniffin - updated: 9/12/2003
Ada Hamosh - updated: 2/5/2001
Ada Hamosh - updated: 2/2/2000
*FIELD* CD
Rebekah S. Rasooly: 8/4/1998
*FIELD* ED
carol: 09/26/2013
alopez: 2/25/2013
terry: 2/21/2013
carol: 1/10/2013
ckniffin: 1/2/2013
mgross: 2/16/2011
terry: 2/11/2011
wwang: 11/18/2009
ckniffin: 11/5/2009
alopez: 9/30/2008
terry: 9/29/2008
alopez: 7/18/2008
ckniffin: 7/10/2008
mgross: 1/16/2008
terry: 1/4/2008
alopez: 2/8/2007
wwang: 9/6/2005
ckniffin: 8/26/2005
alopez: 10/16/2003
carol: 9/16/2003
ckniffin: 9/12/2003
alopez: 2/7/2001
terry: 2/5/2001
alopez: 2/3/2000
terry: 2/2/2000
mgross: 3/8/1999
psherman: 1/21/1999
alopez: 8/4/1998
MIM
612164
*RECORD*
*FIELD* NO
612164
*FIELD* TI
#612164 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4; EIEE4
*FIELD* TX
A number sign (#) is used with this entry because early infantile
read moreepileptic encephalopathy-4 (EIEE4) is caused by heterozygous mutation in
the STXBP1 gene (602926) on chromosome 9q34.1.
For a general phenotypic description and a discussion of genetic
heterogeneity of EIEE, see EIEE1 (308350).
CLINICAL FEATURES
Tohyama et al. (2008) reported a Japanese infant girl who developed
tonic seizures, tremulous arm movements, and oral automatisms at 45 days
of age. Her dizygotic twin was unaffected; the pregnancy resulted from
in vivo fertilization. The proband continued to have seizures with
increased frequency, spastic quadriplegia, and poor visual attention.
EEG showed a suppression-burst pattern and hypsarrhythmia, consistent
with EIEE. She had severely delayed psychomotor development with no
language. Brain MRI showed diffuse hypomyelination, cortical atrophy,
and a thin corpus callosum.
Saitsu et al. (2008) reported 4 Japanese patients with EIEE. All had
neonatal or infantile onset of tonic-clonic or tonic seizures,
suppression-burst pattern on EEG, profound mental retardation, and MRI
evidence of hypomyelination. Other features included hypsarrhythmia and
spastic di- or quadriplegia. Major structural brain abnormalities were
not observed.
Hamdan et al. (2009) reported 2 unrelated French Canadian patients with
EIEE4. One patient was a 27-year-old woman who first developed partial
complex seizures at age 6 weeks. The second patient was a 15-year-old
girl who first developed partial complex seizures at 2 years, 9 months
of age. Both patients had severe mental retardation, hypotonia, and
tremor. Brain scan in both patients was normal. Hamdan et al. (2009)
noted that the phenotypes of both patients were slightly different than
that reported by Saitsu et al. (2008), with later onset of seizures and
some response to antiepileptic medication. In addition, hypsarrhythmia
was never observed.
Deprez et al. (2010) identified heterozygous truncating mutations in the
STXBP1 gene in 6 (5.7%) of 106 patients with various types of
early-onset epileptic encephalopathies. Variable seizures first occurred
between 3 days and 4.5 months of life, and all patients subsequently had
severe to profound mental retardation. Three patients developed
hypsarrhythmia by 5 months of age, consistent with a clinical diagnosis
of West syndrome. Four patients showed an initial favorable response to
vigabatrin and became seizure-free later in childhood even without
medication, but 2 had continued seizures despite treatment with
antiepileptic medications. None of the patients had a burst-suppression
pattern on EEG, as had been observed in the patients reported by Saitsu
et al. (2008). Three patients were wheelchair-bound due to hypotonia or
dyskinesias. Five patients had proven de novo mutations; parental DNA
from the sixth patient was not available. Deprez et al. (2010)
emphasized the phenotypic variability in the severity of the epilepsy,
but noted that all patients had mental retardation, which suggested that
neurodegeneration is an intrinsic property of the disorder.
INHERITANCE
Saitsu et al. (2011) noted that de novo mutations in the STXBP1 gene
have been reported in patients with EIEE4, consistent with sporadic
occurrence of the disorder. They reported a girl with EIEE4 confirmed by
genetic analysis revealing a heterozygous truncating mutation in the
STXBP1 gene that was inherited from her unaffected father, who was
somatic mosaic for the mutation. Cloning of PCR products amplified with
the paternal DNA samples extracted from his blood, saliva, buccal cells,
and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles
harbored the mutation, respectively. Although sperm was not tested, the
father likely carried the mutation in the mosaic state in his germ
cells. Saitsu et al. (2011) emphasized the importance of the finding for
genetic counseling, as recurrence of the disorder in this family is
possible.
MOLECULAR GENETICS
In a Japanese girl with early infantile epileptic encephalopathy
(Tohyama et al., 2008), Saitsu et al. (2008) identified a de novo
heterozygous microdeletion at chromosome 9q33.3-q34.11 including the
STXBP1 gene. Screening of this gene in 13 additional unrelated patients
with a similar phenotype identified 4 different heterozygous mutations
in the STXBP1 gene (602926.0001-602926.0004) in 4 patients. In 3 of the
patients the mutation was shown to be de novo. Saitsu et al. (2008)
concluded that haploinsufficiency of STXBP1 results in impaired synaptic
vesicle release and the phenotype of EIEE.
In 2 unrelated French Canadian patients with severe mental retardation
and epilepsy, Hamdan et al. (2009) identified respective de novo
heterozygous truncating mutations in the STXBP1 gene (602926.0005 and
602926.0006). The patients were ascertained from a larger group of 95
patients with idiopathic mental retardation.
CYTOGENETICS
Saitsu et al. (2010) reported that the microdeletion in the patient
previously reported by Tohyama et al. (2008) and Saitsu et al. (2008)
was 2.25 Mb long and encompassed both the STXBP1 and SPTAN1 (182810)
genes. This patient had hypomyelination at 12 months, but showed
progression of myelination at age 4 years. Saitsu et al. (2010)
hypothesized that this patient's phenotype was due more to
haploinsufficiency of STXBP1, but that haploinsufficiency of SPTAN1 may
have had some effect on myelination, because dominant-negative SPTAN1
mutations were found to cause severe hypomyelination and widespread
brain atrophy (see EIEE5, 613447).
Using array CGH, Saitsu et al. (2012) identified 2 different de novo
heterozygous deletions involving the STXBP1 gene in 2 (7.1%) of 28
patients with cryptogenic early-onset epileptic encephalopathy. One was
a 4.6-kb deletion involving only exon 4 of the STXBP1 gene, and the
other was a 2.85-Mb deletion involving 70 genes, including both STXBP1
and SPTAN1. The patient with the smaller deletion developed tonic and
myoclonic seizures on day 32 of life. EEG showed a suppression-burst
pattern, and brain MRI was normal. Seizure frequency was reduced with
high-dose phenobarbital. The patient with the larger deletion had
multiple anomalies, including low birth weight, cleft lip and palate,
ventricular septal defect, small penis, thin corpus callosum, and small
cerebellum. Seizures with suppression-burst pattern on EEG developed
around age 1 month. At 19 months, the child showed spastic quadriplegia
and profound intellectual disability. Analysis of the breakpoints in
both patients suggested that nonhomologous recombination led to the
rearrangements.
*FIELD* RF
1. Deprez, L.; Weckhuysen, S.; Holmgren, P.; Suls, A.; Van Dyck, T.;
Goossens, D.; Del-Favero, J.; Jansen, A.; Verhaert, K.; Lagae, L.;
Jordanova, A.; Van Coster, R.; Yendle, S.; Berkovic, S. F.; Scheffer,
I.; Ceulemans, B.; De Jonghe, P.: Clinical spectrum of early-onset
epileptic encephalopathies associated with STXBP1 mutations. Neurology 75:
1159-1165, 2010.
2. Hamdan, F. F.; Piton, A.; Gauthier, J.; Lortie, A.; Dubeau, F.;
Dobrzeniecka, S.; Spiegelman, D.; Noreau, A.; Pellerin, S.; Cote,
M.; Henrion, E.; Fombonne, E.; Mottron, L.; Marineau, C.; Drapeau,
P.; Lafreniere, R. G.; Lacaille, J. C.; Rouleau, G. A.; Michaud, J.
L.: De novo STXBP1 mutations in mental retardation and nonsyndromic
epilepsy. Ann. Neurol. 65: 748-753, 2009.
3. Saitsu, H.; Hoshino, H.; Kato, M.; Nishiyama, K.; Okada, I.; Yoneda,
Y.; Tsurusaki, Y.; Doi, H.; Miyake, N.; Kubota, M.; Hayasaka, K.;
Matsumoto, N.: Paternal mosaicism of an STXBP1 mutation in OS. Clin.
Genet. 80: 484-488, 2011.
4. Saitsu, H.; Kato, M.; Mizuguchi, T.; Hamada, K.; Osaka, H.; Tohyama,
J.; Uruno, K.; Kumada, S.; Nishiyama, K.; Nishimura, A.; Okada, I.;
Yoshimura, Y.; Hirai, S.; Kumada, T.; Hayasaka, K.; Fukuda, A.; Ogata,
K.; Matsumoto, N.: De novo mutations in the gene encoding STXBP1
(MUNC18-1) cause early infantile epileptic encephalopathy. Nature
Genet. 40: 782-788, 2008.
5. Saitsu, H.; Kato, M.; Shimono, M.; Senju, A.; Tanabe, S.; Kimura,
T.; Nishiyama, K.; Yoneda, Y.; Kondo, Y.; Tsurusaki, Y.; Doi, H.;
Miyake, N.; Hayasaka, K.; Matsumoto, N.: Association of genomic deletions
in the STXBP1 gene with Ohtahara syndrome. (Letter) Clin. Genet. 81:
399-402, 2012.
6. Saitsu, H.; Tohyama, J.; Kumada, T.; Egawa, K.; Hamada, K.; Okada,
I.; Mizuguchi, T.; Osaka, H.; Miyata, R.; Furukawa, T.; Haginoya,
K.; Hoshino, H.; and 15 others: Dominant-negative mutations in
alpha-II spectrin cause West syndrome with severe cerebral hypomyelination,
spastic quadriplegia, and developmental delay. Am. J. Hum. Genet. 86:
881-891, 2010.
7. Tohyama, J.; Akasaka, N.; Osaka, H.; Maegaki, Y.; Kato, M.; Saito,
N.; Yamashita, S.; Ohno, K.: Early onset West syndrome with cerebral
hypomyelination and reduced cerebral white matter. Brain Dev. 30:
349-355, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Poor visual pursuit
NEUROLOGIC:
[Central nervous system];
Seizures, clonic-tonic;
Seizures, tonic;
Seizures, myoclonic;
Hypsarrhythmia;
Mental retardation, severe;
No language development;
Hypotonia;
Tremor;
Spastic paraplegia;
Spastic quadriplegia;
Brain hypomyelination;
Thin corpus callosum;
Cerebral atrophy;
EEG shows suppression-burst pattern;
West syndrome
MISCELLANEOUS:
Onset in neonatal period or infancy;
Seizures are usually intractable;
See also EIEE1 (308350)
MOLECULAR BASIS:
Caused by mutation in the syntaxin-binding protein 1 gene (STXBP1,
602926.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 11/5/2009
*FIELD* CD
Cassandra L. Kniffin: 7/10/2008
*FIELD* ED
joanna: 04/26/2013
joanna: 4/26/2013
ckniffin: 11/5/2009
joanna: 1/28/2009
ckniffin: 7/10/2008
*FIELD* CN
Cassandra L. Kniffin - updated: 1/2/2013
Cassandra L. Kniffin - updated: 10/27/2011
Cassandra L. Kniffin - updated: 6/22/2011
Cassandra L. Kniffin - updated: 7/12/2010
Cassandra L. Kniffin - updated: 11/5/2009
*FIELD* CD
Cassandra L. Kniffin: 7/10/2008
*FIELD* ED
carol: 01/10/2013
ckniffin: 1/2/2013
terry: 10/31/2011
carol: 10/28/2011
ckniffin: 10/27/2011
wwang: 6/29/2011
ckniffin: 6/22/2011
carol: 2/11/2011
wwang: 7/13/2010
ckniffin: 7/12/2010
wwang: 11/18/2009
ckniffin: 11/5/2009
alopez: 7/18/2008
ckniffin: 7/10/2008
*RECORD*
*FIELD* NO
612164
*FIELD* TI
#612164 EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 4; EIEE4
*FIELD* TX
A number sign (#) is used with this entry because early infantile
read moreepileptic encephalopathy-4 (EIEE4) is caused by heterozygous mutation in
the STXBP1 gene (602926) on chromosome 9q34.1.
For a general phenotypic description and a discussion of genetic
heterogeneity of EIEE, see EIEE1 (308350).
CLINICAL FEATURES
Tohyama et al. (2008) reported a Japanese infant girl who developed
tonic seizures, tremulous arm movements, and oral automatisms at 45 days
of age. Her dizygotic twin was unaffected; the pregnancy resulted from
in vivo fertilization. The proband continued to have seizures with
increased frequency, spastic quadriplegia, and poor visual attention.
EEG showed a suppression-burst pattern and hypsarrhythmia, consistent
with EIEE. She had severely delayed psychomotor development with no
language. Brain MRI showed diffuse hypomyelination, cortical atrophy,
and a thin corpus callosum.
Saitsu et al. (2008) reported 4 Japanese patients with EIEE. All had
neonatal or infantile onset of tonic-clonic or tonic seizures,
suppression-burst pattern on EEG, profound mental retardation, and MRI
evidence of hypomyelination. Other features included hypsarrhythmia and
spastic di- or quadriplegia. Major structural brain abnormalities were
not observed.
Hamdan et al. (2009) reported 2 unrelated French Canadian patients with
EIEE4. One patient was a 27-year-old woman who first developed partial
complex seizures at age 6 weeks. The second patient was a 15-year-old
girl who first developed partial complex seizures at 2 years, 9 months
of age. Both patients had severe mental retardation, hypotonia, and
tremor. Brain scan in both patients was normal. Hamdan et al. (2009)
noted that the phenotypes of both patients were slightly different than
that reported by Saitsu et al. (2008), with later onset of seizures and
some response to antiepileptic medication. In addition, hypsarrhythmia
was never observed.
Deprez et al. (2010) identified heterozygous truncating mutations in the
STXBP1 gene in 6 (5.7%) of 106 patients with various types of
early-onset epileptic encephalopathies. Variable seizures first occurred
between 3 days and 4.5 months of life, and all patients subsequently had
severe to profound mental retardation. Three patients developed
hypsarrhythmia by 5 months of age, consistent with a clinical diagnosis
of West syndrome. Four patients showed an initial favorable response to
vigabatrin and became seizure-free later in childhood even without
medication, but 2 had continued seizures despite treatment with
antiepileptic medications. None of the patients had a burst-suppression
pattern on EEG, as had been observed in the patients reported by Saitsu
et al. (2008). Three patients were wheelchair-bound due to hypotonia or
dyskinesias. Five patients had proven de novo mutations; parental DNA
from the sixth patient was not available. Deprez et al. (2010)
emphasized the phenotypic variability in the severity of the epilepsy,
but noted that all patients had mental retardation, which suggested that
neurodegeneration is an intrinsic property of the disorder.
INHERITANCE
Saitsu et al. (2011) noted that de novo mutations in the STXBP1 gene
have been reported in patients with EIEE4, consistent with sporadic
occurrence of the disorder. They reported a girl with EIEE4 confirmed by
genetic analysis revealing a heterozygous truncating mutation in the
STXBP1 gene that was inherited from her unaffected father, who was
somatic mosaic for the mutation. Cloning of PCR products amplified with
the paternal DNA samples extracted from his blood, saliva, buccal cells,
and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles
harbored the mutation, respectively. Although sperm was not tested, the
father likely carried the mutation in the mosaic state in his germ
cells. Saitsu et al. (2011) emphasized the importance of the finding for
genetic counseling, as recurrence of the disorder in this family is
possible.
MOLECULAR GENETICS
In a Japanese girl with early infantile epileptic encephalopathy
(Tohyama et al., 2008), Saitsu et al. (2008) identified a de novo
heterozygous microdeletion at chromosome 9q33.3-q34.11 including the
STXBP1 gene. Screening of this gene in 13 additional unrelated patients
with a similar phenotype identified 4 different heterozygous mutations
in the STXBP1 gene (602926.0001-602926.0004) in 4 patients. In 3 of the
patients the mutation was shown to be de novo. Saitsu et al. (2008)
concluded that haploinsufficiency of STXBP1 results in impaired synaptic
vesicle release and the phenotype of EIEE.
In 2 unrelated French Canadian patients with severe mental retardation
and epilepsy, Hamdan et al. (2009) identified respective de novo
heterozygous truncating mutations in the STXBP1 gene (602926.0005 and
602926.0006). The patients were ascertained from a larger group of 95
patients with idiopathic mental retardation.
CYTOGENETICS
Saitsu et al. (2010) reported that the microdeletion in the patient
previously reported by Tohyama et al. (2008) and Saitsu et al. (2008)
was 2.25 Mb long and encompassed both the STXBP1 and SPTAN1 (182810)
genes. This patient had hypomyelination at 12 months, but showed
progression of myelination at age 4 years. Saitsu et al. (2010)
hypothesized that this patient's phenotype was due more to
haploinsufficiency of STXBP1, but that haploinsufficiency of SPTAN1 may
have had some effect on myelination, because dominant-negative SPTAN1
mutations were found to cause severe hypomyelination and widespread
brain atrophy (see EIEE5, 613447).
Using array CGH, Saitsu et al. (2012) identified 2 different de novo
heterozygous deletions involving the STXBP1 gene in 2 (7.1%) of 28
patients with cryptogenic early-onset epileptic encephalopathy. One was
a 4.6-kb deletion involving only exon 4 of the STXBP1 gene, and the
other was a 2.85-Mb deletion involving 70 genes, including both STXBP1
and SPTAN1. The patient with the smaller deletion developed tonic and
myoclonic seizures on day 32 of life. EEG showed a suppression-burst
pattern, and brain MRI was normal. Seizure frequency was reduced with
high-dose phenobarbital. The patient with the larger deletion had
multiple anomalies, including low birth weight, cleft lip and palate,
ventricular septal defect, small penis, thin corpus callosum, and small
cerebellum. Seizures with suppression-burst pattern on EEG developed
around age 1 month. At 19 months, the child showed spastic quadriplegia
and profound intellectual disability. Analysis of the breakpoints in
both patients suggested that nonhomologous recombination led to the
rearrangements.
*FIELD* RF
1. Deprez, L.; Weckhuysen, S.; Holmgren, P.; Suls, A.; Van Dyck, T.;
Goossens, D.; Del-Favero, J.; Jansen, A.; Verhaert, K.; Lagae, L.;
Jordanova, A.; Van Coster, R.; Yendle, S.; Berkovic, S. F.; Scheffer,
I.; Ceulemans, B.; De Jonghe, P.: Clinical spectrum of early-onset
epileptic encephalopathies associated with STXBP1 mutations. Neurology 75:
1159-1165, 2010.
2. Hamdan, F. F.; Piton, A.; Gauthier, J.; Lortie, A.; Dubeau, F.;
Dobrzeniecka, S.; Spiegelman, D.; Noreau, A.; Pellerin, S.; Cote,
M.; Henrion, E.; Fombonne, E.; Mottron, L.; Marineau, C.; Drapeau,
P.; Lafreniere, R. G.; Lacaille, J. C.; Rouleau, G. A.; Michaud, J.
L.: De novo STXBP1 mutations in mental retardation and nonsyndromic
epilepsy. Ann. Neurol. 65: 748-753, 2009.
3. Saitsu, H.; Hoshino, H.; Kato, M.; Nishiyama, K.; Okada, I.; Yoneda,
Y.; Tsurusaki, Y.; Doi, H.; Miyake, N.; Kubota, M.; Hayasaka, K.;
Matsumoto, N.: Paternal mosaicism of an STXBP1 mutation in OS. Clin.
Genet. 80: 484-488, 2011.
4. Saitsu, H.; Kato, M.; Mizuguchi, T.; Hamada, K.; Osaka, H.; Tohyama,
J.; Uruno, K.; Kumada, S.; Nishiyama, K.; Nishimura, A.; Okada, I.;
Yoshimura, Y.; Hirai, S.; Kumada, T.; Hayasaka, K.; Fukuda, A.; Ogata,
K.; Matsumoto, N.: De novo mutations in the gene encoding STXBP1
(MUNC18-1) cause early infantile epileptic encephalopathy. Nature
Genet. 40: 782-788, 2008.
5. Saitsu, H.; Kato, M.; Shimono, M.; Senju, A.; Tanabe, S.; Kimura,
T.; Nishiyama, K.; Yoneda, Y.; Kondo, Y.; Tsurusaki, Y.; Doi, H.;
Miyake, N.; Hayasaka, K.; Matsumoto, N.: Association of genomic deletions
in the STXBP1 gene with Ohtahara syndrome. (Letter) Clin. Genet. 81:
399-402, 2012.
6. Saitsu, H.; Tohyama, J.; Kumada, T.; Egawa, K.; Hamada, K.; Okada,
I.; Mizuguchi, T.; Osaka, H.; Miyata, R.; Furukawa, T.; Haginoya,
K.; Hoshino, H.; and 15 others: Dominant-negative mutations in
alpha-II spectrin cause West syndrome with severe cerebral hypomyelination,
spastic quadriplegia, and developmental delay. Am. J. Hum. Genet. 86:
881-891, 2010.
7. Tohyama, J.; Akasaka, N.; Osaka, H.; Maegaki, Y.; Kato, M.; Saito,
N.; Yamashita, S.; Ohno, K.: Early onset West syndrome with cerebral
hypomyelination and reduced cerebral white matter. Brain Dev. 30:
349-355, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
HEAD AND NECK:
[Eyes];
Poor visual pursuit
NEUROLOGIC:
[Central nervous system];
Seizures, clonic-tonic;
Seizures, tonic;
Seizures, myoclonic;
Hypsarrhythmia;
Mental retardation, severe;
No language development;
Hypotonia;
Tremor;
Spastic paraplegia;
Spastic quadriplegia;
Brain hypomyelination;
Thin corpus callosum;
Cerebral atrophy;
EEG shows suppression-burst pattern;
West syndrome
MISCELLANEOUS:
Onset in neonatal period or infancy;
Seizures are usually intractable;
See also EIEE1 (308350)
MOLECULAR BASIS:
Caused by mutation in the syntaxin-binding protein 1 gene (STXBP1,
602926.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 11/5/2009
*FIELD* CD
Cassandra L. Kniffin: 7/10/2008
*FIELD* ED
joanna: 04/26/2013
joanna: 4/26/2013
ckniffin: 11/5/2009
joanna: 1/28/2009
ckniffin: 7/10/2008
*FIELD* CN
Cassandra L. Kniffin - updated: 1/2/2013
Cassandra L. Kniffin - updated: 10/27/2011
Cassandra L. Kniffin - updated: 6/22/2011
Cassandra L. Kniffin - updated: 7/12/2010
Cassandra L. Kniffin - updated: 11/5/2009
*FIELD* CD
Cassandra L. Kniffin: 7/10/2008
*FIELD* ED
carol: 01/10/2013
ckniffin: 1/2/2013
terry: 10/31/2011
carol: 10/28/2011
ckniffin: 10/27/2011
wwang: 6/29/2011
ckniffin: 6/22/2011
carol: 2/11/2011
wwang: 7/13/2010
ckniffin: 7/12/2010
wwang: 11/18/2009
ckniffin: 11/5/2009
alopez: 7/18/2008
ckniffin: 7/10/2008