Full text data of VPS35
VPS35
(MEM3)
[Confidence: low (only semi-automatic identification from reviews)]
Vacuolar protein sorting-associated protein 35; hVPS35 (Maternal-embryonic 3; Vesicle protein sorting 35)
Vacuolar protein sorting-associated protein 35; hVPS35 (Maternal-embryonic 3; Vesicle protein sorting 35)
UniProt
Q96QK1
ID VPS35_HUMAN Reviewed; 796 AA.
AC Q96QK1; Q561W2; Q9H016; Q9H096; Q9H4P3; Q9H8J0; Q9NRS7; Q9NVG2;
read moreAC Q9NX80; Q9NZK2;
DT 25-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2002, sequence version 2.
DT 22-JAN-2014, entry version 123.
DE RecName: Full=Vacuolar protein sorting-associated protein 35;
DE Short=hVPS35;
DE AltName: Full=Maternal-embryonic 3;
DE AltName: Full=Vesicle protein sorting 35;
GN Name=VPS35; Synonyms=MEM3; ORFNames=TCCCTA00141;
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].
RC TISSUE=Lung;
RX PubMed=11062004; DOI=10.1006/bbrc.2000.3727;
RA Edgar A.J., Polak J.M.;
RT "Human homologues of yeast vacuolar protein sorting 29 and 35.";
RL Biochem. Biophys. Res. Commun. 277:622-630(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RX PubMed=11112353; DOI=10.1006/geno.2000.6380;
RA Zhang P., Yu L., Gao J., Fu Q., Dai F., Zhao Y., Zheng L., Zhao S.;
RT "Cloning and characterization of human VPS35 and mouse Vps35 and
RT mapping of VPS35 to human chromosome 16q13-q21.";
RL Genomics 70:253-257(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH VPS29; VPS26A; SNX1
RP AND SNX2.
RC TISSUE=Colon;
RX PubMed=11102511; DOI=10.1091/mbc.11.12.4105;
RA Renfrew Haft C., de la Luz Sierra M., Bafford R., Lesniak M.A.,
RA Barr V.A., Taylor S.I.;
RT "Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29,
RT and 35: assembly into multimeric complexes.";
RL Mol. Biol. Cell 11:4105-4116(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pheochromocytoma;
RA Peng Y., Li Y., Tu Y., Xu S., Han Z., Fu G., Chen Z.;
RT "A novel gene expressed in human pheochromocytoma.";
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ileal mucosa, Placenta, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Placenta, and Prostate;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 469-796.
RC TISSUE=Leukemia;
RA Zhou J., Yu W., Tang H., Mei G., Tsang Y.T.M., Bouck J., Gibbs R.A.,
RA Margolin J.F.;
RT "Pediatric leukemia cDNA sequencing project.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH XPO7; ARHGAP1; EIF4A1; VPS26A; VPS29
RP AND SFN.
RX PubMed=15282546; DOI=10.1038/sj.emboj.7600338;
RA Mingot J.-M., Bohnsack M.T., Jaekle U., Goerlich D.;
RT "Exportin 7 defines a novel general nuclear export pathway.";
RL EMBO J. 23:3227-3236(2004).
RN [10]
RP FUNCTION.
RX PubMed=15247922; DOI=10.1038/ncb1153;
RA Verges M., Luton F., Gruber C., Tiemann F., Reinders L.G., Huang L.,
RA Burlingame A.L., Haft C.R., Mostov K.E.;
RT "The mammalian retromer regulates transcytosis of the polymeric
RT immunoglobulin receptor.";
RL Nat. Cell Biol. 6:763-769(2004).
RN [11]
RP INTERACTION WITH GOLPH3.
RX PubMed=19553991; DOI=10.1038/nature08109;
RA Scott K.L., Kabbarah O., Liang M.C., Ivanova E., Anagnostou V., Wu J.,
RA Dhakal S., Wu M., Chen S., Feinberg T., Huang J., Saci A.,
RA Widlund H.R., Fisher D.E., Xiao Y., Rimm D.L., Protopopov A.,
RA Wong K.K., Chin L.;
RT "GOLPH3 modulates mTOR signalling and rapamycin sensitivity in
RT cancer.";
RL Nature 459:1085-1090(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 483-780 IN COMPLEX WITH
RP VPS29, AND ELECTRON MICROSCOPY OF THE RETROMER COMPLEX CONTAINING
RP VPS29; VPS35 AND VPS26.
RX PubMed=17891154; DOI=10.1038/nature06216;
RA Hierro A., Rojas A.L., Rojas R., Murthy N., Effantin G., Kajava A.V.,
RA Steven A.C., Bonifacino J.S., Hurley J.H.;
RT "Functional architecture of the retromer cargo-recognition complex.";
RL Nature 449:1063-1067(2007).
RN [15]
RP VARIANT PARK17 ASN-620, AND VARIANTS SER-316 AND VAL-737.
RX PubMed=21763482; DOI=10.1016/j.ajhg.2011.06.001;
RA Vilarino-Guell C., Wider C., Ross O.A., Dachsel J.C., Kachergus J.M.,
RA Lincoln S.J., Soto-Ortolaza A.I., Cobb S.A., Wilhoite G.J.,
RA Bacon J.A., Behrouz B., Melrose H.L., Hentati E., Puschmann A.,
RA Evans D.M., Conibear E., Wasserman W.W., Aasly J.O., Burkhard P.R.,
RA Djaldetti R., Ghika J., Hentati F., Krygowska-Wajs A., Lynch T.,
RA Melamed E., Rajput A., Rajput A.H., Solida A., Wu R.M., Uitti R.J.,
RA Wszolek Z.K., Vingerhoets F., Farrer M.J.;
RT "VPS35 mutations in Parkinson disease.";
RL Am. J. Hum. Genet. 89:162-167(2011).
RN [16]
RP VARIANT PARK17 ASN-620, AND VARIANTS SER-51; ILE-57; ARG-82; MET-241;
RP TRP-524 AND MET-774.
RX PubMed=21763483; DOI=10.1016/j.ajhg.2011.06.008;
RA Zimprich A., Benet-Pages A., Struhal W., Graf E., Eck S.H.,
RA Offman M.N., Haubenberger D., Spielberger S., Schulte E.C.,
RA Lichtner P., Rossle S.C., Klopp N., Wolf E., Seppi K., Pirker W.,
RA Reinthaler E., Harutyunyan A., Kralovics R., Peters A., Zimprich F.,
RA Brucke T., Poewe W., Auff E., Trenkwalder C., Rost B., Ransmayr G.,
RA Winkelmann J., Meitinger T., Strom T.M.;
RT "A mutation in VPS35, encoding a subunit of the retromer complex,
RT causes late-onset Parkinson disease.";
RL Am. J. Hum. Genet. 89:168-175(2011).
RN [17]
RP VARIANT PARK17 ASN-620.
RX PubMed=22517097; DOI=10.1212/WNL.0b013e318253d5f2;
RA Lesage S., Condroyer C., Klebe S., Honore A., Tison F.,
RA Brefel-Courbon C., Durr A., Brice A.;
RT "Identification of VPS35 mutations replicated in French families with
RT Parkinson disease.";
RL Neurology 78:1449-1450(2012).
CC -!- FUNCTION: Essential component of the retromer complex, a complex
CC required to retrieve lysosomal enzyme receptors (IGF2R and M6PR)
CC from endosomes to the trans-Golgi network. Also required to
CC regulate transcytosis of the polymeric immunoglobulin receptor
CC (pIgR-pIgA).
CC -!- SUBUNIT: Component of the retromer complex composed of VPS26
CC (VPS26A or VPS26B), VPS29, VPS35, SNX1 and SNX2. Interacts
CC directly with VPS26A and VPS26B. Found in a complex with XPO7,
CC EIF4A1, ARHGAP1, VPS26A, VPS29, VPS35 and SFN. Interacts with
CC GOLPH3.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane
CC protein.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, brain,
CC placenta, skeletal muscle, spleen, thymus, testis, ovary, small
CC intestine, kidney and colon.
CC -!- DISEASE: Parkinson disease 17 (PARK17) [MIM:614203]: An autosomal
CC dominant, adult-onset form of Parkinson disease. Parkinson disease
CC is a complex neurodegenerative disorder characterized by
CC bradykinesia, resting tremor, muscular rigidity and postural
CC instability, as well as by a clinically significant response to
CC treatment with levodopa. The pathology involves the loss of
CC dopaminergic neurons in the substantia nigra and the presence of
CC Lewy bodies (intraneuronal accumulations of aggregated proteins),
CC in surviving neurons in various areas of the brain. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the VPS35 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAG01989.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAA91137.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAB14626.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AF191298; AAF02778.2; -; mRNA.
DR EMBL; AF186382; AAG40619.1; -; mRNA.
DR EMBL; AF175265; AAF89953.1; -; mRNA.
DR EMBL; AF183418; AAG09687.1; -; mRNA.
DR EMBL; AK001614; BAA91790.1; -; mRNA.
DR EMBL; AK023650; BAB14626.1; ALT_INIT; mRNA.
DR EMBL; AK000395; BAA91137.1; ALT_INIT; mRNA.
DR EMBL; AL136888; CAB66822.1; -; mRNA.
DR EMBL; AL512769; CAC21686.1; -; mRNA.
DR EMBL; BC002414; AAH02414.1; -; mRNA.
DR EMBL; BC010362; AAH10362.1; -; mRNA.
DR EMBL; BC093036; AAH93036.1; -; mRNA.
DR EMBL; AY007112; AAG01989.1; ALT_INIT; mRNA.
DR PIR; JC7516; JC7516.
DR RefSeq; NP_060676.2; NM_018206.4.
DR UniGene; Hs.454528; -.
DR PDB; 2R17; X-ray; 2.80 A; C/D=483-780.
DR PDBsum; 2R17; -.
DR ProteinModelPortal; Q96QK1; -.
DR SMR; Q96QK1; 483-780.
DR DIP; DIP-29076N; -.
DR IntAct; Q96QK1; 17.
DR MINT; MINT-5001902; -.
DR ChEMBL; CHEMBL2216744; -.
DR PhosphoSite; Q96QK1; -.
DR DMDM; 25453321; -.
DR PaxDb; Q96QK1; -.
DR PeptideAtlas; Q96QK1; -.
DR PRIDE; Q96QK1; -.
DR DNASU; 55737; -.
DR Ensembl; ENST00000299138; ENSP00000299138; ENSG00000069329.
DR GeneID; 55737; -.
DR KEGG; hsa:55737; -.
DR UCSC; uc002eed.3; human.
DR CTD; 55737; -.
DR GeneCards; GC16M046691; -.
DR HGNC; HGNC:13487; VPS35.
DR HPA; HPA040802; -.
DR MIM; 601501; gene.
DR MIM; 614203; phenotype.
DR neXtProt; NX_Q96QK1; -.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA37783; -.
DR eggNOG; NOG252873; -.
DR HOVERGEN; HBG054277; -.
DR InParanoid; Q96QK1; -.
DR OMA; VNCRDSL; -.
DR OrthoDB; EOG7TMZR5; -.
DR PhylomeDB; Q96QK1; -.
DR Reactome; REACT_111102; Signal Transduction.
DR ChiTaRS; VPS35; human.
DR EvolutionaryTrace; Q96QK1; -.
DR GeneWiki; VPS35; -.
DR GenomeRNAi; 55737; -.
DR NextBio; 60680; -.
DR PRO; PR:Q96QK1; -.
DR ArrayExpress; Q96QK1; -.
DR Bgee; Q96QK1; -.
DR Genevestigator; Q96QK1; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:LIFEdb.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; NAS:UniProtKB.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR005378; Vps35.
DR PANTHER; PTHR11099; PTHR11099; 1.
DR Pfam; PF03635; Vps35; 1.
DR PIRSF; PIRSF009375; Retromer_Vps35; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Membrane;
KW Neurodegeneration; Parkinson disease; Parkinsonism; Phosphoprotein;
KW Polymorphism; Protein transport; Reference proteome; Transport.
FT CHAIN 1 796 Vacuolar protein sorting-associated
FT protein 35.
FT /FTId=PRO_0000065896.
FT MOD_RES 7 7 Phosphoserine.
FT MOD_RES 791 791 Phosphotyrosine (By similarity).
FT VARIANT 51 51 G -> S.
FT /FTId=VAR_066653.
FT VARIANT 57 57 M -> I.
FT /FTId=VAR_066654.
FT VARIANT 82 82 T -> R.
FT /FTId=VAR_066655.
FT VARIANT 241 241 I -> M (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066656.
FT VARIANT 316 316 P -> S (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066657.
FT VARIANT 524 524 R -> W (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066658.
FT VARIANT 602 602 V -> D (in dbSNP:rs34687100).
FT /FTId=VAR_054046.
FT VARIANT 620 620 D -> N (in PARK17).
FT /FTId=VAR_066659.
FT VARIANT 737 737 A -> V.
FT /FTId=VAR_066660.
FT VARIANT 774 774 L -> M.
FT /FTId=VAR_066661.
FT CONFLICT 42 42 A -> S (in Ref. 6; CAB66822).
FT CONFLICT 160 160 I -> T (in Ref. 5; BAB14626).
FT CONFLICT 168 168 T -> P (in Ref. 3; AAF89953).
FT CONFLICT 453 453 S -> F (in Ref. 7; AAH10362).
FT CONFLICT 526 526 R -> G (in Ref. 5; BAA91790).
FT CONFLICT 694 694 K -> E (in Ref. 5; BAA91790).
FT CONFLICT 796 796 L -> H (in Ref. 5; BAA91137).
FT TURN 484 487
FT HELIX 488 498
FT HELIX 503 518
FT STRAND 522 524
FT HELIX 525 544
FT TURN 545 549
FT HELIX 553 573
FT HELIX 578 594
FT HELIX 599 617
FT HELIX 621 635
FT HELIX 643 658
FT HELIX 663 672
FT HELIX 674 678
FT TURN 683 687
FT HELIX 693 709
FT HELIX 713 731
FT TURN 732 734
FT HELIX 740 751
FT TURN 752 755
FT HELIX 761 776
SQ SEQUENCE 796 AA; 91707 MW; 28D2DD1C6B920A0A CRC64;
MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML GELRTSMLSP
KSYYELYMAI SDELHYLEVY LTDEFAKGRK VADLYELVQY AGNIIPRLYL LITVGVVYVK
SFPQSRKDIL KDLVEMCRGV QHPLRGLFLR NYLLQCTRNI LPDEGEPTDE ETTGDISDSM
DFVLLNFAEM NKLWVRMQHQ GHSRDREKRE RERQELRILV GTNLVRLSQL EGVNVERYKQ
IVLTGILEQV VNCRDALAQE YLMECIIQVF PDEFHLQTLN PFLRACAELH QNVNVKNIII
ALIDRLALFA HREDGPGIPA DIKLFDIFSQ QVATVIQSRQ DMPSEDVVSL QVSLINLAMK
CYPDRVDYVD KVLETTVEIF NKLNLEHIAT SSAVSKELTR LLKIPVDTYN NILTVLKLKH
FHPLFEYFDY ESRKSMSCYV LSNVLDYNTE IVSQDQVDSI MNLVSTLIQD QPDQPVEDPD
PEDFADEQSL VGRFIHLLRS EDPDQQYLIL NTARKHFGAG GNQRIRFTLP PLVFAAYQLA
FRYKENSKVD DKWEKKCQKI FSFAHQTISA LIKAELAELP LRLFLQGALA AGEIGFENHE
TVAYEFMSQA FSLYEDEISD SKAQLAAITL IIGTFERMKC FSEENHEPLR TQCALAASKL
LKKPDQGRAV STCAHLFWSG RNTDKNGEEL HGGKRVMECL KKALKIANQC MDPSLQVQLF
IEILNRYIYF YEKENDAVTI QVLNQLIQKI REDLPNLESS EETEQINKHF HNTLEHLRLR
RESPESEGPI YEGLIL
//
ID VPS35_HUMAN Reviewed; 796 AA.
AC Q96QK1; Q561W2; Q9H016; Q9H096; Q9H4P3; Q9H8J0; Q9NRS7; Q9NVG2;
read moreAC Q9NX80; Q9NZK2;
DT 25-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2002, sequence version 2.
DT 22-JAN-2014, entry version 123.
DE RecName: Full=Vacuolar protein sorting-associated protein 35;
DE Short=hVPS35;
DE AltName: Full=Maternal-embryonic 3;
DE AltName: Full=Vesicle protein sorting 35;
GN Name=VPS35; Synonyms=MEM3; ORFNames=TCCCTA00141;
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].
RC TISSUE=Lung;
RX PubMed=11062004; DOI=10.1006/bbrc.2000.3727;
RA Edgar A.J., Polak J.M.;
RT "Human homologues of yeast vacuolar protein sorting 29 and 35.";
RL Biochem. Biophys. Res. Commun. 277:622-630(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Testis;
RX PubMed=11112353; DOI=10.1006/geno.2000.6380;
RA Zhang P., Yu L., Gao J., Fu Q., Dai F., Zhao Y., Zheng L., Zhao S.;
RT "Cloning and characterization of human VPS35 and mouse Vps35 and
RT mapping of VPS35 to human chromosome 16q13-q21.";
RL Genomics 70:253-257(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], AND INTERACTION WITH VPS29; VPS26A; SNX1
RP AND SNX2.
RC TISSUE=Colon;
RX PubMed=11102511; DOI=10.1091/mbc.11.12.4105;
RA Renfrew Haft C., de la Luz Sierra M., Bafford R., Lesniak M.A.,
RA Barr V.A., Taylor S.I.;
RT "Human orthologs of yeast vacuolar protein sorting proteins Vps26, 29,
RT and 35: assembly into multimeric complexes.";
RL Mol. Biol. Cell 11:4105-4116(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pheochromocytoma;
RA Peng Y., Li Y., Tu Y., Xu S., Han Z., Fu G., Chen Z.;
RT "A novel gene expressed in human pheochromocytoma.";
RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ileal mucosa, Placenta, and Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Placenta, and Prostate;
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 469-796.
RC TISSUE=Leukemia;
RA Zhou J., Yu W., Tang H., Mei G., Tsang Y.T.M., Bouck J., Gibbs R.A.,
RA Margolin J.F.;
RT "Pediatric leukemia cDNA sequencing project.";
RL Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP IDENTIFICATION IN A COMPLEX WITH XPO7; ARHGAP1; EIF4A1; VPS26A; VPS29
RP AND SFN.
RX PubMed=15282546; DOI=10.1038/sj.emboj.7600338;
RA Mingot J.-M., Bohnsack M.T., Jaekle U., Goerlich D.;
RT "Exportin 7 defines a novel general nuclear export pathway.";
RL EMBO J. 23:3227-3236(2004).
RN [10]
RP FUNCTION.
RX PubMed=15247922; DOI=10.1038/ncb1153;
RA Verges M., Luton F., Gruber C., Tiemann F., Reinders L.G., Huang L.,
RA Burlingame A.L., Haft C.R., Mostov K.E.;
RT "The mammalian retromer regulates transcytosis of the polymeric
RT immunoglobulin receptor.";
RL Nat. Cell Biol. 6:763-769(2004).
RN [11]
RP INTERACTION WITH GOLPH3.
RX PubMed=19553991; DOI=10.1038/nature08109;
RA Scott K.L., Kabbarah O., Liang M.C., Ivanova E., Anagnostou V., Wu J.,
RA Dhakal S., Wu M., Chen S., Feinberg T., Huang J., Saci A.,
RA Widlund H.R., Fisher D.E., Xiao Y., Rimm D.L., Protopopov A.,
RA Wong K.K., Chin L.;
RT "GOLPH3 modulates mTOR signalling and rapamycin sensitivity in
RT cancer.";
RL Nature 459:1085-1090(2009).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-7, 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 483-780 IN COMPLEX WITH
RP VPS29, AND ELECTRON MICROSCOPY OF THE RETROMER COMPLEX CONTAINING
RP VPS29; VPS35 AND VPS26.
RX PubMed=17891154; DOI=10.1038/nature06216;
RA Hierro A., Rojas A.L., Rojas R., Murthy N., Effantin G., Kajava A.V.,
RA Steven A.C., Bonifacino J.S., Hurley J.H.;
RT "Functional architecture of the retromer cargo-recognition complex.";
RL Nature 449:1063-1067(2007).
RN [15]
RP VARIANT PARK17 ASN-620, AND VARIANTS SER-316 AND VAL-737.
RX PubMed=21763482; DOI=10.1016/j.ajhg.2011.06.001;
RA Vilarino-Guell C., Wider C., Ross O.A., Dachsel J.C., Kachergus J.M.,
RA Lincoln S.J., Soto-Ortolaza A.I., Cobb S.A., Wilhoite G.J.,
RA Bacon J.A., Behrouz B., Melrose H.L., Hentati E., Puschmann A.,
RA Evans D.M., Conibear E., Wasserman W.W., Aasly J.O., Burkhard P.R.,
RA Djaldetti R., Ghika J., Hentati F., Krygowska-Wajs A., Lynch T.,
RA Melamed E., Rajput A., Rajput A.H., Solida A., Wu R.M., Uitti R.J.,
RA Wszolek Z.K., Vingerhoets F., Farrer M.J.;
RT "VPS35 mutations in Parkinson disease.";
RL Am. J. Hum. Genet. 89:162-167(2011).
RN [16]
RP VARIANT PARK17 ASN-620, AND VARIANTS SER-51; ILE-57; ARG-82; MET-241;
RP TRP-524 AND MET-774.
RX PubMed=21763483; DOI=10.1016/j.ajhg.2011.06.008;
RA Zimprich A., Benet-Pages A., Struhal W., Graf E., Eck S.H.,
RA Offman M.N., Haubenberger D., Spielberger S., Schulte E.C.,
RA Lichtner P., Rossle S.C., Klopp N., Wolf E., Seppi K., Pirker W.,
RA Reinthaler E., Harutyunyan A., Kralovics R., Peters A., Zimprich F.,
RA Brucke T., Poewe W., Auff E., Trenkwalder C., Rost B., Ransmayr G.,
RA Winkelmann J., Meitinger T., Strom T.M.;
RT "A mutation in VPS35, encoding a subunit of the retromer complex,
RT causes late-onset Parkinson disease.";
RL Am. J. Hum. Genet. 89:168-175(2011).
RN [17]
RP VARIANT PARK17 ASN-620.
RX PubMed=22517097; DOI=10.1212/WNL.0b013e318253d5f2;
RA Lesage S., Condroyer C., Klebe S., Honore A., Tison F.,
RA Brefel-Courbon C., Durr A., Brice A.;
RT "Identification of VPS35 mutations replicated in French families with
RT Parkinson disease.";
RL Neurology 78:1449-1450(2012).
CC -!- FUNCTION: Essential component of the retromer complex, a complex
CC required to retrieve lysosomal enzyme receptors (IGF2R and M6PR)
CC from endosomes to the trans-Golgi network. Also required to
CC regulate transcytosis of the polymeric immunoglobulin receptor
CC (pIgR-pIgA).
CC -!- SUBUNIT: Component of the retromer complex composed of VPS26
CC (VPS26A or VPS26B), VPS29, VPS35, SNX1 and SNX2. Interacts
CC directly with VPS26A and VPS26B. Found in a complex with XPO7,
CC EIF4A1, ARHGAP1, VPS26A, VPS29, VPS35 and SFN. Interacts with
CC GOLPH3.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Membrane; Peripheral membrane
CC protein.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, brain,
CC placenta, skeletal muscle, spleen, thymus, testis, ovary, small
CC intestine, kidney and colon.
CC -!- DISEASE: Parkinson disease 17 (PARK17) [MIM:614203]: An autosomal
CC dominant, adult-onset form of Parkinson disease. Parkinson disease
CC is a complex neurodegenerative disorder characterized by
CC bradykinesia, resting tremor, muscular rigidity and postural
CC instability, as well as by a clinically significant response to
CC treatment with levodopa. The pathology involves the loss of
CC dopaminergic neurons in the substantia nigra and the presence of
CC Lewy bodies (intraneuronal accumulations of aggregated proteins),
CC in surviving neurons in various areas of the brain. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- SIMILARITY: Belongs to the VPS35 family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAG01989.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAA91137.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC Sequence=BAB14626.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; AF191298; AAF02778.2; -; mRNA.
DR EMBL; AF186382; AAG40619.1; -; mRNA.
DR EMBL; AF175265; AAF89953.1; -; mRNA.
DR EMBL; AF183418; AAG09687.1; -; mRNA.
DR EMBL; AK001614; BAA91790.1; -; mRNA.
DR EMBL; AK023650; BAB14626.1; ALT_INIT; mRNA.
DR EMBL; AK000395; BAA91137.1; ALT_INIT; mRNA.
DR EMBL; AL136888; CAB66822.1; -; mRNA.
DR EMBL; AL512769; CAC21686.1; -; mRNA.
DR EMBL; BC002414; AAH02414.1; -; mRNA.
DR EMBL; BC010362; AAH10362.1; -; mRNA.
DR EMBL; BC093036; AAH93036.1; -; mRNA.
DR EMBL; AY007112; AAG01989.1; ALT_INIT; mRNA.
DR PIR; JC7516; JC7516.
DR RefSeq; NP_060676.2; NM_018206.4.
DR UniGene; Hs.454528; -.
DR PDB; 2R17; X-ray; 2.80 A; C/D=483-780.
DR PDBsum; 2R17; -.
DR ProteinModelPortal; Q96QK1; -.
DR SMR; Q96QK1; 483-780.
DR DIP; DIP-29076N; -.
DR IntAct; Q96QK1; 17.
DR MINT; MINT-5001902; -.
DR ChEMBL; CHEMBL2216744; -.
DR PhosphoSite; Q96QK1; -.
DR DMDM; 25453321; -.
DR PaxDb; Q96QK1; -.
DR PeptideAtlas; Q96QK1; -.
DR PRIDE; Q96QK1; -.
DR DNASU; 55737; -.
DR Ensembl; ENST00000299138; ENSP00000299138; ENSG00000069329.
DR GeneID; 55737; -.
DR KEGG; hsa:55737; -.
DR UCSC; uc002eed.3; human.
DR CTD; 55737; -.
DR GeneCards; GC16M046691; -.
DR HGNC; HGNC:13487; VPS35.
DR HPA; HPA040802; -.
DR MIM; 601501; gene.
DR MIM; 614203; phenotype.
DR neXtProt; NX_Q96QK1; -.
DR Orphanet; 2828; Young adult-onset Parkinsonism.
DR PharmGKB; PA37783; -.
DR eggNOG; NOG252873; -.
DR HOVERGEN; HBG054277; -.
DR InParanoid; Q96QK1; -.
DR OMA; VNCRDSL; -.
DR OrthoDB; EOG7TMZR5; -.
DR PhylomeDB; Q96QK1; -.
DR Reactome; REACT_111102; Signal Transduction.
DR ChiTaRS; VPS35; human.
DR EvolutionaryTrace; Q96QK1; -.
DR GeneWiki; VPS35; -.
DR GenomeRNAi; 55737; -.
DR NextBio; 60680; -.
DR PRO; PR:Q96QK1; -.
DR ArrayExpress; Q96QK1; -.
DR Bgee; Q96QK1; -.
DR Genevestigator; Q96QK1; -.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:LIFEdb.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0042147; P:retrograde transport, endosome to Golgi; NAS:UniProtKB.
DR InterPro; IPR016024; ARM-type_fold.
DR InterPro; IPR005378; Vps35.
DR PANTHER; PTHR11099; PTHR11099; 1.
DR Pfam; PF03635; Vps35; 1.
DR PIRSF; PIRSF009375; Retromer_Vps35; 1.
DR SUPFAM; SSF48371; SSF48371; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; Cytoplasm; Membrane;
KW Neurodegeneration; Parkinson disease; Parkinsonism; Phosphoprotein;
KW Polymorphism; Protein transport; Reference proteome; Transport.
FT CHAIN 1 796 Vacuolar protein sorting-associated
FT protein 35.
FT /FTId=PRO_0000065896.
FT MOD_RES 7 7 Phosphoserine.
FT MOD_RES 791 791 Phosphotyrosine (By similarity).
FT VARIANT 51 51 G -> S.
FT /FTId=VAR_066653.
FT VARIANT 57 57 M -> I.
FT /FTId=VAR_066654.
FT VARIANT 82 82 T -> R.
FT /FTId=VAR_066655.
FT VARIANT 241 241 I -> M (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066656.
FT VARIANT 316 316 P -> S (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066657.
FT VARIANT 524 524 R -> W (found in a patient with Parkinson
FT disease).
FT /FTId=VAR_066658.
FT VARIANT 602 602 V -> D (in dbSNP:rs34687100).
FT /FTId=VAR_054046.
FT VARIANT 620 620 D -> N (in PARK17).
FT /FTId=VAR_066659.
FT VARIANT 737 737 A -> V.
FT /FTId=VAR_066660.
FT VARIANT 774 774 L -> M.
FT /FTId=VAR_066661.
FT CONFLICT 42 42 A -> S (in Ref. 6; CAB66822).
FT CONFLICT 160 160 I -> T (in Ref. 5; BAB14626).
FT CONFLICT 168 168 T -> P (in Ref. 3; AAF89953).
FT CONFLICT 453 453 S -> F (in Ref. 7; AAH10362).
FT CONFLICT 526 526 R -> G (in Ref. 5; BAA91790).
FT CONFLICT 694 694 K -> E (in Ref. 5; BAA91790).
FT CONFLICT 796 796 L -> H (in Ref. 5; BAA91137).
FT TURN 484 487
FT HELIX 488 498
FT HELIX 503 518
FT STRAND 522 524
FT HELIX 525 544
FT TURN 545 549
FT HELIX 553 573
FT HELIX 578 594
FT HELIX 599 617
FT HELIX 621 635
FT HELIX 643 658
FT HELIX 663 672
FT HELIX 674 678
FT TURN 683 687
FT HELIX 693 709
FT HELIX 713 731
FT TURN 732 734
FT HELIX 740 751
FT TURN 752 755
FT HELIX 761 776
SQ SEQUENCE 796 AA; 91707 MW; 28D2DD1C6B920A0A CRC64;
MPTTQQSPQD EQEKLLDEAI QAVKVQSFQM KRCLDKNKLM DALKHASNML GELRTSMLSP
KSYYELYMAI SDELHYLEVY LTDEFAKGRK VADLYELVQY AGNIIPRLYL LITVGVVYVK
SFPQSRKDIL KDLVEMCRGV QHPLRGLFLR NYLLQCTRNI LPDEGEPTDE ETTGDISDSM
DFVLLNFAEM NKLWVRMQHQ GHSRDREKRE RERQELRILV GTNLVRLSQL EGVNVERYKQ
IVLTGILEQV VNCRDALAQE YLMECIIQVF PDEFHLQTLN PFLRACAELH QNVNVKNIII
ALIDRLALFA HREDGPGIPA DIKLFDIFSQ QVATVIQSRQ DMPSEDVVSL QVSLINLAMK
CYPDRVDYVD KVLETTVEIF NKLNLEHIAT SSAVSKELTR LLKIPVDTYN NILTVLKLKH
FHPLFEYFDY ESRKSMSCYV LSNVLDYNTE IVSQDQVDSI MNLVSTLIQD QPDQPVEDPD
PEDFADEQSL VGRFIHLLRS EDPDQQYLIL NTARKHFGAG GNQRIRFTLP PLVFAAYQLA
FRYKENSKVD DKWEKKCQKI FSFAHQTISA LIKAELAELP LRLFLQGALA AGEIGFENHE
TVAYEFMSQA FSLYEDEISD SKAQLAAITL IIGTFERMKC FSEENHEPLR TQCALAASKL
LKKPDQGRAV STCAHLFWSG RNTDKNGEEL HGGKRVMECL KKALKIANQC MDPSLQVQLF
IEILNRYIYF YEKENDAVTI QVLNQLIQKI REDLPNLESS EETEQINKHF HNTLEHLRLR
RESPESEGPI YEGLIL
//
MIM
601501
*RECORD*
*FIELD* NO
601501
*FIELD* TI
*601501 VACUOLAR PROTEIN SORTING 35, YEAST, HOMOLOG OF; VPS35
;;MEM3, MOUSE, HOMOLOG OF; MEM3
read more*FIELD* TX
DESCRIPTION
The VPS35 gene encodes a component of the retromer cargo-recognition
complex critical for endosome-trans-Golgi trafficking and the recycling
of membrane-associated proteins (summary by Vilarino-Guell et al.,
2011).
CLONING
To study the molecular function of genes expressed during
preimplantation development, Hwang et al. (1996) isolated a novel
maternal transcript, stage specific embryonic cDNA-26 (SSEC-26), from a
partial subtraction library of mouse unfertilized eggs and
preimplantation embryos. The SSEC-26 transcript was abundant in the
unfertilized egg and also actively transcribed from the newly formed
zygotic genome. On the basis of its expression in eggs and embryos, this
mouse gene was named Mem3 (maternal-embryonic-3). The deduced amino acid
sequence of Mem3 resembles that of the yeast VPS35 protein in 2 separate
domains. Hwang et al. (1996) assembled a cDNA sequence of the putative
human homolog of Mem3 (VPS35) with partial clones from an EST database.
By EST database searching for sequences homologous to yeast VPS35, Zhang
et al. (2000) identified human VPS35. They cloned a full-length cDNA
from a human testis cDNA library. The deduced 796-amino acid protein
contains 2 polyadenylation signals. Both human and yeast VPS35, which
share 30% identity, lack a hydrophobic region. Northern blot analysis
revealed bands at 5.5, 3.6, and 3.0 kb. The major 3.6-kb transcript was
expressed at highest levels in brain, heart, testis, ovary, small
intestine, spleen, skeletal muscle, and placenta, at moderate levels in
pancreas, thymus, prostate, and colon, and at low levels in lung, liver,
kidney, and peripheral blood leukocytes. Weaker expression of the 3.0-kb
transcript followed the same distribution except in brain, where it was
not detected. The 5.5-kb transcript showed low expression in all tissues
tested. Zhang et al. (2000) also cloned mouse Vps35, which encodes a
796-amino acid protein containing a single polyadenylation signal. This
sequence shares 99% identity with human VPS35 and 49% similarity with
yeast VPS35. Northern blot analysis detected a single 3.4-kb transcript
expressed at varying levels in all tissues examined.
Edgar and Polak (2000) independently cloned VPS35 from a human lung cDNA
library. Their sequence analysis revealed the presence of a third
polyadenylation signal. They found ubiquitous expression of transcripts
of 2.8, 3.3, and 6.8 kb corresponding to the use of all 3
polyadenylation signals. Expression was highest in heart, skeletal
muscle, kidney, and brain, and lowest in peripheral blood leukocytes. In
brain, only the 3.3-kb transcript was observed. By sequence analysis,
Edgar and Polak (2000) determined that the protein is predominantly
alpha-helical.
BIOCHEMICAL FEATURES
- Crystal Structure
Hierro et al. (2007) reported the crystal structure of a VPS29-VPS35
subcomplex showing how the metallophosphoesterase-fold subunit VPS29
acts as a scaffold for the C-terminal half of VPS35. VPS35 forms a
horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face
of which completely covers the metal-binding site of VPS29, whereas the
convex face exposes a series of hydrophobic interhelical grooves.
Electron microscopy showed that the intact VPS26-VPS29-VPS35 complex is
a stick-shaped, flexible structure, approximately 21 nanometers long. A
hybrid structural model derived from crystal structures, electron
microscopy, interaction studies, and bioinformatics showed that the
alpha-solenoid fold extends the full length of VPS35, and that VPS26 is
bound at the opposite end from VPS29. This extended structure presents
multiple binding sites for the SNX complex and receptor cargo, and
appears capable of flexing to conform to curved vesicular membranes.
GENE STRUCTURE
Edgar and Polak (2000) determined that VPS35 is present in the genome in
single copy, has 17 exons, and spans 29.6 kb. Analysis of the 5-prime
region revealed no evidence of a CpG island.
MAPPING
By radiation hybrid analysis, Zhang et al. (2000) mapped the VPS35 gene
to chromosome 16q13-q21.
By PCR-based analysis of an interspecific mapping panel, Hwang et al.
(1996) mapped the mouse Mem3 gene to chromosome 8 near the glutaryl CoA
dehydrogenase locus (608801).
GENE FUNCTION
Zhang et al. (2000) and Edgar and Polak (2000) noted that human VPS35
contains a conserved asp residue within an N-terminal domain shown by
Nothwehr et al. (1999) to be specifically involved in a resident
trans-Golgi network protein interaction in yeast.
Haft et al. (2000) used yeast 2-hybrid assays, mutation analysis, and
expression in mammalian cells to define the binding interactions among
VPS35 and other human orthologs of yeast vacuolar protein sorting
proteins, VPS26 (605506), SNX1 (601272), and VPS29 (606932). Their
results are consistent with a model in which VPS35 is the core of a
multimeric complex. Haft et al. (2000) identified discrete amino acid
domains within VPS35 that mediate specific binding to each of these
proteins. Gel filtration chromatography of COS-7 cells showed that both
recombinant and endogenous VPS proteins coelute as a 220- to 240-kD
complex. In the absence of VPS35, neither VPS26 nor VPS29 is found in
the complex.
MOLECULAR GENETICS
By exome sequencing of affected members of a Swiss family with autosomal
dominant Parkinson disease-17 (PARK17; 614203) reported by Wider et al.
(2008), Vilarino-Guell et al. (2011) identified a heterozygous mutation
in the VPS35 gene (D620N; 601501.0001). Subsequent sequencing of this
gene in 4,326 PD patients identified 4 with the same mutation: 3
familial cases and 1 with sporadic disease. Haplotype analysis indicated
independent mutational events, suggesting a mutational hotspot. The
findings suggested that disruption of endosomal trafficking may underlie
neurodegeneration.
Simultaneously and independently and by the same method, Zimprich et al.
(2011) identified the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. Two additional
carriers of this mutation were found among 486 PD patients in Austria.
Age-dependent incomplete penetrance was observed. Zimprich et al. (2011)
identified several other possibly pathogenic VPS35 variants in patients
with PD, but the evidence was inconclusive.
*FIELD* AV
.0001
PARKINSON DISEASE 17
VPS35, ASP620ASN
By exome sequencing of affected members of a Swiss family with autosomal
dominant Parkinson disease-17 (PARK17; 614203) reported by Wider et al.
(2008), Vilarino-Guell et al. (2011) identified a heterozygous 1858G-A
transition in the VPS35 gene, resulting in an asp620-to-asn (D620N)
substitution in a highly conserved residue. Subsequent sequencing of
this gene in 4,326 PD patients identified 4 more with the same mutation:
3 familial cases and 1 with sporadic disease. Haplotype analysis
indicated independent mutational events, suggesting a mutational
hotspot. The mutation was not found in 3,309 controls. The average age
at onset was 50.6 years, and patients had tremor-predominant,
levodopa-responsive parkinsonism.
Simultaneously and independently, Zimprich et al. (2011) used exome
sequencing to identify the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. The mutation
occurred in exon 15 of the gene. Two additional carriers of this
mutation were found among 486 PD patients in Austria. Age-dependent
incomplete penetrance was observed.
By specific screening for the D620N mutation among Japanese patients
with Parkinson disease, Ando et al. (2012) identified the heterozygous
mutation in 3 (1.0%) of 330 patients with autosomal dominant PD and in 1
(0.23%) of 433 patients with sporadic PD. Haplotype analysis suggested
at least 3 independent founders in this population, indicating that it
may be a mutational hotspot. Patients with this mutation showed typical
adult-onset, tremor-predominant PD with good response to levodopa
treatment. The mutation was not found in 1,158 control chromosomes.
Lesage et al. (2012) identified a heterozygous D620N mutation in 3
(1.2%) of 246 mostly French probands with autosomal dominant typical PD.
All 3 index patients were of French origin, and the mutation was shown
to segregate with the disorder in 1 family; segregation analyses were
not available for the 2 remaining families. Two of the French families
shared a common haplotype. The mutation was not found in 245 European
controls, and no additional pathogenic VPS35 variants were identified.
By targeted sequencing, Kumar et al. (2012) identified a heterozygous
VPS35 D620N mutation in 1 of 1,774 patients with Parkinson disease. The
patients were ascertained from several tertiary referral centers in
Germany, Serbia, Chile, and the United States. The patient with the
mutation was a German man who developed typical PD at age 45 years.
Family history revealed an affected paternal aunt who carried the
mutation, as well as 3 reportedly unaffected sibs in their fifties and
sixties who also carried the mutation, indicating incomplete penetrance.
Kumar et al. (2012) concluded that VPS35 mutations are a rare cause of
PD, and they estimated a carrier frequency for the D620N mutation of
0.1% among patients with PD.
*FIELD* RF
1. Ando, M,; Funayama, M.; Li, Y.; Kashihara, K.; Murakami, Y.; Ishizu,
N.; Toyoda, C.; Noguchi, K.; Hashimoto, T.; Nakano, N.; Sasaki, R.;
Kokubo, Y.; Kuzuhara, S.; Ogaki, K.; Yamashita, C.; Yoshino, H.; Hatano,
T.; Tomiyama, H.; Hattori, N.: VPS35 mutation in Japanese patients
with typical Parkinson's disease. Mov. Disord. 27: 1413-1417, 2012.
2. Edgar, A. J.; Polak, J. M.: Human homologues of yeast vacuolar
protein sorting 29 and 35. Biochem. Biophys. Res. Commun. 277: 622-630,
2000.
3. Haft, C. R.; de la Luz Sierra, M.; Bafford, R.; Lesniak, M. A.;
Barr, V. A.; Taylor, S. I.: Human orthologs of yeast vacuolar protein
sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Molec.
Biol. Cell 11: 4105-4116, 2000.
4. Hierro, A.; Rojas, A. L.; Rojas, R.; Murthy, N.; Effantin, G.;
Kajava, A. V.; Steven, A. C.; Bonifacino, J. S.; Hurley, J. H.: Functional
architecture of the retromer cargo-recognition complex. Nature 449:
1063-1067, 2007.
5. Hwang, S.-Y.; Benjamin, L. E.; Oh, B.; Rothstein, J. L.; Ackerman,
S. L.; Beddington, R. S. P.; Solter, D.; Knowles, B. B.: Genetic
mapping and embryonic expression of a novel, maternally transcribed
gene Mem3. Mammalian Genome 7: 586-590, 1996.
6. Kumar, K. R.; Weissbach, A.; Heldmann, M.; Kasten, M.; Tunc, S.;
Sue, C. M.; Svetel, M.; Kostic, V. S.; Segura-Aguilar, J.; Ramirez,
A.; Simon, D. K.; Vieregge, P.; Munte, T. F.; Hagenah, J.; Klein,
C.; Lohmann, K.: Frequency of the D620N mutation in VPS35 in Parkinson
disease. Arch. Neurol. 69: 1360-1364, 2012.
7. Lesage, S.; Condroyer, C.; Klebe, S.; Honore, A.; Tison, F.; Brefel-Courbon,
C.; Durr, A.; Brice, A.: Identification of VPS35 mutations replicated
in French families with Parkinson disease. Neurology 78: 1449-1450,
2012.
8. Nothwehr, S. F.; Bruinsma, P.; Strawn, L. A.: Distinct domains
within Vps35p mediate the retrieval of two different cargo proteins
from the yeast prevacuolar/endosomal compartment. Molec. Biol. Cell 10:
875-890, 1999.
9. Vilarino-Guell, C.; Wider, C.; Ross, O. A.; Dachsel, J. C.; Kachergus,
J. M.; Lincoln, S. J.; Soto-Ortolaza, A. I.; Cobb, S. A.; Wilhoite,
G. J.; Bacon, J. A.; Behrouz, B.; Melrose, H. L.; and 21 others
: VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89: 162-167,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011.
10. Wider, C.; Skipper, L.; Solida, A.; Brown, L.; Farrer, M.; Dickson,
D.; Wszolek, Z. K.; Vingerhoets, F. J. G.: Autosomal dominant dopa-responsive
parkinsonism in a multigenerational Swiss family. Parkinsonism Relat.
Disord. 14: 465-470, 2008.
11. Zhang, P.; Yu, L.; Gao, J.; Fu, Q.; Dai, F.; Zhao, Y.; Zheng,
L.; Zhao, S.: Cloning and characterization of human VPS35 and mouse
Vps35 and mapping of VPS35 to human chromosome 16q13-q21. Genomics 70:
253-257, 2000.
12. Zimprich, A.; Benet-Pages, A.; Struhal, W.; Graf, E.; Eck, S.
H.; Offman, M. N.; Haubenberger, D.; Spielberger, S.; Schulte, E.
C.; Lichtner, P.; Rossle, S. C.; Klopp, N.; and 22 others: A mutation
in VPS35, encoding a subunit of the retromer complex, causes late-onset
Parkinson disease. Am. J. Hum. Genet. 89: 168-175, 2011.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Cassandra L. Kniffin - updated: 10/31/2012
Cassandra L. Kniffin - updated: 10/15/2012
Cassandra L. Kniffin - updated: 9/1/2011
*FIELD* CD
Victor A. McKusick: 11/14/1996
*FIELD* ED
carol: 01/08/2014
ckniffin: 1/7/2014
terry: 3/14/2013
carol: 11/6/2012
ckniffin: 10/31/2012
carol: 10/16/2012
ckniffin: 10/15/2012
carol: 9/2/2011
ckniffin: 9/1/2011
carol: 3/20/2009
ckniffin: 7/22/2004
alopez: 5/10/2002
dkim: 9/28/1998
terry: 11/14/1996
mark: 11/14/1996
*RECORD*
*FIELD* NO
601501
*FIELD* TI
*601501 VACUOLAR PROTEIN SORTING 35, YEAST, HOMOLOG OF; VPS35
;;MEM3, MOUSE, HOMOLOG OF; MEM3
read more*FIELD* TX
DESCRIPTION
The VPS35 gene encodes a component of the retromer cargo-recognition
complex critical for endosome-trans-Golgi trafficking and the recycling
of membrane-associated proteins (summary by Vilarino-Guell et al.,
2011).
CLONING
To study the molecular function of genes expressed during
preimplantation development, Hwang et al. (1996) isolated a novel
maternal transcript, stage specific embryonic cDNA-26 (SSEC-26), from a
partial subtraction library of mouse unfertilized eggs and
preimplantation embryos. The SSEC-26 transcript was abundant in the
unfertilized egg and also actively transcribed from the newly formed
zygotic genome. On the basis of its expression in eggs and embryos, this
mouse gene was named Mem3 (maternal-embryonic-3). The deduced amino acid
sequence of Mem3 resembles that of the yeast VPS35 protein in 2 separate
domains. Hwang et al. (1996) assembled a cDNA sequence of the putative
human homolog of Mem3 (VPS35) with partial clones from an EST database.
By EST database searching for sequences homologous to yeast VPS35, Zhang
et al. (2000) identified human VPS35. They cloned a full-length cDNA
from a human testis cDNA library. The deduced 796-amino acid protein
contains 2 polyadenylation signals. Both human and yeast VPS35, which
share 30% identity, lack a hydrophobic region. Northern blot analysis
revealed bands at 5.5, 3.6, and 3.0 kb. The major 3.6-kb transcript was
expressed at highest levels in brain, heart, testis, ovary, small
intestine, spleen, skeletal muscle, and placenta, at moderate levels in
pancreas, thymus, prostate, and colon, and at low levels in lung, liver,
kidney, and peripheral blood leukocytes. Weaker expression of the 3.0-kb
transcript followed the same distribution except in brain, where it was
not detected. The 5.5-kb transcript showed low expression in all tissues
tested. Zhang et al. (2000) also cloned mouse Vps35, which encodes a
796-amino acid protein containing a single polyadenylation signal. This
sequence shares 99% identity with human VPS35 and 49% similarity with
yeast VPS35. Northern blot analysis detected a single 3.4-kb transcript
expressed at varying levels in all tissues examined.
Edgar and Polak (2000) independently cloned VPS35 from a human lung cDNA
library. Their sequence analysis revealed the presence of a third
polyadenylation signal. They found ubiquitous expression of transcripts
of 2.8, 3.3, and 6.8 kb corresponding to the use of all 3
polyadenylation signals. Expression was highest in heart, skeletal
muscle, kidney, and brain, and lowest in peripheral blood leukocytes. In
brain, only the 3.3-kb transcript was observed. By sequence analysis,
Edgar and Polak (2000) determined that the protein is predominantly
alpha-helical.
BIOCHEMICAL FEATURES
- Crystal Structure
Hierro et al. (2007) reported the crystal structure of a VPS29-VPS35
subcomplex showing how the metallophosphoesterase-fold subunit VPS29
acts as a scaffold for the C-terminal half of VPS35. VPS35 forms a
horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face
of which completely covers the metal-binding site of VPS29, whereas the
convex face exposes a series of hydrophobic interhelical grooves.
Electron microscopy showed that the intact VPS26-VPS29-VPS35 complex is
a stick-shaped, flexible structure, approximately 21 nanometers long. A
hybrid structural model derived from crystal structures, electron
microscopy, interaction studies, and bioinformatics showed that the
alpha-solenoid fold extends the full length of VPS35, and that VPS26 is
bound at the opposite end from VPS29. This extended structure presents
multiple binding sites for the SNX complex and receptor cargo, and
appears capable of flexing to conform to curved vesicular membranes.
GENE STRUCTURE
Edgar and Polak (2000) determined that VPS35 is present in the genome in
single copy, has 17 exons, and spans 29.6 kb. Analysis of the 5-prime
region revealed no evidence of a CpG island.
MAPPING
By radiation hybrid analysis, Zhang et al. (2000) mapped the VPS35 gene
to chromosome 16q13-q21.
By PCR-based analysis of an interspecific mapping panel, Hwang et al.
(1996) mapped the mouse Mem3 gene to chromosome 8 near the glutaryl CoA
dehydrogenase locus (608801).
GENE FUNCTION
Zhang et al. (2000) and Edgar and Polak (2000) noted that human VPS35
contains a conserved asp residue within an N-terminal domain shown by
Nothwehr et al. (1999) to be specifically involved in a resident
trans-Golgi network protein interaction in yeast.
Haft et al. (2000) used yeast 2-hybrid assays, mutation analysis, and
expression in mammalian cells to define the binding interactions among
VPS35 and other human orthologs of yeast vacuolar protein sorting
proteins, VPS26 (605506), SNX1 (601272), and VPS29 (606932). Their
results are consistent with a model in which VPS35 is the core of a
multimeric complex. Haft et al. (2000) identified discrete amino acid
domains within VPS35 that mediate specific binding to each of these
proteins. Gel filtration chromatography of COS-7 cells showed that both
recombinant and endogenous VPS proteins coelute as a 220- to 240-kD
complex. In the absence of VPS35, neither VPS26 nor VPS29 is found in
the complex.
MOLECULAR GENETICS
By exome sequencing of affected members of a Swiss family with autosomal
dominant Parkinson disease-17 (PARK17; 614203) reported by Wider et al.
(2008), Vilarino-Guell et al. (2011) identified a heterozygous mutation
in the VPS35 gene (D620N; 601501.0001). Subsequent sequencing of this
gene in 4,326 PD patients identified 4 with the same mutation: 3
familial cases and 1 with sporadic disease. Haplotype analysis indicated
independent mutational events, suggesting a mutational hotspot. The
findings suggested that disruption of endosomal trafficking may underlie
neurodegeneration.
Simultaneously and independently and by the same method, Zimprich et al.
(2011) identified the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. Two additional
carriers of this mutation were found among 486 PD patients in Austria.
Age-dependent incomplete penetrance was observed. Zimprich et al. (2011)
identified several other possibly pathogenic VPS35 variants in patients
with PD, but the evidence was inconclusive.
*FIELD* AV
.0001
PARKINSON DISEASE 17
VPS35, ASP620ASN
By exome sequencing of affected members of a Swiss family with autosomal
dominant Parkinson disease-17 (PARK17; 614203) reported by Wider et al.
(2008), Vilarino-Guell et al. (2011) identified a heterozygous 1858G-A
transition in the VPS35 gene, resulting in an asp620-to-asn (D620N)
substitution in a highly conserved residue. Subsequent sequencing of
this gene in 4,326 PD patients identified 4 more with the same mutation:
3 familial cases and 1 with sporadic disease. Haplotype analysis
indicated independent mutational events, suggesting a mutational
hotspot. The mutation was not found in 3,309 controls. The average age
at onset was 50.6 years, and patients had tremor-predominant,
levodopa-responsive parkinsonism.
Simultaneously and independently, Zimprich et al. (2011) used exome
sequencing to identify the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. The mutation
occurred in exon 15 of the gene. Two additional carriers of this
mutation were found among 486 PD patients in Austria. Age-dependent
incomplete penetrance was observed.
By specific screening for the D620N mutation among Japanese patients
with Parkinson disease, Ando et al. (2012) identified the heterozygous
mutation in 3 (1.0%) of 330 patients with autosomal dominant PD and in 1
(0.23%) of 433 patients with sporadic PD. Haplotype analysis suggested
at least 3 independent founders in this population, indicating that it
may be a mutational hotspot. Patients with this mutation showed typical
adult-onset, tremor-predominant PD with good response to levodopa
treatment. The mutation was not found in 1,158 control chromosomes.
Lesage et al. (2012) identified a heterozygous D620N mutation in 3
(1.2%) of 246 mostly French probands with autosomal dominant typical PD.
All 3 index patients were of French origin, and the mutation was shown
to segregate with the disorder in 1 family; segregation analyses were
not available for the 2 remaining families. Two of the French families
shared a common haplotype. The mutation was not found in 245 European
controls, and no additional pathogenic VPS35 variants were identified.
By targeted sequencing, Kumar et al. (2012) identified a heterozygous
VPS35 D620N mutation in 1 of 1,774 patients with Parkinson disease. The
patients were ascertained from several tertiary referral centers in
Germany, Serbia, Chile, and the United States. The patient with the
mutation was a German man who developed typical PD at age 45 years.
Family history revealed an affected paternal aunt who carried the
mutation, as well as 3 reportedly unaffected sibs in their fifties and
sixties who also carried the mutation, indicating incomplete penetrance.
Kumar et al. (2012) concluded that VPS35 mutations are a rare cause of
PD, and they estimated a carrier frequency for the D620N mutation of
0.1% among patients with PD.
*FIELD* RF
1. Ando, M,; Funayama, M.; Li, Y.; Kashihara, K.; Murakami, Y.; Ishizu,
N.; Toyoda, C.; Noguchi, K.; Hashimoto, T.; Nakano, N.; Sasaki, R.;
Kokubo, Y.; Kuzuhara, S.; Ogaki, K.; Yamashita, C.; Yoshino, H.; Hatano,
T.; Tomiyama, H.; Hattori, N.: VPS35 mutation in Japanese patients
with typical Parkinson's disease. Mov. Disord. 27: 1413-1417, 2012.
2. Edgar, A. J.; Polak, J. M.: Human homologues of yeast vacuolar
protein sorting 29 and 35. Biochem. Biophys. Res. Commun. 277: 622-630,
2000.
3. Haft, C. R.; de la Luz Sierra, M.; Bafford, R.; Lesniak, M. A.;
Barr, V. A.; Taylor, S. I.: Human orthologs of yeast vacuolar protein
sorting proteins Vps26, 29, and 35: assembly into multimeric complexes. Molec.
Biol. Cell 11: 4105-4116, 2000.
4. Hierro, A.; Rojas, A. L.; Rojas, R.; Murthy, N.; Effantin, G.;
Kajava, A. V.; Steven, A. C.; Bonifacino, J. S.; Hurley, J. H.: Functional
architecture of the retromer cargo-recognition complex. Nature 449:
1063-1067, 2007.
5. Hwang, S.-Y.; Benjamin, L. E.; Oh, B.; Rothstein, J. L.; Ackerman,
S. L.; Beddington, R. S. P.; Solter, D.; Knowles, B. B.: Genetic
mapping and embryonic expression of a novel, maternally transcribed
gene Mem3. Mammalian Genome 7: 586-590, 1996.
6. Kumar, K. R.; Weissbach, A.; Heldmann, M.; Kasten, M.; Tunc, S.;
Sue, C. M.; Svetel, M.; Kostic, V. S.; Segura-Aguilar, J.; Ramirez,
A.; Simon, D. K.; Vieregge, P.; Munte, T. F.; Hagenah, J.; Klein,
C.; Lohmann, K.: Frequency of the D620N mutation in VPS35 in Parkinson
disease. Arch. Neurol. 69: 1360-1364, 2012.
7. Lesage, S.; Condroyer, C.; Klebe, S.; Honore, A.; Tison, F.; Brefel-Courbon,
C.; Durr, A.; Brice, A.: Identification of VPS35 mutations replicated
in French families with Parkinson disease. Neurology 78: 1449-1450,
2012.
8. Nothwehr, S. F.; Bruinsma, P.; Strawn, L. A.: Distinct domains
within Vps35p mediate the retrieval of two different cargo proteins
from the yeast prevacuolar/endosomal compartment. Molec. Biol. Cell 10:
875-890, 1999.
9. Vilarino-Guell, C.; Wider, C.; Ross, O. A.; Dachsel, J. C.; Kachergus,
J. M.; Lincoln, S. J.; Soto-Ortolaza, A. I.; Cobb, S. A.; Wilhoite,
G. J.; Bacon, J. A.; Behrouz, B.; Melrose, H. L.; and 21 others
: VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89: 162-167,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011.
10. Wider, C.; Skipper, L.; Solida, A.; Brown, L.; Farrer, M.; Dickson,
D.; Wszolek, Z. K.; Vingerhoets, F. J. G.: Autosomal dominant dopa-responsive
parkinsonism in a multigenerational Swiss family. Parkinsonism Relat.
Disord. 14: 465-470, 2008.
11. Zhang, P.; Yu, L.; Gao, J.; Fu, Q.; Dai, F.; Zhao, Y.; Zheng,
L.; Zhao, S.: Cloning and characterization of human VPS35 and mouse
Vps35 and mapping of VPS35 to human chromosome 16q13-q21. Genomics 70:
253-257, 2000.
12. Zimprich, A.; Benet-Pages, A.; Struhal, W.; Graf, E.; Eck, S.
H.; Offman, M. N.; Haubenberger, D.; Spielberger, S.; Schulte, E.
C.; Lichtner, P.; Rossle, S. C.; Klopp, N.; and 22 others: A mutation
in VPS35, encoding a subunit of the retromer complex, causes late-onset
Parkinson disease. Am. J. Hum. Genet. 89: 168-175, 2011.
*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Cassandra L. Kniffin - updated: 10/31/2012
Cassandra L. Kniffin - updated: 10/15/2012
Cassandra L. Kniffin - updated: 9/1/2011
*FIELD* CD
Victor A. McKusick: 11/14/1996
*FIELD* ED
carol: 01/08/2014
ckniffin: 1/7/2014
terry: 3/14/2013
carol: 11/6/2012
ckniffin: 10/31/2012
carol: 10/16/2012
ckniffin: 10/15/2012
carol: 9/2/2011
ckniffin: 9/1/2011
carol: 3/20/2009
ckniffin: 7/22/2004
alopez: 5/10/2002
dkim: 9/28/1998
terry: 11/14/1996
mark: 11/14/1996
MIM
614203
*RECORD*
*FIELD* NO
614203
*FIELD* TI
#614203 PARKINSON DISEASE 17; PARK17
*FIELD* TX
A number sign (#) is used with this entry because Parkinson disease-17
read more(PARK17) is caused by heterozygous mutation in the VPS35 gene (601501)
on chromosome 16q13.
DESCRIPTION
Parkinson disease-17 is an autosomal dominant, adult-onset form of the
disorder. It is phenotypically similar to idiopathic Parkinson disease
(summary by Wider et al., 2008).
For a general phenotypic description and a discussion of genetic
heterogeneity of Parkinson disease (PD), see 168600.
CLINICAL FEATURES
Wider et al. (2008) reported a large family of Swiss origin with
autosomal dominant levodopa-responsive Parkinson disease. Age at onset
ranged from 42 to 64 years (mean of 52), and most presented with resting
tremor. Other features included akinesia, tremor, rigidity, and cramps.
Most had severe motor fluctuations with dyskinesia and dystonia. Three
of 11 affected individuals had learning difficulties, and 1 with mental
retardation and schizophrenia became demented at the end of her life.
Brain fluorodopa PET scan of 1 patient showed marked asymmetric tracer
uptake deficiency. Brain MRIs of 3 patients were normal. Limited
neuropathologic examination of 1 patient showed no Lewy bodies and
negative staining for alpha-synuclein. The phenotype could not be
distinguished from idiopathic Parkinson disease. Known genetic causes of
autosomal dominant PD were excluded.
Zimprich et al. (2011) reported a large Austrian family with autosomal
dominant adult-onset Parkinson disease. The mean age at onset was 53
years (range, 40-68 years), and presenting symptoms included postural
instability, resting tremor, and bradykinesia. All showed clinical
improvement after dopaminergic treatment. Age-dependent incomplete
penetrance was observed.
Kumar et al. (2012) reported a German man with tremor-dominant
levodopa-responsive PARK17 with onset at age 45 years. The disorder was
progressive, and he later developed impulse control behaviors, likely
due to dopamine-agonist therapy, hyperhidrosis, impaired smell, and mild
memory impairment. His deceased father developed PD in his late forties,
and a deceased paternal grandfather, deceased paternal uncle, and living
paternal aunt were also affected.
INHERITANCE
The transmission pattern in the family with PARK17 reported by Kumar et
al. (2012) was consistent with autosomal dominant inheritance and
incomplete penetrance.
MOLECULAR GENETICS
By exome sequencing of affected members of the Swiss family with
Parkinson disease reported by Wider et al. (2008), Vilarino-Guell et al.
(2011) identified a heterozygous mutation in the VPS35 gene (D620N;
601501.0001). Subsequent sequencing of this gene in 4,326 PD patients
identified 4 with the same mutation: 3 familial cases and 1 with
sporadic disease. Haplotype analysis indicated independent mutational
events, suggesting a mutational hotspot.
Simultaneously and independently and by the same method, Zimprich et al.
(2011) identified the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. Two additional
carriers of this mutation were found among 486 PD patients in Austria.
Zimprich et al. (2011) identified several other possibly pathogenic
VPS35 variants in patients with PD, but the evidence was inconclusive.
By targeted sequencing, Kumar et al. (2012) identified heterozygosity
for the D620N mutation in 1 of 1,774 patients with Parkinson disease.
The patients were ascertained from several tertiary referral centers in
Germany, Serbia, Chile, and the United States. Family history of the
German mutation carrier revealed an affected paternal aunt who carried
the mutation, as well as 3 reportedly unaffected sibs in their fifties
and sixties who also carried the mutation, indicating incomplete
penetrance. Kumar et al. (2012) concluded that VPS35 mutations are a
rare cause of PD, and they estimated a carrier frequency for the D620N
mutation of 0.1% among patients with PD.
POPULATION GENETICS
By specific screening for the D620N mutation (601501.0001) among
Japanese patients with Parkinson disease, Ando et al. (2012) identified
the heterozygous mutation in 3 (1.0%) of 330 patients with autosomal
dominant PD and in 1 (0.23%) of 433 patients with sporadic PD. Haplotype
analysis suggested at least 3 independent founders in this population,
indicating that it may be a mutation hotspot. Patients with this
mutation showed typical adult-onset, tremor-predominant PD, with good
response to levodopa treatment. The mutation was not found in 1,158
control chromosomes.
NOMENCLATURE
Parkinson disease caused by mutation in the VPS35 gene on chromosome
16q12 is designated here as PARK17. Although PARK17 had been used in the
literature to refer to a possible locus on chromosome 4p (Hamza et al.,
2010), validation for this locus had not yet been achieved (Mata et al.,
2011).
*FIELD* RF
1. Ando, M,; Funayama, M.; Li, Y.; Kashihara, K.; Murakami, Y.; Ishizu,
N.; Toyoda, C.; Noguchi, K.; Hashimoto, T.; Nakano, N.; Sasaki, R.;
Kokubo, Y.; Kuzuhara, S.; Ogaki, K.; Yamashita, C.; Yoshino, H.; Hatano,
T.; Tomiyama, H.; Hattori, N.: VPS35 mutation in Japanese patients
with typical Parkinson's disease. Mov. Disord. 27: 1413-1417, 2012.
2. Hamza, T. H.; Zabetian, C. P.; Tenesa, A.; Laederach, A.; Montimurro,
J.; Yearout, D.; Kay, D. M.; Doheny, K. F.; Paschall, J.; Pugh, E.;
Kusel, V. I.; Collura, R.; Roberts, J.; Griffith, A.; Samii, A.; Scott,
W. K.; Nutt, J.; Factor, S. A.; Payami, H.: Common genetic variation
in the HLA region is associated with late-onset sporadic Parkinson's
disease. Nature Genet. 42: 781-785, 2010.
3. Kumar, K. R.; Weissbach, A.; Heldmann, M.; Kasten, M.; Tunc, S.;
Sue, C. M.; Svetel, M.; Kostic, V. S.; Segura-Aguilar, J.; Ramirez,
A.; Simon, D. K.; Vieregge, P.; Munte, T. F.; Hagenah, J.; Klein,
C.; Lohmann, K.: Frequency of the D620N mutation in VPS35 in Parkinson
disease. Arch. Neurol. 69: 1360-1364, 2012.
4. Mata, I. F.; Yearout, D.; Alvarez, V.; Coto, E.; de Mena, L.; Ribacoba,
R.; Lorenzo-Betancor, O.; Samaranch, L.; Pastor, P.; Cervantes, S.;
Infante, J.; Garcia-Gorostiaga, I.; Sierra, M.; Combarros, O.; Snapinn,
K. W.; Edwards, K. L.; Zabetian, C. P.: Replication of MAPT and SNCA,
but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov.
Disord. 26: 819-823, 2011.
5. Vilarino-Guell, C.; Wider, C.; Ross, O. A.; Dachsel, J. C.; Kachergus,
J. M.; Lincoln, S. J.; Soto-Ortolaza, A. I.; Cobb, S. A.; Wilhoite,
G. J.; Bacon, J. A.; Behrouz, B.; Melrose, H. L.; and 21 others
: VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89: 162-167,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011.
6. Wider, C.; Skipper, L.; Solida, A.; Brown, L.; Farrer, M.; Dickson,
D.; Wszolek, Z. K.; Vingerhoets, F. J. G.: Autosomal dominant dopa-responsive
parkinsonism in a multigenerational Swiss family. Parkinsonism Relat.
Disord. 14: 465-470, 2008.
7. Zimprich, A.; Benet-Pages, A.; Struhal, W.; Graf, E.; Eck, S. H.;
Offman, M. N.; Haubenberger, D.; Spielberger, S.; Schulte, E. C.;
Lichtner, P.; Rossle, S. C.; Klopp, N.; and 22 others: A mutation
in VPS35, encoding a subunit of the retromer complex, causes late-onset
Parkinson disease. Am. J. Hum. Genet. 89: 168-175, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Resting tremor;
Tremor;
Bradykinesia;
Akinesia;
Rigidity;
Postural instability;
Cramps;
Dyskinesias
MISCELLANEOUS:
Mean age of onset 50 to 52 years;
Incomplete, age-associated penetrance;
Motor fluctuation;
Levodopa-responsive
MOLECULAR BASIS:
Caused by mutation in the homolog of the yeast vacuolar protein sorting
35 gene (VPS35, 601501.0001)
*FIELD* CD
Cassandra L. Kniffin: 9/1/2011
*FIELD* ED
joanna: 09/16/2011
ckniffin: 9/1/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Cassandra L. Kniffin - updated: 10/15/2012
*FIELD* CD
Cassandra L. Kniffin: 9/1/2011
*FIELD* ED
carol: 01/08/2014
ckniffin: 1/7/2014
terry: 3/14/2013
carol: 10/16/2012
ckniffin: 10/15/2012
carol: 9/6/2011
ckniffin: 9/6/2011
carol: 9/2/2011
ckniffin: 9/1/2011
*RECORD*
*FIELD* NO
614203
*FIELD* TI
#614203 PARKINSON DISEASE 17; PARK17
*FIELD* TX
A number sign (#) is used with this entry because Parkinson disease-17
read more(PARK17) is caused by heterozygous mutation in the VPS35 gene (601501)
on chromosome 16q13.
DESCRIPTION
Parkinson disease-17 is an autosomal dominant, adult-onset form of the
disorder. It is phenotypically similar to idiopathic Parkinson disease
(summary by Wider et al., 2008).
For a general phenotypic description and a discussion of genetic
heterogeneity of Parkinson disease (PD), see 168600.
CLINICAL FEATURES
Wider et al. (2008) reported a large family of Swiss origin with
autosomal dominant levodopa-responsive Parkinson disease. Age at onset
ranged from 42 to 64 years (mean of 52), and most presented with resting
tremor. Other features included akinesia, tremor, rigidity, and cramps.
Most had severe motor fluctuations with dyskinesia and dystonia. Three
of 11 affected individuals had learning difficulties, and 1 with mental
retardation and schizophrenia became demented at the end of her life.
Brain fluorodopa PET scan of 1 patient showed marked asymmetric tracer
uptake deficiency. Brain MRIs of 3 patients were normal. Limited
neuropathologic examination of 1 patient showed no Lewy bodies and
negative staining for alpha-synuclein. The phenotype could not be
distinguished from idiopathic Parkinson disease. Known genetic causes of
autosomal dominant PD were excluded.
Zimprich et al. (2011) reported a large Austrian family with autosomal
dominant adult-onset Parkinson disease. The mean age at onset was 53
years (range, 40-68 years), and presenting symptoms included postural
instability, resting tremor, and bradykinesia. All showed clinical
improvement after dopaminergic treatment. Age-dependent incomplete
penetrance was observed.
Kumar et al. (2012) reported a German man with tremor-dominant
levodopa-responsive PARK17 with onset at age 45 years. The disorder was
progressive, and he later developed impulse control behaviors, likely
due to dopamine-agonist therapy, hyperhidrosis, impaired smell, and mild
memory impairment. His deceased father developed PD in his late forties,
and a deceased paternal grandfather, deceased paternal uncle, and living
paternal aunt were also affected.
INHERITANCE
The transmission pattern in the family with PARK17 reported by Kumar et
al. (2012) was consistent with autosomal dominant inheritance and
incomplete penetrance.
MOLECULAR GENETICS
By exome sequencing of affected members of the Swiss family with
Parkinson disease reported by Wider et al. (2008), Vilarino-Guell et al.
(2011) identified a heterozygous mutation in the VPS35 gene (D620N;
601501.0001). Subsequent sequencing of this gene in 4,326 PD patients
identified 4 with the same mutation: 3 familial cases and 1 with
sporadic disease. Haplotype analysis indicated independent mutational
events, suggesting a mutational hotspot.
Simultaneously and independently and by the same method, Zimprich et al.
(2011) identified the D620N mutation in affected members of a large
Austrian family with autosomal dominant parkinsonism. Two additional
carriers of this mutation were found among 486 PD patients in Austria.
Zimprich et al. (2011) identified several other possibly pathogenic
VPS35 variants in patients with PD, but the evidence was inconclusive.
By targeted sequencing, Kumar et al. (2012) identified heterozygosity
for the D620N mutation in 1 of 1,774 patients with Parkinson disease.
The patients were ascertained from several tertiary referral centers in
Germany, Serbia, Chile, and the United States. Family history of the
German mutation carrier revealed an affected paternal aunt who carried
the mutation, as well as 3 reportedly unaffected sibs in their fifties
and sixties who also carried the mutation, indicating incomplete
penetrance. Kumar et al. (2012) concluded that VPS35 mutations are a
rare cause of PD, and they estimated a carrier frequency for the D620N
mutation of 0.1% among patients with PD.
POPULATION GENETICS
By specific screening for the D620N mutation (601501.0001) among
Japanese patients with Parkinson disease, Ando et al. (2012) identified
the heterozygous mutation in 3 (1.0%) of 330 patients with autosomal
dominant PD and in 1 (0.23%) of 433 patients with sporadic PD. Haplotype
analysis suggested at least 3 independent founders in this population,
indicating that it may be a mutation hotspot. Patients with this
mutation showed typical adult-onset, tremor-predominant PD, with good
response to levodopa treatment. The mutation was not found in 1,158
control chromosomes.
NOMENCLATURE
Parkinson disease caused by mutation in the VPS35 gene on chromosome
16q12 is designated here as PARK17. Although PARK17 had been used in the
literature to refer to a possible locus on chromosome 4p (Hamza et al.,
2010), validation for this locus had not yet been achieved (Mata et al.,
2011).
*FIELD* RF
1. Ando, M,; Funayama, M.; Li, Y.; Kashihara, K.; Murakami, Y.; Ishizu,
N.; Toyoda, C.; Noguchi, K.; Hashimoto, T.; Nakano, N.; Sasaki, R.;
Kokubo, Y.; Kuzuhara, S.; Ogaki, K.; Yamashita, C.; Yoshino, H.; Hatano,
T.; Tomiyama, H.; Hattori, N.: VPS35 mutation in Japanese patients
with typical Parkinson's disease. Mov. Disord. 27: 1413-1417, 2012.
2. Hamza, T. H.; Zabetian, C. P.; Tenesa, A.; Laederach, A.; Montimurro,
J.; Yearout, D.; Kay, D. M.; Doheny, K. F.; Paschall, J.; Pugh, E.;
Kusel, V. I.; Collura, R.; Roberts, J.; Griffith, A.; Samii, A.; Scott,
W. K.; Nutt, J.; Factor, S. A.; Payami, H.: Common genetic variation
in the HLA region is associated with late-onset sporadic Parkinson's
disease. Nature Genet. 42: 781-785, 2010.
3. Kumar, K. R.; Weissbach, A.; Heldmann, M.; Kasten, M.; Tunc, S.;
Sue, C. M.; Svetel, M.; Kostic, V. S.; Segura-Aguilar, J.; Ramirez,
A.; Simon, D. K.; Vieregge, P.; Munte, T. F.; Hagenah, J.; Klein,
C.; Lohmann, K.: Frequency of the D620N mutation in VPS35 in Parkinson
disease. Arch. Neurol. 69: 1360-1364, 2012.
4. Mata, I. F.; Yearout, D.; Alvarez, V.; Coto, E.; de Mena, L.; Ribacoba,
R.; Lorenzo-Betancor, O.; Samaranch, L.; Pastor, P.; Cervantes, S.;
Infante, J.; Garcia-Gorostiaga, I.; Sierra, M.; Combarros, O.; Snapinn,
K. W.; Edwards, K. L.; Zabetian, C. P.: Replication of MAPT and SNCA,
but not PARK16-18, as susceptibility genes for Parkinson's disease. Mov.
Disord. 26: 819-823, 2011.
5. Vilarino-Guell, C.; Wider, C.; Ross, O. A.; Dachsel, J. C.; Kachergus,
J. M.; Lincoln, S. J.; Soto-Ortolaza, A. I.; Cobb, S. A.; Wilhoite,
G. J.; Bacon, J. A.; Behrouz, B.; Melrose, H. L.; and 21 others
: VPS35 mutations in Parkinson disease. Am. J. Hum. Genet. 89: 162-167,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011.
6. Wider, C.; Skipper, L.; Solida, A.; Brown, L.; Farrer, M.; Dickson,
D.; Wszolek, Z. K.; Vingerhoets, F. J. G.: Autosomal dominant dopa-responsive
parkinsonism in a multigenerational Swiss family. Parkinsonism Relat.
Disord. 14: 465-470, 2008.
7. Zimprich, A.; Benet-Pages, A.; Struhal, W.; Graf, E.; Eck, S. H.;
Offman, M. N.; Haubenberger, D.; Spielberger, S.; Schulte, E. C.;
Lichtner, P.; Rossle, S. C.; Klopp, N.; and 22 others: A mutation
in VPS35, encoding a subunit of the retromer complex, causes late-onset
Parkinson disease. Am. J. Hum. Genet. 89: 168-175, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Parkinsonism;
Resting tremor;
Tremor;
Bradykinesia;
Akinesia;
Rigidity;
Postural instability;
Cramps;
Dyskinesias
MISCELLANEOUS:
Mean age of onset 50 to 52 years;
Incomplete, age-associated penetrance;
Motor fluctuation;
Levodopa-responsive
MOLECULAR BASIS:
Caused by mutation in the homolog of the yeast vacuolar protein sorting
35 gene (VPS35, 601501.0001)
*FIELD* CD
Cassandra L. Kniffin: 9/1/2011
*FIELD* ED
joanna: 09/16/2011
ckniffin: 9/1/2011
*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2014
Cassandra L. Kniffin - updated: 10/15/2012
*FIELD* CD
Cassandra L. Kniffin: 9/1/2011
*FIELD* ED
carol: 01/08/2014
ckniffin: 1/7/2014
terry: 3/14/2013
carol: 10/16/2012
ckniffin: 10/15/2012
carol: 9/6/2011
ckniffin: 9/6/2011
carol: 9/2/2011
ckniffin: 9/1/2011