Full text data of SYNJ1
SYNJ1
(KIAA0910)
[Confidence: low (only semi-automatic identification from reviews)]
Synaptojanin-1; 3.1.3.36 (Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Synaptojanin-1; 3.1.3.36 (Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O43426
ID SYNJ1_HUMAN Reviewed; 1573 AA.
AC O43426; O43425; O94984; Q4KMR1;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Synaptojanin-1;
DE EC=3.1.3.36;
DE AltName: Full=Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1;
GN Name=SYNJ1; Synonyms=KIAA0910;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANT ARG-295.
RC TISSUE=Cerebellum;
RX PubMed=9428629; DOI=10.1016/S0014-5793(97)01451-8;
RA Haffner C., Takei K., Chen H., Ringstad N., Hudson A., Butler M.H.,
RA Salcini A.E., Di Fiore P.P., De Camilli P.;
RT "Synaptojanin 1: localization on coated endocytic intermediates in
RT nerve terminals and interaction of its 170 kDa isoform with Eps15.";
RL FEBS Lett. 419:175-180(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M.,
RA Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [3]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Placenta;
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 AMPH; SH3GL1; SH3GL2 AND SH3GL3.
RX PubMed=10542231; DOI=10.1074/jbc.274.45.32001;
RA Cestra G., Castagnoli L., Dente L., Minenkova O., Petrelli A.,
RA Migone N., Hoffmueller U., Schneider-Mergener J., Cesareni G.;
RT "The SH3 domains of endophilin and amphiphysin bind to the proline-
RT rich region of synaptojanin 1 at distinct sites that display an
RT unconventional binding specificity.";
RL J. Biol. Chem. 274:32001-32007(1999).
RN [7]
RP INTERACTION WITH MYO1E.
RX PubMed=17257598; DOI=10.1016/j.febslet.2007.01.021;
RA Krendel M., Osterweil E.K., Mooseker M.S.;
RT "Myosin 1E interacts with synaptojanin-1 and dynamin and is involved
RT in endocytosis.";
RL FEBS Lett. 581:644-650(2007).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830; THR-1220; SER-1551
RP AND SER-1565, AND MASS SPECTROMETRY.
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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1318, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP STRUCTURE BY NMR OF 894-971.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RNA binding domain in synaptojanin 1.";
RL Submitted (OCT-2006) to the PDB data bank.
CC -!- FUNCTION: Inositol 5-phosphatase which has a role in clathrin-
CC mediated endocytosis.
CC -!- CATALYTIC ACTIVITY: 1-phosphatidyl-1D-myo-inositol 4,5-
CC bisphosphate + H(2)O = 1-phosphatidyl-1D-myo-inositol 4-phosphate
CC + phosphate.
CC -!- SUBUNIT: Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2
CC and PACSIN3 (By similarity). Binds AMPH, SH3GL1, SH3GL2 and
CC SH3GL3. Interacts with MYO1E (via SH3 domain).
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Synaptojanin-170;
CC IsoId=O43426-1; Sequence=Displayed;
CC Name=2; Synonyms=Synaptojanin-145;
CC IsoId=O43426-2; Sequence=VSP_002682, VSP_002683;
CC Name=3;
CC IsoId=O43426-4; Sequence=VSP_041578, VSP_002682, VSP_002683;
CC Name=4;
CC IsoId=O43426-5; Sequence=VSP_035709, VSP_035710, VSP_035711;
CC -!- TISSUE SPECIFICITY: Concentrated at clathrin-coated endocytic
CC intermediates in nerve terminals. Isoform 1 is more enriched than
CC isoform 2 in developing brain as well as non-neuronal cells.
CC Isoform 2 is very abundant in nerve terminals.
CC -!- DOMAIN: Binds to EPS15 (a clathrin coat-associated protein) via a
CC C-terminal domain containing three Asn-Pro-Phe (NPF) repeats (By
CC similarity).
CC -!- DOMAIN: The C-terminal proline-rich region mediates binding to a
CC variety of SH3 domain-containing proteins including AMPH, SH3GL1,
CC SH3GL2, SH3GL3 and GRB2.
CC -!- SIMILARITY: Belongs to the synaptojanin family.
CC -!- SIMILARITY: In the central section; belongs to the inositol 1,4,5-
CC trisphosphate 5-phosphatase family.
CC -!- SIMILARITY: Contains 1 RRM (RNA recognition motif) domain.
CC -!- SIMILARITY: Contains 1 SAC domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA74933.2; Type=Erroneous initiation;
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DR EMBL; AF009039; AAC51921.1; -; mRNA.
DR EMBL; AF009040; AAC51922.1; -; mRNA.
DR EMBL; AB020717; BAA74933.2; ALT_INIT; mRNA.
DR EMBL; AP000275; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000276; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000277; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000278; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000279; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC098395; AAH98395.1; -; mRNA.
DR RefSeq; NP_001153774.1; NM_001160302.1.
DR RefSeq; NP_001153778.1; NM_001160306.1.
DR RefSeq; NP_003886.3; NM_003895.3.
DR RefSeq; NP_982271.2; NM_203446.2.
DR UniGene; Hs.473632; -.
DR PDB; 1W80; X-ray; 1.90 A; P=1477-1488, Q=1458-1469.
DR PDB; 2DNR; NMR; -; A=894-971.
DR PDB; 2VJ0; X-ray; 1.60 A; P=1477-1488.
DR PDBsum; 1W80; -.
DR PDBsum; 2DNR; -.
DR PDBsum; 2VJ0; -.
DR ProteinModelPortal; O43426; -.
DR SMR; O43426; 44-444, 527-870, 895-971.
DR IntAct; O43426; 6.
DR MINT; MINT-109209; -.
DR STRING; 9606.ENSP00000322234; -.
DR PhosphoSite; O43426; -.
DR PaxDb; O43426; -.
DR PRIDE; O43426; -.
DR Ensembl; ENST00000322229; ENSP00000322234; ENSG00000159082.
DR Ensembl; ENST00000357345; ENSP00000349903; ENSG00000159082.
DR GeneID; 8867; -.
DR KEGG; hsa:8867; -.
DR CTD; 8867; -.
DR GeneCards; GC21M033997; -.
DR HGNC; HGNC:11503; SYNJ1.
DR HPA; HPA011916; -.
DR MIM; 604297; gene.
DR neXtProt; NX_O43426; -.
DR PharmGKB; PA36285; -.
DR eggNOG; COG5411; -.
DR HOGENOM; HOG000007937; -.
DR HOVERGEN; HBG079225; -.
DR InParanoid; O43426; -.
DR KO; K01099; -.
DR BioCyc; MetaCyc:HS08354-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; O43426; -.
DR GenomeRNAi; 8867; -.
DR NextBio; 33289; -.
DR PRO; PR:O43426; -.
DR ArrayExpress; O43426; -.
DR Bgee; O43426; -.
DR CleanEx; HS_SYNJ1; -.
DR Genevestigator; O43426; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; TAS:ProtInc.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
DR GO; GO:0048488; P:synaptic vesicle endocytosis; TAS:ProtInc.
DR Gene3D; 3.30.70.330; -; 1.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR015047; DUF1866.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR000300; IPPc.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR InterPro; IPR002013; Syja_N.
DR Pfam; PF08952; DUF1866; 1.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR Pfam; PF02383; Syja_N; 1.
DR SMART; SM00128; IPPc; 1.
DR SUPFAM; SSF56219; SSF56219; 2.
DR PROSITE; PS50102; RRM; 1.
DR PROSITE; PS50275; SAC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Endocytosis; Hydrolase; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; RNA-binding.
FT CHAIN 1 1573 Synaptojanin-1.
FT /FTId=PRO_0000209730.
FT DOMAIN 119 442 SAC.
FT DOMAIN 902 971 RRM.
FT REPEAT 1396 1398 1.
FT REPEAT 1406 1408 2.
FT REPEAT 1417 1419 3.
FT REGION 500 899 Catalytic (Potential).
FT REGION 1396 1419 3 X 3 AA repeats of N-P-F.
FT COMPBIAS 900 1573 Pro-rich.
FT COMPBIAS 1033 1036 Poly-Ser.
FT COMPBIAS 1108 1113 Poly-Pro.
FT COMPBIAS 1126 1129 Poly-Pro.
FT COMPBIAS 1485 1488 Poly-Glu.
FT COMPBIAS 1538 1544 Poly-Pro.
FT MOD_RES 830 830 Phosphoserine.
FT MOD_RES 1220 1220 Phosphothreonine.
FT MOD_RES 1318 1318 Phosphoserine.
FT MOD_RES 1551 1551 Phosphoserine.
FT MOD_RES 1565 1565 Phosphoserine.
FT VAR_SEQ 451 451 K -> KAGK (in isoform 4).
FT /FTId=VSP_035709.
FT VAR_SEQ 504 511 Missing (in isoform 4).
FT /FTId=VSP_035710.
FT VAR_SEQ 525 1573 Missing (in isoform 4).
FT /FTId=VSP_035711.
FT VAR_SEQ 1144 1159 Missing (in isoform 3).
FT /FTId=VSP_041578.
FT VAR_SEQ 1306 1311 VKTNGI -> QEQPSG (in isoform 2 and
FT isoform 3).
FT /FTId=VSP_002682.
FT VAR_SEQ 1312 1573 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_002683.
FT VARIANT 295 295 K -> R (in dbSNP:rs2254562).
FT /FTId=VAR_047308.
FT VARIANT 1366 1366 V -> A (in dbSNP:rs9980589).
FT /FTId=VAR_047309.
FT VARIANT 1508 1508 P -> L (in dbSNP:rs2230767).
FT /FTId=VAR_059357.
FT VARIANT 1545 1545 L -> P (in dbSNP:rs2230767).
FT /FTId=VAR_047310.
FT VARIANT 1547 1547 P -> L (in dbSNP:rs2230767).
FT /FTId=VAR_049603.
FT CONFLICT 1093 1108 Missing (in Ref. 1; BAA74933).
FT CONFLICT 1366 1366 V -> VNT (in Ref. 1; AAC51922).
FT STRAND 895 901
FT TURN 905 907
FT HELIX 912 923
FT STRAND 928 933
FT STRAND 935 944
FT HELIX 945 950
FT HELIX 951 954
FT STRAND 962 968
SQ SEQUENCE 1573 AA; 173103 MW; D50B249B1EBFFC18 CRC64;
MAFSKGFRIY HKLDPPPFSL IVETRHKEEC LMFESGAVAV LSSAEKEAIK GTYSKVLDAY
GLLGVLRLNL GDTMLHYLVL VTGCMSVGKI QESEVFRVTS TEFISLRIDS SDEDRISEVR
KVLNSGNFYF AWSASGISLD LSLNAHRSMQ EQTTDNRFFW NQSLHLHLKH YGVNCDDWLL
RLMCGGVEIR TIYAAHKQAK ACLISRLSCE RAGTRFNVRG TNDDGHVANF VETEQVVYLD
DSVSSFIQIR GSVPLFWEQP GLQVGSHRVR MSRGFEANAP AFDRHFRTLK NLYGKQIIVN
LLGSKEGEHM LSKAFQSHLK ASEHAADIQM VNFDYHQMVK GGKAEKLHSV LKPQVQKFLD
YGFFYFNGSE VQRCQSGTVR TNCLDCLDRT NSVQAFLGLE MLAKQLEALG LAEKPQLVTR
FQEVFRSMWS VNGDSISKIY AGTGALEGKA KLKDGARSVT RTIQNNFFDS SKQEAIDVLL
LGNTLNSDLA DKARALLTTG SLRVSEQTLQ SASSKVLKSM CENFYKYSKP KKIRVCVGTW
NVNGGKQFRS IAFKNQTLTD WLLDAPKLAG IQEFQDKRSK PTDIFAIGFE EMVELNAGNI
VSASTTNQKL WAVELQKTIS RDNKYVLLAS EQLVGVCLFV FIRPQHAPFI RDVAVDTVKT
GMGGATGNKG AVAIRMLFHT TSLCFVCSHF AAGQSQVKER NEDFIEIARK LSFPMGRMLF
SHDYVFWCGD FNYRIDLPNE EVKELIRQQN WDSLIAGDQL INQKNAGQVF RGFLEGKVTF
APTYKYDLFS DDYDTSEKCR TPAWTDRVLW RRRKWPFDRS AEDLDLLNAS FQDESKILYT
WTPGTLLHYG RAELKTSDHR PVVALIDIDI FEVEAEERQN IYKEVIAVQG PPDGTVLVSI
KSSLPENNFF DDALIDELLQ QFASFGEVIL IRFVEDKMWV TFLEGSSALN VLSLNGKELL
NRTITIALKS PDWIKNLEEE MSLEKISIAL PSSTSSTLLG EDAEVAADFD MEGDVDDYSA
EVEELLPQHL QPSSSSGLGT SPSSSPRTSP CQSPTISEGP VPSLPIRPSR APSRTPGPPS
AQSSPIDAQP ATPLPQKDPA QPLEPKRPPP PRPVAPPTRP APPQRPPPPS GARSPAPTRK
EFGGIGAPPS PGVARREMEA PKSPGTTRKD NIGRSQPSPQ AGLAGPGPAG YSTARPTIPP
RAGVISAPQS HARASAGRLT PESQSKTSET SKGSTFLPEP LKPQAAFPPQ SSLPPPAQRL
QEPLVPVAAP MPQSGPQPNL ETPPQPPPRS RSSHSLPSEA SSQPQVKTNG ISDGKRESPL
KIDPFEDLSF NLLAVSKAQL SVQTSPVPTP DPKRLIQLPS ATQSNVLSSV SCMPTMPPIP
ARSQSQENMR SSPNPFITGL TRTNPFSDRT AAPGNPFRAK SEESEATSWF SKEEPVTISP
FPSLQPLGHN KSRASSSLDG FKDSFDLQGQ STLKISNPKG WVTFEEEEDF GVKGKSKSAC
SDLLGNQPSS FSGSNLTLND DWNKGTNVSF CVLPSRRPPP PPVPLLPPGT SPPVDPFTTL
ASKASPTLDF TER
//
ID SYNJ1_HUMAN Reviewed; 1573 AA.
AC O43426; O43425; O94984; Q4KMR1;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
read moreDT 25-NOV-2008, sequence version 2.
DT 22-JAN-2014, entry version 139.
DE RecName: Full=Synaptojanin-1;
DE EC=3.1.3.36;
DE AltName: Full=Synaptic inositol 1,4,5-trisphosphate 5-phosphatase 1;
GN Name=SYNJ1; Synonyms=KIAA0910;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), AND VARIANT ARG-295.
RC TISSUE=Cerebellum;
RX PubMed=9428629; DOI=10.1016/S0014-5793(97)01451-8;
RA Haffner C., Takei K., Chen H., Ringstad N., Hudson A., Butler M.H.,
RA Salcini A.E., Di Fiore P.P., De Camilli P.;
RT "Synaptojanin 1: localization on coated endocytic intermediates in
RT nerve terminals and interaction of its 170 kDa isoform with Eps15.";
RL FEBS Lett. 419:175-180(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Brain;
RX PubMed=10048485; DOI=10.1093/dnares/5.6.355;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M.,
RA Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XII.
RT The complete sequences of 100 new cDNA clones from brain which code
RT for large proteins in vitro.";
RL DNA Res. 5:355-364(1998).
RN [3]
RP SEQUENCE REVISION.
RX PubMed=12168954; DOI=10.1093/dnares/9.3.99;
RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.;
RT "Construction of expression-ready cDNA clones for KIAA genes: manual
RT curation of 330 KIAA cDNA clones.";
RL DNA Res. 9:99-106(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=10830953; DOI=10.1038/35012518;
RA Hattori M., Fujiyama A., Taylor T.D., Watanabe H., Yada T.,
RA Park H.-S., Toyoda A., Ishii K., Totoki Y., Choi D.-K., Groner Y.,
RA Soeda E., Ohki M., Takagi T., Sakaki Y., Taudien S., Blechschmidt K.,
RA Polley A., Menzel U., Delabar J., Kumpf K., Lehmann R., Patterson D.,
RA Reichwald K., Rump A., Schillhabel M., Schudy A., Zimmermann W.,
RA Rosenthal A., Kudoh J., Shibuya K., Kawasaki K., Asakawa S.,
RA Shintani A., Sasaki T., Nagamine K., Mitsuyama S., Antonarakis S.E.,
RA Minoshima S., Shimizu N., Nordsiek G., Hornischer K., Brandt P.,
RA Scharfe M., Schoen O., Desario A., Reichelt J., Kauer G., Bloecker H.,
RA Ramser J., Beck A., Klages S., Hennig S., Riesselmann L., Dagand E.,
RA Wehrmeyer S., Borzym K., Gardiner K., Nizetic D., Francis F.,
RA Lehrach H., Reinhardt R., Yaspo M.-L.;
RT "The DNA sequence of human chromosome 21.";
RL Nature 405:311-319(2000).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4).
RC TISSUE=Placenta;
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 AMPH; SH3GL1; SH3GL2 AND SH3GL3.
RX PubMed=10542231; DOI=10.1074/jbc.274.45.32001;
RA Cestra G., Castagnoli L., Dente L., Minenkova O., Petrelli A.,
RA Migone N., Hoffmueller U., Schneider-Mergener J., Cesareni G.;
RT "The SH3 domains of endophilin and amphiphysin bind to the proline-
RT rich region of synaptojanin 1 at distinct sites that display an
RT unconventional binding specificity.";
RL J. Biol. Chem. 274:32001-32007(1999).
RN [7]
RP INTERACTION WITH MYO1E.
RX PubMed=17257598; DOI=10.1016/j.febslet.2007.01.021;
RA Krendel M., Osterweil E.K., Mooseker M.S.;
RT "Myosin 1E interacts with synaptojanin-1 and dynamin and is involved
RT in endocytosis.";
RL FEBS Lett. 581:644-650(2007).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830; THR-1220; SER-1551
RP AND SER-1565, AND MASS SPECTROMETRY.
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 [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-830, AND MASS
RP SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1318, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [11]
RP STRUCTURE BY NMR OF 894-971.
RG RIKEN structural genomics initiative (RSGI);
RT "Solution structure of RNA binding domain in synaptojanin 1.";
RL Submitted (OCT-2006) to the PDB data bank.
CC -!- FUNCTION: Inositol 5-phosphatase which has a role in clathrin-
CC mediated endocytosis.
CC -!- CATALYTIC ACTIVITY: 1-phosphatidyl-1D-myo-inositol 4,5-
CC bisphosphate + H(2)O = 1-phosphatidyl-1D-myo-inositol 4-phosphate
CC + phosphate.
CC -!- SUBUNIT: Interacts with ASH/GRB2. Interacts with PACSIN1, PACSIN2
CC and PACSIN3 (By similarity). Binds AMPH, SH3GL1, SH3GL2 and
CC SH3GL3. Interacts with MYO1E (via SH3 domain).
CC -!- SUBCELLULAR LOCATION: Cytoplasm (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=Synaptojanin-170;
CC IsoId=O43426-1; Sequence=Displayed;
CC Name=2; Synonyms=Synaptojanin-145;
CC IsoId=O43426-2; Sequence=VSP_002682, VSP_002683;
CC Name=3;
CC IsoId=O43426-4; Sequence=VSP_041578, VSP_002682, VSP_002683;
CC Name=4;
CC IsoId=O43426-5; Sequence=VSP_035709, VSP_035710, VSP_035711;
CC -!- TISSUE SPECIFICITY: Concentrated at clathrin-coated endocytic
CC intermediates in nerve terminals. Isoform 1 is more enriched than
CC isoform 2 in developing brain as well as non-neuronal cells.
CC Isoform 2 is very abundant in nerve terminals.
CC -!- DOMAIN: Binds to EPS15 (a clathrin coat-associated protein) via a
CC C-terminal domain containing three Asn-Pro-Phe (NPF) repeats (By
CC similarity).
CC -!- DOMAIN: The C-terminal proline-rich region mediates binding to a
CC variety of SH3 domain-containing proteins including AMPH, SH3GL1,
CC SH3GL2, SH3GL3 and GRB2.
CC -!- SIMILARITY: Belongs to the synaptojanin family.
CC -!- SIMILARITY: In the central section; belongs to the inositol 1,4,5-
CC trisphosphate 5-phosphatase family.
CC -!- SIMILARITY: Contains 1 RRM (RNA recognition motif) domain.
CC -!- SIMILARITY: Contains 1 SAC domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA74933.2; Type=Erroneous initiation;
CC -----------------------------------------------------------------------
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DR EMBL; AF009039; AAC51921.1; -; mRNA.
DR EMBL; AF009040; AAC51922.1; -; mRNA.
DR EMBL; AB020717; BAA74933.2; ALT_INIT; mRNA.
DR EMBL; AP000275; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000276; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000277; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000278; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AP000279; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC098395; AAH98395.1; -; mRNA.
DR RefSeq; NP_001153774.1; NM_001160302.1.
DR RefSeq; NP_001153778.1; NM_001160306.1.
DR RefSeq; NP_003886.3; NM_003895.3.
DR RefSeq; NP_982271.2; NM_203446.2.
DR UniGene; Hs.473632; -.
DR PDB; 1W80; X-ray; 1.90 A; P=1477-1488, Q=1458-1469.
DR PDB; 2DNR; NMR; -; A=894-971.
DR PDB; 2VJ0; X-ray; 1.60 A; P=1477-1488.
DR PDBsum; 1W80; -.
DR PDBsum; 2DNR; -.
DR PDBsum; 2VJ0; -.
DR ProteinModelPortal; O43426; -.
DR SMR; O43426; 44-444, 527-870, 895-971.
DR IntAct; O43426; 6.
DR MINT; MINT-109209; -.
DR STRING; 9606.ENSP00000322234; -.
DR PhosphoSite; O43426; -.
DR PaxDb; O43426; -.
DR PRIDE; O43426; -.
DR Ensembl; ENST00000322229; ENSP00000322234; ENSG00000159082.
DR Ensembl; ENST00000357345; ENSP00000349903; ENSG00000159082.
DR GeneID; 8867; -.
DR KEGG; hsa:8867; -.
DR CTD; 8867; -.
DR GeneCards; GC21M033997; -.
DR HGNC; HGNC:11503; SYNJ1.
DR HPA; HPA011916; -.
DR MIM; 604297; gene.
DR neXtProt; NX_O43426; -.
DR PharmGKB; PA36285; -.
DR eggNOG; COG5411; -.
DR HOGENOM; HOG000007937; -.
DR HOVERGEN; HBG079225; -.
DR InParanoid; O43426; -.
DR KO; K01099; -.
DR BioCyc; MetaCyc:HS08354-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; O43426; -.
DR GenomeRNAi; 8867; -.
DR NextBio; 33289; -.
DR PRO; PR:O43426; -.
DR ArrayExpress; O43426; -.
DR Bgee; O43426; -.
DR CleanEx; HS_SYNJ1; -.
DR Genevestigator; O43426; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0004445; F:inositol-polyphosphate 5-phosphatase activity; TAS:ProtInc.
DR GO; GO:0000166; F:nucleotide binding; IEA:InterPro.
DR GO; GO:0004439; F:phosphatidylinositol-4,5-bisphosphate 5-phosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0003723; F:RNA binding; IEA:UniProtKB-KW.
DR GO; GO:0043647; P:inositol phosphate metabolic process; TAS:Reactome.
DR GO; GO:0006661; P:phosphatidylinositol biosynthetic process; TAS:Reactome.
DR GO; GO:0046856; P:phosphatidylinositol dephosphorylation; IEA:InterPro.
DR GO; GO:0048488; P:synaptic vesicle endocytosis; TAS:ProtInc.
DR Gene3D; 3.30.70.330; -; 1.
DR Gene3D; 3.60.10.10; -; 1.
DR InterPro; IPR015047; DUF1866.
DR InterPro; IPR005135; Endo/exonuclease/phosphatase.
DR InterPro; IPR000300; IPPc.
DR InterPro; IPR012677; Nucleotide-bd_a/b_plait.
DR InterPro; IPR000504; RRM_dom.
DR InterPro; IPR002013; Syja_N.
DR Pfam; PF08952; DUF1866; 1.
DR Pfam; PF03372; Exo_endo_phos; 1.
DR Pfam; PF02383; Syja_N; 1.
DR SMART; SM00128; IPPc; 1.
DR SUPFAM; SSF56219; SSF56219; 2.
DR PROSITE; PS50102; RRM; 1.
DR PROSITE; PS50275; SAC; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Endocytosis; Hydrolase; Phosphoprotein; Polymorphism;
KW Reference proteome; Repeat; RNA-binding.
FT CHAIN 1 1573 Synaptojanin-1.
FT /FTId=PRO_0000209730.
FT DOMAIN 119 442 SAC.
FT DOMAIN 902 971 RRM.
FT REPEAT 1396 1398 1.
FT REPEAT 1406 1408 2.
FT REPEAT 1417 1419 3.
FT REGION 500 899 Catalytic (Potential).
FT REGION 1396 1419 3 X 3 AA repeats of N-P-F.
FT COMPBIAS 900 1573 Pro-rich.
FT COMPBIAS 1033 1036 Poly-Ser.
FT COMPBIAS 1108 1113 Poly-Pro.
FT COMPBIAS 1126 1129 Poly-Pro.
FT COMPBIAS 1485 1488 Poly-Glu.
FT COMPBIAS 1538 1544 Poly-Pro.
FT MOD_RES 830 830 Phosphoserine.
FT MOD_RES 1220 1220 Phosphothreonine.
FT MOD_RES 1318 1318 Phosphoserine.
FT MOD_RES 1551 1551 Phosphoserine.
FT MOD_RES 1565 1565 Phosphoserine.
FT VAR_SEQ 451 451 K -> KAGK (in isoform 4).
FT /FTId=VSP_035709.
FT VAR_SEQ 504 511 Missing (in isoform 4).
FT /FTId=VSP_035710.
FT VAR_SEQ 525 1573 Missing (in isoform 4).
FT /FTId=VSP_035711.
FT VAR_SEQ 1144 1159 Missing (in isoform 3).
FT /FTId=VSP_041578.
FT VAR_SEQ 1306 1311 VKTNGI -> QEQPSG (in isoform 2 and
FT isoform 3).
FT /FTId=VSP_002682.
FT VAR_SEQ 1312 1573 Missing (in isoform 2 and isoform 3).
FT /FTId=VSP_002683.
FT VARIANT 295 295 K -> R (in dbSNP:rs2254562).
FT /FTId=VAR_047308.
FT VARIANT 1366 1366 V -> A (in dbSNP:rs9980589).
FT /FTId=VAR_047309.
FT VARIANT 1508 1508 P -> L (in dbSNP:rs2230767).
FT /FTId=VAR_059357.
FT VARIANT 1545 1545 L -> P (in dbSNP:rs2230767).
FT /FTId=VAR_047310.
FT VARIANT 1547 1547 P -> L (in dbSNP:rs2230767).
FT /FTId=VAR_049603.
FT CONFLICT 1093 1108 Missing (in Ref. 1; BAA74933).
FT CONFLICT 1366 1366 V -> VNT (in Ref. 1; AAC51922).
FT STRAND 895 901
FT TURN 905 907
FT HELIX 912 923
FT STRAND 928 933
FT STRAND 935 944
FT HELIX 945 950
FT HELIX 951 954
FT STRAND 962 968
SQ SEQUENCE 1573 AA; 173103 MW; D50B249B1EBFFC18 CRC64;
MAFSKGFRIY HKLDPPPFSL IVETRHKEEC LMFESGAVAV LSSAEKEAIK GTYSKVLDAY
GLLGVLRLNL GDTMLHYLVL VTGCMSVGKI QESEVFRVTS TEFISLRIDS SDEDRISEVR
KVLNSGNFYF AWSASGISLD LSLNAHRSMQ EQTTDNRFFW NQSLHLHLKH YGVNCDDWLL
RLMCGGVEIR TIYAAHKQAK ACLISRLSCE RAGTRFNVRG TNDDGHVANF VETEQVVYLD
DSVSSFIQIR GSVPLFWEQP GLQVGSHRVR MSRGFEANAP AFDRHFRTLK NLYGKQIIVN
LLGSKEGEHM LSKAFQSHLK ASEHAADIQM VNFDYHQMVK GGKAEKLHSV LKPQVQKFLD
YGFFYFNGSE VQRCQSGTVR TNCLDCLDRT NSVQAFLGLE MLAKQLEALG LAEKPQLVTR
FQEVFRSMWS VNGDSISKIY AGTGALEGKA KLKDGARSVT RTIQNNFFDS SKQEAIDVLL
LGNTLNSDLA DKARALLTTG SLRVSEQTLQ SASSKVLKSM CENFYKYSKP KKIRVCVGTW
NVNGGKQFRS IAFKNQTLTD WLLDAPKLAG IQEFQDKRSK PTDIFAIGFE EMVELNAGNI
VSASTTNQKL WAVELQKTIS RDNKYVLLAS EQLVGVCLFV FIRPQHAPFI RDVAVDTVKT
GMGGATGNKG AVAIRMLFHT TSLCFVCSHF AAGQSQVKER NEDFIEIARK LSFPMGRMLF
SHDYVFWCGD FNYRIDLPNE EVKELIRQQN WDSLIAGDQL INQKNAGQVF RGFLEGKVTF
APTYKYDLFS DDYDTSEKCR TPAWTDRVLW RRRKWPFDRS AEDLDLLNAS FQDESKILYT
WTPGTLLHYG RAELKTSDHR PVVALIDIDI FEVEAEERQN IYKEVIAVQG PPDGTVLVSI
KSSLPENNFF DDALIDELLQ QFASFGEVIL IRFVEDKMWV TFLEGSSALN VLSLNGKELL
NRTITIALKS PDWIKNLEEE MSLEKISIAL PSSTSSTLLG EDAEVAADFD MEGDVDDYSA
EVEELLPQHL QPSSSSGLGT SPSSSPRTSP CQSPTISEGP VPSLPIRPSR APSRTPGPPS
AQSSPIDAQP ATPLPQKDPA QPLEPKRPPP PRPVAPPTRP APPQRPPPPS GARSPAPTRK
EFGGIGAPPS PGVARREMEA PKSPGTTRKD NIGRSQPSPQ AGLAGPGPAG YSTARPTIPP
RAGVISAPQS HARASAGRLT PESQSKTSET SKGSTFLPEP LKPQAAFPPQ SSLPPPAQRL
QEPLVPVAAP MPQSGPQPNL ETPPQPPPRS RSSHSLPSEA SSQPQVKTNG ISDGKRESPL
KIDPFEDLSF NLLAVSKAQL SVQTSPVPTP DPKRLIQLPS ATQSNVLSSV SCMPTMPPIP
ARSQSQENMR SSPNPFITGL TRTNPFSDRT AAPGNPFRAK SEESEATSWF SKEEPVTISP
FPSLQPLGHN KSRASSSLDG FKDSFDLQGQ STLKISNPKG WVTFEEEEDF GVKGKSKSAC
SDLLGNQPSS FSGSNLTLND DWNKGTNVSF CVLPSRRPPP PPVPLLPPGT SPPVDPFTTL
ASKASPTLDF TER
//
MIM
604297
*RECORD*
*FIELD* NO
604297
*FIELD* TI
*604297 SYNAPTOJANIN 1; SYNJ1
*FIELD* TX
DESCRIPTION
Synaptojanin-1 is a phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2)
read morethat has a role in clathrin-coated pit dynamics (Perera et al., 2006).
CLONING
Haffner et al. (1997) used rat synaptojanin probes to isolate from a
human cerebellum cDNA library 2 overlapping clones encompassing the
complete coding region of the human SYNJ1 gene, which encodes a major
presynaptic protein concentrated at clathrin-coated endocytic
intermediates in nerve terminals. The authors found that
synaptojanin-170, an alternatively spliced isoform of SYNJ1, binds EPS15
(600051), a clathrin coat-associated protein. Binding was mediated by
the C-terminal region of synaptojanin-170, which contains 3
asparagine-proline-phenylalanine (NPF) repeats. This motif had been
found to be the core of the binding site for the EH domains of EPS15.
These findings suggested that SYNJ1 can be recruited to clathrin-coated
pits via a multiplicity of interactions.
In the rat, McPherson et al. (1996) found that synaptojanin is a nerve
terminal protein that appears to participate with dynamin (see 602377)
in synaptic vesicle recycling It has a molecular mass of 145 kD and is a
member of the inositol-5-phosphatase family, which includes the product
of the gene that is defective in the oculocerebrorenal syndrome of Lowe
(OCRL; 300535). Synaptojanin has 5-phosphatase activity, and its
N-terminal domain is homologous with yeast Sac1 (SACM1L; 606569), which
is genetically implicated in phospholipid metabolism and in the function
of the actin cytoskeleton. The C terminus, which is of different lengths
in adult and developing neurons due to the alternative use of 2
termination sites, is proline-rich, consistent with the reported
interaction of synaptojanin with the SH3 domains of GRB2 (108355).
Synaptojanin also bound the SH3 domain of amphiphysin (AMPH; 600418), a
presynaptic protein with a putative function in endocytosis. These data
suggested a link between phosphoinositide metabolism and synaptic
vesicle recycling.
Perera et al. (2006) stated that both the 145-kD and 170-kD synaptojanin
isoforms contain an N-terminal SAC1-like domain, followed by a 5-prime
phosphatase domain and a proline-rich domain. Only the 170-kD isoform
has an NPF domain and a C-terminal region containing binding sites for
the ear domains of AP2 (see AP2A1; 601026) and clathrin.
GENE FUNCTION
Cremona et al. (1999) generated mice with targeted disruption of the
Synj1 gene. These Synj1-deficient mice exhibited neurologic defects and
died shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels
were increased, and clathrin-coated vesicles accumulated in the
cytomatrix-rich area surrounding the synaptic vesicle cluster in nerve
endings. In cell-free assays, reduced phosphoinositide phosphatase
activity correlated with increased association of clathrin coats with
liposomes. Intracellular recording in hippocampal slices revealed
enhanced synaptic depression during prolonged high-frequency
stimulation, followed by delayed recovery. These results provided
genetic evidence for a crucial role of phosphoinositide metabolism in
synaptic vesicle recycling.
Using multicolor total internal reflection fluorescence microscopy,
Perera et al. (2006) found that the 2 major SYNJ1 isoforms were
differentially recruited to clathrin-coated pits in transiently
transfected COS-7 cells. The ubiquitously expressed 170-kD isoform was
present at all stages of clathrin-coated pit formation, whereas the
145-kD isoform, which is predominantly expressed in brain, was rapidly
recruited as a burst, together with endophilin (SH3GL2; 604465), at a
late stage of clathrin-coated pit formation. Perera et al. (2006)
concluded that dynamic phosphoinositide metabolism may occur throughout
the lifetime of a clathrin-coated pit.
MAPPING
By fluorescence in situ hybridization, Cremona et al. (2000) mapped the
human SYNJ1 gene to chromosome 21q22.2 and the mouse homolog to a region
showing homology of synteny on chromosome 16C3-4.
MOLECULAR GENETICS
- Early-Onset Parkinson Disease 20
Independently and simultaneously, Krebs et al. (2013) and Quadri et al.
(2013) identified the same homozygous missense mutation in the SYNJ1
gene (R258Q; 604297.0001) in affected sibs with autosomal recessive
early-onset Parkinson disease-20 (PARK20; 615530) from an Iranian and an
Italian consanguineous family, respectively. The mutations were found by
homozygosity mapping combined with whole-exome sequencing and segregated
with the disorder in both families. In vitro functional expression
studies by Krebs et al. (2013) indicated that the mutant protein had
impaired phosphatase activity of SYNJ1 against its Sac1 domain
substrates (PI3P and PI4P). All patients developed signs of progressive
parkinsonism in their twenties. The Iranian sibs also had early-onset
generalized seizures, and the Italian sibs had cognitive decline. Quadri
et al. (2013) stated that the SYNJ1 gene interacts with DNAJC6 (608375),
mutation in which causes PARK19 (615528), and noted that the
PD-associated LRRK2 (609007) gene is also involved in synaptic vesicle
endocytosis. The findings of both Krebs et al. (2013) and Quadri et al.
(2013) suggested that defective recycling of synaptic vesicles may play
a role in the neurodegeneration observed in Parkinson disease.
- Associations Pending Confirmation
Saito et al. (2001) studied the SYNJ1 gene as a possible candidate for
chromosome 21q22-linked bipolar disorder (see 125480). By mutation
analysis of 32 exons, intron-exon junctions, and 839 bases of
5-prime-flanking DNA, they identified 11 mutations, of which 4 were very
common and 7 very rare. Several of the 11 mutations may have functional
significance, including 2 coding variants, 2 that may affect the binding
of a transcription factor, and 2 that involve known splicing regulatory
domains. Although no unequivocal identification of a specific SYNJ1
allele associated with bipolar disorder was found, several variants were
increased in bipolar subjects.
ANIMAL MODEL
Voronov et al. (2008) found altered
phosphatidylinositol-4,5-bisphosphate metabolism in the brains of Ts65Dn
mice, a commonly used mouse model of Down syndrome (190685). The defect
could be rescued by restoring Synj1 to disomy in Ts65Dn mice and could
also be recapitulated in transgenic mice overexpressing Synj1. The
transgenic mice exhibited deficits in performance of the Morris water
maze task, suggesting that perturbation of this signaling pathway may
contribute to brain dysfunction in patients with Down syndrome. The
findings suggested that correct dosage of the Synj1 gene is important
for normal brain development and function.
*FIELD* AV
.0001
PARKINSON DISEASE 20, EARLY-ONSET
SYNJ1, ARG258GLN
In 2 sibs, born of consanguineous Iranian parents, with early-onset
atypical Parkinson disease-20 (PARK20; 615530), Krebs et al. (2013)
identified a homozygous c.773G-A transition in the SYNJ1 gene, resulting
in an arg258-to-gln (R258Q) substitution at a highly conserved residue
in the N-terminal SAC1-like phosphatase domain of transcripts 1 and 2
(R219Q for transcripts 3 and 4). The mutation was found by homozygosity
mapping combined with whole-exome sequencing and confirmed by Sanger
sequencing. The mutation segregated with the disorder in the family and
was not found in the dbSNP, 1000 Genomes Project, or Exome Variant
Server databases or in 376 control chromosomes. In vitro functional
expression studies showed that the mutation impaired phosphatase
activity of SYNJ1 against its Sac1 domain substrates (PI3P and PI4P).
SYNJ1 mutations were not found in 20 additional DNA samples from
patients with early-onset Parkinson disease.
Quadri et al. (2013) identified the same homozygous R258Q mutation in 2
sibs with early-onset atypical parkinsonism who were born of Italian
consanguineous parents with origins in Sicily. The mutation was found by
genomewide homozygosity mapping followed by exome sequencing and was
confirmed by Sanger sequencing. The mutation segregated with the
disorder in the family and was not present in the dbSNP, 1000 Genomes
Project, or Exome Variant Server databases or in 360 control
chromosomes. Clearly pathogenic biallelic mutations were not found in
118 unrelated patients with early-onset Parkinson disease, but 2 rare
heterozygous variants of uncertain significance were found in 2
patients, 1 of whom also carried a pathogenic mutation in the PINK1 gene
(608309). The findings of both Krebs et al. (2013) and Quadri et al.
(2013) suggested that defective recycling of synaptic vesicles may play
a role in the neurodegeneration observed in Parkinson disease.
*FIELD* RF
1. Cremona, O.; Di Paolo, G.; Wenk, M. R.; Luthi, A.; Kim, W. T.;
Takei, K.; Daniell, L.; Nemoto, Y.; Shears, S. B.; Flavell, R. A.;
McCormick, D. A.; De Camilli, P.: Essential role of phosphoinositide
metabolism in synaptic vesicle recycling. Cell 99: 179-188, 1999.
2. Cremona, O.; Nimmakayalu, M.; Haffner, C.; Bray-Ward, P.; Ward,
D. C.; De Camilli, P.: Assignment of SYNJ1 to human chromosome 21q22.2
and Synj12 (sic) to the murine homologous region on chromosome 16C3-4
by in situ hybridization. Cytogenet. Cell Genet. 88: 89-90, 2000.
3. Haffner, C.; Takei, K.; Chen, H.; Ringstad, N.; Hudson, A.; Butler,
M. H.; Salcini, A. E.; Di Fiore, P. P.; De Camilli, P.: Synaptojanin
1: localization on coated endocytic intermediates in nerve terminals
and interaction of its 170 kDa isoform with Eps15. FEBS Lett. 419:
175-180, 1997.
4. Krebs, C. E.; Karkheiran, S.; Powell, J. C.; Cao, M.; Makarov,
V.; Darvish, H.; Di Paolo, G.; Walker, R. H.; Shahidi, G. A.; Buxbaum,
J. D.; De Camilli, P.; Yue, Z.; Paisan-Ruiz, C.: The Sac1 domain
of SYNJ1 identified mutated in a family with early-onset progressive
parkinsonism with generalized seizures. Hum. Mutat. 34: 1200-1207,
2013.
5. McPherson, P. S.; Garcia, E. P.; Slepnev, V. I.; David, C.; Zhang,
X.; Grabs, D.; Sossin, W. S.; Bauerfeind, R.; Nemoto, Y.; De Camilli,
P.: A presynaptic inositol-5-phosphatase. Nature 379: 353-357,
1996.
6. Perera, R. M.; Zoncu, R.; Lucast, L.; De Camilli, P.; Toomre, D.
: Two synaptojanin 1 isoforms are recruited to clathrin-coated pits
at different stages. Proc. Nat. Acad. Sci. 103: 19332-19337, 2006.
7. Quadri, M.; Fang, M.; Picillo, M.; Olgiati, S.; Breedveld, G. J.;
Graafland, J.; Wu, B.; Xu, F.; Erro, R.; Amboni, M.; Pappata, S.;
Quarantelli, M.; and 9 others: Mutation in the SYNJ1 gene associated
with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 34:
1208-1215, 2013.
8. Saito, T.; Guan, F.; Papolos, D. F.; Lau, S.; Klein, M.; Fann,
C. S. J.; Lachman, H. M.: Mutation analysis of SYNJ1: a possible
candidate gene for chromosome 21q22-linked bipolar disorder. Molec.
Psychiat. 6: 387-395, 2001.
9. Voronov, S. V.; Frere, S. G.; Giovedi, S.; Pollina, E. A.; Borel,
C.; Zhang, H.; Schmidt, C.; Akeson, E. C.; Wenk, M. R.; Cimasoni,
L.; Arancio, O.; Davisson, M. T.; Antonarakis, S. E.; Gardiner, K.;
De Camilli, P.; Di Paolo, G.: Synaptojanin 1-linked phosphoinositide
dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. Proc.
Nat. Acad. Sci. 105: 9415-9420, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/19/2013
Cassandra L. Kniffin - updated: 7/29/2009
Patricia A. Hartz - updated: 4/27/2007
Victor A. McKusick - updated: 8/7/2001
Carol A. Bocchini - updated: 1/7/2001
*FIELD* CD
Stylianos E. Antonarakis: 11/15/1999
*FIELD* ED
carol: 11/22/2013
carol: 11/21/2013
mcolton: 11/21/2013
ckniffin: 11/19/2013
wwang: 8/11/2009
ckniffin: 7/29/2009
wwang: 2/25/2009
wwang: 4/27/2007
alopez: 4/18/2005
mcapotos: 8/10/2001
mcapotos: 8/9/2001
terry: 8/7/2001
carol: 1/7/2001
mgross: 11/16/1999
mgross: 11/15/1999
*RECORD*
*FIELD* NO
604297
*FIELD* TI
*604297 SYNAPTOJANIN 1; SYNJ1
*FIELD* TX
DESCRIPTION
Synaptojanin-1 is a phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2)
read morethat has a role in clathrin-coated pit dynamics (Perera et al., 2006).
CLONING
Haffner et al. (1997) used rat synaptojanin probes to isolate from a
human cerebellum cDNA library 2 overlapping clones encompassing the
complete coding region of the human SYNJ1 gene, which encodes a major
presynaptic protein concentrated at clathrin-coated endocytic
intermediates in nerve terminals. The authors found that
synaptojanin-170, an alternatively spliced isoform of SYNJ1, binds EPS15
(600051), a clathrin coat-associated protein. Binding was mediated by
the C-terminal region of synaptojanin-170, which contains 3
asparagine-proline-phenylalanine (NPF) repeats. This motif had been
found to be the core of the binding site for the EH domains of EPS15.
These findings suggested that SYNJ1 can be recruited to clathrin-coated
pits via a multiplicity of interactions.
In the rat, McPherson et al. (1996) found that synaptojanin is a nerve
terminal protein that appears to participate with dynamin (see 602377)
in synaptic vesicle recycling It has a molecular mass of 145 kD and is a
member of the inositol-5-phosphatase family, which includes the product
of the gene that is defective in the oculocerebrorenal syndrome of Lowe
(OCRL; 300535). Synaptojanin has 5-phosphatase activity, and its
N-terminal domain is homologous with yeast Sac1 (SACM1L; 606569), which
is genetically implicated in phospholipid metabolism and in the function
of the actin cytoskeleton. The C terminus, which is of different lengths
in adult and developing neurons due to the alternative use of 2
termination sites, is proline-rich, consistent with the reported
interaction of synaptojanin with the SH3 domains of GRB2 (108355).
Synaptojanin also bound the SH3 domain of amphiphysin (AMPH; 600418), a
presynaptic protein with a putative function in endocytosis. These data
suggested a link between phosphoinositide metabolism and synaptic
vesicle recycling.
Perera et al. (2006) stated that both the 145-kD and 170-kD synaptojanin
isoforms contain an N-terminal SAC1-like domain, followed by a 5-prime
phosphatase domain and a proline-rich domain. Only the 170-kD isoform
has an NPF domain and a C-terminal region containing binding sites for
the ear domains of AP2 (see AP2A1; 601026) and clathrin.
GENE FUNCTION
Cremona et al. (1999) generated mice with targeted disruption of the
Synj1 gene. These Synj1-deficient mice exhibited neurologic defects and
died shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels
were increased, and clathrin-coated vesicles accumulated in the
cytomatrix-rich area surrounding the synaptic vesicle cluster in nerve
endings. In cell-free assays, reduced phosphoinositide phosphatase
activity correlated with increased association of clathrin coats with
liposomes. Intracellular recording in hippocampal slices revealed
enhanced synaptic depression during prolonged high-frequency
stimulation, followed by delayed recovery. These results provided
genetic evidence for a crucial role of phosphoinositide metabolism in
synaptic vesicle recycling.
Using multicolor total internal reflection fluorescence microscopy,
Perera et al. (2006) found that the 2 major SYNJ1 isoforms were
differentially recruited to clathrin-coated pits in transiently
transfected COS-7 cells. The ubiquitously expressed 170-kD isoform was
present at all stages of clathrin-coated pit formation, whereas the
145-kD isoform, which is predominantly expressed in brain, was rapidly
recruited as a burst, together with endophilin (SH3GL2; 604465), at a
late stage of clathrin-coated pit formation. Perera et al. (2006)
concluded that dynamic phosphoinositide metabolism may occur throughout
the lifetime of a clathrin-coated pit.
MAPPING
By fluorescence in situ hybridization, Cremona et al. (2000) mapped the
human SYNJ1 gene to chromosome 21q22.2 and the mouse homolog to a region
showing homology of synteny on chromosome 16C3-4.
MOLECULAR GENETICS
- Early-Onset Parkinson Disease 20
Independently and simultaneously, Krebs et al. (2013) and Quadri et al.
(2013) identified the same homozygous missense mutation in the SYNJ1
gene (R258Q; 604297.0001) in affected sibs with autosomal recessive
early-onset Parkinson disease-20 (PARK20; 615530) from an Iranian and an
Italian consanguineous family, respectively. The mutations were found by
homozygosity mapping combined with whole-exome sequencing and segregated
with the disorder in both families. In vitro functional expression
studies by Krebs et al. (2013) indicated that the mutant protein had
impaired phosphatase activity of SYNJ1 against its Sac1 domain
substrates (PI3P and PI4P). All patients developed signs of progressive
parkinsonism in their twenties. The Iranian sibs also had early-onset
generalized seizures, and the Italian sibs had cognitive decline. Quadri
et al. (2013) stated that the SYNJ1 gene interacts with DNAJC6 (608375),
mutation in which causes PARK19 (615528), and noted that the
PD-associated LRRK2 (609007) gene is also involved in synaptic vesicle
endocytosis. The findings of both Krebs et al. (2013) and Quadri et al.
(2013) suggested that defective recycling of synaptic vesicles may play
a role in the neurodegeneration observed in Parkinson disease.
- Associations Pending Confirmation
Saito et al. (2001) studied the SYNJ1 gene as a possible candidate for
chromosome 21q22-linked bipolar disorder (see 125480). By mutation
analysis of 32 exons, intron-exon junctions, and 839 bases of
5-prime-flanking DNA, they identified 11 mutations, of which 4 were very
common and 7 very rare. Several of the 11 mutations may have functional
significance, including 2 coding variants, 2 that may affect the binding
of a transcription factor, and 2 that involve known splicing regulatory
domains. Although no unequivocal identification of a specific SYNJ1
allele associated with bipolar disorder was found, several variants were
increased in bipolar subjects.
ANIMAL MODEL
Voronov et al. (2008) found altered
phosphatidylinositol-4,5-bisphosphate metabolism in the brains of Ts65Dn
mice, a commonly used mouse model of Down syndrome (190685). The defect
could be rescued by restoring Synj1 to disomy in Ts65Dn mice and could
also be recapitulated in transgenic mice overexpressing Synj1. The
transgenic mice exhibited deficits in performance of the Morris water
maze task, suggesting that perturbation of this signaling pathway may
contribute to brain dysfunction in patients with Down syndrome. The
findings suggested that correct dosage of the Synj1 gene is important
for normal brain development and function.
*FIELD* AV
.0001
PARKINSON DISEASE 20, EARLY-ONSET
SYNJ1, ARG258GLN
In 2 sibs, born of consanguineous Iranian parents, with early-onset
atypical Parkinson disease-20 (PARK20; 615530), Krebs et al. (2013)
identified a homozygous c.773G-A transition in the SYNJ1 gene, resulting
in an arg258-to-gln (R258Q) substitution at a highly conserved residue
in the N-terminal SAC1-like phosphatase domain of transcripts 1 and 2
(R219Q for transcripts 3 and 4). The mutation was found by homozygosity
mapping combined with whole-exome sequencing and confirmed by Sanger
sequencing. The mutation segregated with the disorder in the family and
was not found in the dbSNP, 1000 Genomes Project, or Exome Variant
Server databases or in 376 control chromosomes. In vitro functional
expression studies showed that the mutation impaired phosphatase
activity of SYNJ1 against its Sac1 domain substrates (PI3P and PI4P).
SYNJ1 mutations were not found in 20 additional DNA samples from
patients with early-onset Parkinson disease.
Quadri et al. (2013) identified the same homozygous R258Q mutation in 2
sibs with early-onset atypical parkinsonism who were born of Italian
consanguineous parents with origins in Sicily. The mutation was found by
genomewide homozygosity mapping followed by exome sequencing and was
confirmed by Sanger sequencing. The mutation segregated with the
disorder in the family and was not present in the dbSNP, 1000 Genomes
Project, or Exome Variant Server databases or in 360 control
chromosomes. Clearly pathogenic biallelic mutations were not found in
118 unrelated patients with early-onset Parkinson disease, but 2 rare
heterozygous variants of uncertain significance were found in 2
patients, 1 of whom also carried a pathogenic mutation in the PINK1 gene
(608309). The findings of both Krebs et al. (2013) and Quadri et al.
(2013) suggested that defective recycling of synaptic vesicles may play
a role in the neurodegeneration observed in Parkinson disease.
*FIELD* RF
1. Cremona, O.; Di Paolo, G.; Wenk, M. R.; Luthi, A.; Kim, W. T.;
Takei, K.; Daniell, L.; Nemoto, Y.; Shears, S. B.; Flavell, R. A.;
McCormick, D. A.; De Camilli, P.: Essential role of phosphoinositide
metabolism in synaptic vesicle recycling. Cell 99: 179-188, 1999.
2. Cremona, O.; Nimmakayalu, M.; Haffner, C.; Bray-Ward, P.; Ward,
D. C.; De Camilli, P.: Assignment of SYNJ1 to human chromosome 21q22.2
and Synj12 (sic) to the murine homologous region on chromosome 16C3-4
by in situ hybridization. Cytogenet. Cell Genet. 88: 89-90, 2000.
3. Haffner, C.; Takei, K.; Chen, H.; Ringstad, N.; Hudson, A.; Butler,
M. H.; Salcini, A. E.; Di Fiore, P. P.; De Camilli, P.: Synaptojanin
1: localization on coated endocytic intermediates in nerve terminals
and interaction of its 170 kDa isoform with Eps15. FEBS Lett. 419:
175-180, 1997.
4. Krebs, C. E.; Karkheiran, S.; Powell, J. C.; Cao, M.; Makarov,
V.; Darvish, H.; Di Paolo, G.; Walker, R. H.; Shahidi, G. A.; Buxbaum,
J. D.; De Camilli, P.; Yue, Z.; Paisan-Ruiz, C.: The Sac1 domain
of SYNJ1 identified mutated in a family with early-onset progressive
parkinsonism with generalized seizures. Hum. Mutat. 34: 1200-1207,
2013.
5. McPherson, P. S.; Garcia, E. P.; Slepnev, V. I.; David, C.; Zhang,
X.; Grabs, D.; Sossin, W. S.; Bauerfeind, R.; Nemoto, Y.; De Camilli,
P.: A presynaptic inositol-5-phosphatase. Nature 379: 353-357,
1996.
6. Perera, R. M.; Zoncu, R.; Lucast, L.; De Camilli, P.; Toomre, D.
: Two synaptojanin 1 isoforms are recruited to clathrin-coated pits
at different stages. Proc. Nat. Acad. Sci. 103: 19332-19337, 2006.
7. Quadri, M.; Fang, M.; Picillo, M.; Olgiati, S.; Breedveld, G. J.;
Graafland, J.; Wu, B.; Xu, F.; Erro, R.; Amboni, M.; Pappata, S.;
Quarantelli, M.; and 9 others: Mutation in the SYNJ1 gene associated
with autosomal recessive, early-onset Parkinsonism. Hum. Mutat. 34:
1208-1215, 2013.
8. Saito, T.; Guan, F.; Papolos, D. F.; Lau, S.; Klein, M.; Fann,
C. S. J.; Lachman, H. M.: Mutation analysis of SYNJ1: a possible
candidate gene for chromosome 21q22-linked bipolar disorder. Molec.
Psychiat. 6: 387-395, 2001.
9. Voronov, S. V.; Frere, S. G.; Giovedi, S.; Pollina, E. A.; Borel,
C.; Zhang, H.; Schmidt, C.; Akeson, E. C.; Wenk, M. R.; Cimasoni,
L.; Arancio, O.; Davisson, M. T.; Antonarakis, S. E.; Gardiner, K.;
De Camilli, P.; Di Paolo, G.: Synaptojanin 1-linked phosphoinositide
dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. Proc.
Nat. Acad. Sci. 105: 9415-9420, 2008.
*FIELD* CN
Cassandra L. Kniffin - updated: 11/19/2013
Cassandra L. Kniffin - updated: 7/29/2009
Patricia A. Hartz - updated: 4/27/2007
Victor A. McKusick - updated: 8/7/2001
Carol A. Bocchini - updated: 1/7/2001
*FIELD* CD
Stylianos E. Antonarakis: 11/15/1999
*FIELD* ED
carol: 11/22/2013
carol: 11/21/2013
mcolton: 11/21/2013
ckniffin: 11/19/2013
wwang: 8/11/2009
ckniffin: 7/29/2009
wwang: 2/25/2009
wwang: 4/27/2007
alopez: 4/18/2005
mcapotos: 8/10/2001
mcapotos: 8/9/2001
terry: 8/7/2001
carol: 1/7/2001
mgross: 11/16/1999
mgross: 11/15/1999