Full text data of VAPB
VAPB
[Confidence: high (present in two of the MS resources)]
Vesicle-associated membrane protein-associated protein B/C; VAMP-B/VAMP-C; VAMP-associated protein B/C; VAP-B/VAP-C
Vesicle-associated membrane protein-associated protein B/C; VAMP-B/VAMP-C; VAMP-associated protein B/C; VAP-B/VAP-C
hRBCD
IPI00006211
IPI00006211 Splice isoform 1 of O95292 Vesicle-associated membrane protein-associated protein B/C Splice isoform 1 of O95292 Vesicle-associated membrane protein-associated protein B/C membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 1 2 n/a n/a 1 1 n/a 1 1 Type IV membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00006211 Splice isoform 1 of O95292 Vesicle-associated membrane protein-associated protein B/C Splice isoform 1 of O95292 Vesicle-associated membrane protein-associated protein B/C membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 2 1 2 n/a n/a 1 1 n/a 1 1 Type IV membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
O95292
ID VAPB_HUMAN Reviewed; 243 AA.
AC O95292; A2A2F2; O95293; Q9P0H0;
DT 01-NOV-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Vesicle-associated membrane protein-associated protein B/C;
DE Short=VAMP-B/VAMP-C;
DE Short=VAMP-associated protein B/C;
DE Short=VAP-B/VAP-C;
GN Name=VAPB; ORFNames=UNQ484/PRO983;
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).
RC TISSUE=Brain, and Heart;
RX PubMed=9920726; DOI=10.1006/bbrc.1998.9876;
RA Nishimura Y., Hayashi M., Inada H., Tanaka T.;
RT "Molecular cloning and characterization of mammalian homologues of
RT vesicle-associated membrane protein-associated (VAMP-associated)
RT proteins.";
RL Biochem. Biophys. Res. Commun. 254:21-26(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 PROTEIN SEQUENCE OF 2-19.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP INTERACTION WITH HCV NS5A AND NS5B.
RX PubMed=16227268; DOI=10.1128/JVI.79.21.13473-13482.2005;
RA Hamamoto I., Nishimura Y., Okamoto T., Aizaki H., Liu M., Mori Y.,
RA Abe T., Suzuki T., Lai M.M., Miyamura T., Moriishi K., Matsuura Y.;
RT "Human VAP-B is involved in hepatitis C virus replication through
RT interaction with NS5A and NS5B.";
RL J. Virol. 79:13473-13482(2005).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE, AND
RP CHARACTERIZATION OF VARIANT ALS8 SER-56.
RX PubMed=16891305; DOI=10.1074/jbc.M605049200;
RA Kanekura K., Nishimoto I., Aiso S., Matsuoka M.;
RT "Characterization of amyotrophic lateral sclerosis-linked P56S
RT mutation of vesicle-associated membrane protein-associated protein B
RT (VAPB/ALS8).";
RL J. Biol. Chem. 281:30223-30233(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-150; SER-156 AND
RP SER-160, 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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP INTERACTION WITH ZFYVE27.
RX PubMed=19289470; DOI=10.1074/jbc.M807938200;
RA Saita S., Shirane M., Natume T., Iemura S., Nakayama K.I.;
RT "Promotion of neurite extension by protrudin requires its interaction
RT with vesicle-associated membrane protein-associated protein.";
RL J. Biol. Chem. 284:13766-13777(2009).
RN [14]
RP FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE, VARIANT
RP ALS8 ILE-46, AND CHARACTERIZATION OF VARIANTS ALS8 ILE-46 AND SER-56.
RX PubMed=20940299; DOI=10.1074/jbc.M110.161398;
RA Chen H.J., Anagnostou G., Chai A., Withers J., Morris A.,
RA Adhikaree J., Pennetta G., de Belleroche J.S.;
RT "Characterization of the properties of a novel mutation in VAPB in
RT familial amyotrophic lateral sclerosis.";
RL J. Biol. Chem. 285:40266-40281(2010).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-150; SER-156 AND
RP SER-160, AND MASS 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 [16]
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 [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP FUNCTION IN CELLULAR CALCIUM HOMEOSTASIS REGULATION, SUBCELLULAR
RP LOCATION, INTERACTION WITH RMDN3, AND CHARACTERIZATION OF VARIANT ALS8
RP SER-56.
RX PubMed=22131369; DOI=10.1093/hmg/ddr559;
RA De Vos K.J., Morotz G.M., Stoica R., Tudor E.L., Lau K.F.,
RA Ackerley S., Warley A., Shaw C.E., Miller C.C.;
RT "VAPB interacts with the mitochondrial protein PTPIP51 to regulate
RT calcium homeostasis.";
RL Hum. Mol. Genet. 21:1299-1311(2012).
RN [19]
RP VARIANT ALS8 SER-56, AND VARIANT SMAPAD SER-56.
RX PubMed=15372378; DOI=10.1086/425287;
RA Nishimura A.L., Mitne-Neto M., Silva H.C., Richieri-Costa A.,
RA Middleton S., Cascio D., Kok F., Oliveira J.R., Gillingwater T.,
RA Webb J., Skehel P., Zatz M.;
RT "A mutation in the vesicle-trafficking protein VAPB causes late-onset
RT spinal muscular atrophy and amyotrophic lateral sclerosis.";
RL Am. J. Hum. Genet. 75:822-831(2004).
CC -!- FUNCTION: Participates in the endoplasmic reticulum unfolded
CC protein response (UPR) by inducing ERN1/IRE1 activity. Involved in
CC cellular calcium homeostasis regulation.
CC -!- SUBUNIT: Homodimer, and heterodimer with VAPA. Interacts with
CC VAMP1 and VAMP2. Interacts with HCV NS5A and NS5B. Interacts (via
CC MSP domain) with ZFYVE27. Interacts with RMDN3.
CC -!- INTERACTION:
CC Q03463:- (xeno); NbExp=6; IntAct=EBI-1188298, EBI-8803426;
CC Q03137:Epha4 (xeno); NbExp=2; IntAct=EBI-1188298, EBI-1539152;
CC O95070:YIF1A; NbExp=9; IntAct=EBI-1188298, EBI-2799703;
CC Q5T4F4:ZFYVE27; NbExp=2; IntAct=EBI-1188298, EBI-3892947;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type IV membrane protein (By similarity). Note=Present in
CC mitochondria-associated membranes that are endoplasmic reticulum
CC membrane regions closely apposed to the outer mitochondrial
CC membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=VAP-B;
CC IsoId=O95292-1; Sequence=Displayed;
CC Name=2; Synonyms=VAP-C;
CC IsoId=O95292-2; Sequence=VSP_003277, VSP_003278;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Isoform 1 predominates.
CC -!- DISEASE: Amyotrophic lateral sclerosis 8 (ALS8) [MIM:608627]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spinal muscular atrophy, proximal, adult, autosomal
CC dominant (SMAPAD) [MIM:182980]: A form of spinal muscular atrophy,
CC a neuromuscular disorder characterized by degeneration of the
CC anterior horn cells of the spinal cord, leading to symmetrical
CC muscle weakness and atrophy. SMAPAD is characterized by proximal
CC muscle weakness that begins in the lower limbs and then progresses
CC to upper limbs, onset in late adulthood (after third decade) and a
CC benign course. Most of the patients remain ambulatory 10 to 40
CC years after clinical onset. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the VAMP-associated protein (VAP)
CC (TC 9.B.17) family.
CC -!- SIMILARITY: Contains 1 MSP domain.
CC -!- WEB RESOURCE: Name=Alsod; Note=ALS genetic mutations db;
CC URL="http://alsod.iop.kcl.ac.uk/Als/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VAPB";
CC -!- WEB RESOURCE: Name=Mendelian genes VAMP (vesicle-associated
CC membrane protein)-associated protein B and C (VAPB); Note=Leiden
CC Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/VAPB";
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DR EMBL; AF086628; AAD13577.1; -; mRNA.
DR EMBL; AF086629; AAD13578.1; -; mRNA.
DR EMBL; AF160212; AAF67013.1; -; mRNA.
DR EMBL; AY358464; AAQ88829.1; -; mRNA.
DR EMBL; AL035455; CAC15021.1; -; Genomic_DNA.
DR EMBL; AL035455; CAM27023.1; -; Genomic_DNA.
DR EMBL; BC001712; AAH01712.1; -; mRNA.
DR PIR; JG0186; JG0186.
DR RefSeq; NP_001182606.1; NM_001195677.1.
DR RefSeq; NP_004729.1; NM_004738.4.
DR UniGene; Hs.182625; -.
DR PDB; 2MDK; NMR; -; A=1-125.
DR PDB; 3IKK; X-ray; 2.50 A; A/B=1-125.
DR PDBsum; 2MDK; -.
DR PDBsum; 3IKK; -.
DR ProteinModelPortal; O95292; -.
DR SMR; O95292; 1-125.
DR IntAct; O95292; 21.
DR STRING; 9606.ENSP00000417175; -.
DR TCDB; 9.B.17.1.1; the vamp-associated protein (vap) family.
DR PhosphoSite; O95292; -.
DR PaxDb; O95292; -.
DR PRIDE; O95292; -.
DR DNASU; 9217; -.
DR Ensembl; ENST00000395802; ENSP00000379147; ENSG00000124164.
DR Ensembl; ENST00000475243; ENSP00000417175; ENSG00000124164.
DR GeneID; 9217; -.
DR KEGG; hsa:9217; -.
DR UCSC; uc002xza.3; human.
DR CTD; 9217; -.
DR GeneCards; GC20P056964; -.
DR HGNC; HGNC:12649; VAPB.
DR HPA; CAB013722; -.
DR HPA; HPA013144; -.
DR MIM; 182980; phenotype.
DR MIM; 605704; gene.
DR MIM; 608627; phenotype.
DR neXtProt; NX_O95292; -.
DR Orphanet; 209335; Adult-onset proximal spinal muscular atrophy, autosomal dominant.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA37273; -.
DR eggNOG; COG5066; -.
DR HOGENOM; HOG000293182; -.
DR HOVERGEN; HBG028551; -.
DR InParanoid; O95292; -.
DR KO; K10707; -.
DR OMA; GLRMRKA; -.
DR OrthoDB; EOG7CK389; -.
DR PhylomeDB; O95292; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; VAPB; human.
DR EvolutionaryTrace; O95292; -.
DR GeneWiki; VAPB; -.
DR GenomeRNAi; 9217; -.
DR NextBio; 34553; -.
DR PRO; PR:O95292; -.
DR ArrayExpress; O95292; -.
DR Bgee; O95292; -.
DR CleanEx; HS_VAPB; -.
DR Genevestigator; O95292; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0048487; F:beta-tubulin binding; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IMP:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IDA:UniProtKB.
DR GO; GO:0045070; P:positive regulation of viral genome replication; IMP:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR Gene3D; 2.60.40.360; -; 1.
DR InterPro; IPR000535; MSP_dom.
DR InterPro; IPR008962; PapD-like.
DR InterPro; IPR016763; Vesicle-associated_membrane.
DR Pfam; PF00635; Motile_Sperm; 1.
DR PIRSF; PIRSF019693; VAMP-associated; 1.
DR SUPFAM; SSF49354; SSF49354; 1.
DR PROSITE; PS50202; MSP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Amyotrophic lateral sclerosis; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Endoplasmic reticulum;
KW Host-virus interaction; Membrane; Neurodegeneration; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix;
KW Unfolded protein response.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 243 Vesicle-associated membrane protein-
FT associated protein B/C.
FT /FTId=PRO_0000213473.
FT TOPO_DOM 2 222 Cytoplasmic (Potential).
FT TRANSMEM 223 243 Helical; Anchor for type IV membrane
FT protein; (Potential).
FT DOMAIN 7 124 MSP.
FT COILED 159 196 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 150 150 Phosphothreonine.
FT MOD_RES 156 156 Phosphoserine.
FT MOD_RES 160 160 Phosphoserine.
FT VAR_SEQ 71 99 VMLQPFDYDPNEKSKHKFMVQSMFAPTDT -> GRRWTADE
FT EDSAEQQPHFSISPNWEGRRP (in isoform 2).
FT /FTId=VSP_003277.
FT VAR_SEQ 100 243 Missing (in isoform 2).
FT /FTId=VSP_003278.
FT VARIANT 46 46 T -> I (in ALS8; it forms insoluble
FT cytosolic aggregates; cannot activate the
FT UPR pathway through ERN1/IRE1 induction;
FT results in ubiquitinated aggregates
FT accumulation and cell death;
FT dbSNP:rs281875284).
FT /FTId=VAR_067964.
FT VARIANT 56 56 P -> S (in ALS8 and SMAPAD; it forms
FT insoluble cytosolic aggregates; cannot
FT activate the UPR pathway; affects
FT interaction with RMDN3; affects cellular
FT calcium homeostasis; dbSNP:rs74315431).
FT /FTId=VAR_026743.
FT CONFLICT 60 60 I -> V (in Ref. 2; AAF67013).
FT CONFLICT 67 67 I -> L (in Ref. 2; AAF67013).
FT CONFLICT 97 97 T -> P (in Ref. 2; AAF67013).
FT CONFLICT 103 106 EAVW -> DGTR (in Ref. 2; AAF67013).
FT STRAND 8 20
FT STRAND 26 33
FT STRAND 36 38
FT STRAND 40 47
FT TURN 49 51
FT STRAND 52 61
FT STRAND 66 73
FT STRAND 88 94
FT TURN 104 108
FT STRAND 111 113
FT STRAND 115 124
SQ SEQUENCE 243 AA; 27228 MW; 22AEEF9EC7FC0B3F CRC64;
MAKVEQVLSL EPQHELKFRG PFTDVVTTNL KLGNPTDRNV CFKVKTTAPR RYCVRPNSGI
IDAGASINVS VMLQPFDYDP NEKSKHKFMV QSMFAPTDTS DMEAVWKEAK PEDLMDSKLR
CVFELPAEND KPHDVEINKI ISTTASKTET PIVSKSLSSS LDDTEVKKVM EECKRLQGEV
QRLREENKQF KEEDGLRMRK TVQSNSPISA LAPTGKEEGL STRLLALVVL FFIVGVIIGK
IAL
//
ID VAPB_HUMAN Reviewed; 243 AA.
AC O95292; A2A2F2; O95293; Q9P0H0;
DT 01-NOV-2002, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 132.
DE RecName: Full=Vesicle-associated membrane protein-associated protein B/C;
DE Short=VAMP-B/VAMP-C;
DE Short=VAMP-associated protein B/C;
DE Short=VAP-B/VAP-C;
GN Name=VAPB; ORFNames=UNQ484/PRO983;
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).
RC TISSUE=Brain, and Heart;
RX PubMed=9920726; DOI=10.1006/bbrc.1998.9876;
RA Nishimura Y., Hayashi M., Inada H., Tanaka T.;
RT "Molecular cloning and characterization of mammalian homologues of
RT vesicle-associated membrane protein-associated (VAMP-associated)
RT proteins.";
RL Biochem. Biophys. Res. Commun. 254:21-26(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Adrenal gland;
RX PubMed=10931946; DOI=10.1073/pnas.160270997;
RA Hu R.-M., Han Z.-G., Song H.-D., Peng Y.-D., Huang Q.-H., Ren S.-X.,
RA Gu Y.-J., Huang C.-H., Li Y.-B., Jiang C.-L., Fu G., Zhang Q.-H.,
RA Gu B.-W., Dai M., Mao Y.-F., Gao G.-F., Rong R., Ye M., Zhou J.,
RA Xu S.-H., Gu J., Shi J.-X., Jin W.-R., Zhang C.-K., Wu T.-M.,
RA Huang G.-Y., Chen Z., Chen M.-D., Chen J.-L.;
RT "Gene expression profiling in the human hypothalamus-pituitary-adrenal
RT axis and full-length cDNA cloning.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:9543-9548(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S.,
RA Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J.,
RA Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J.,
RA Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A.,
RA Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H.,
RA Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D.,
RA Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale
RT effort to identify novel human secreted and transmembrane proteins: a
RT bioinformatics assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lymph;
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 PROTEIN SEQUENCE OF 2-19.
RC TISSUE=Platelet;
RX PubMed=12665801; DOI=10.1038/nbt810;
RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A.,
RA Thomas G.R., Vandekerckhove J.;
RT "Exploring proteomes and analyzing protein processing by mass
RT spectrometric identification of sorted N-terminal peptides.";
RL Nat. Biotechnol. 21:566-569(2003).
RN [7]
RP INTERACTION WITH HCV NS5A AND NS5B.
RX PubMed=16227268; DOI=10.1128/JVI.79.21.13473-13482.2005;
RA Hamamoto I., Nishimura Y., Okamoto T., Aizaki H., Liu M., Mori Y.,
RA Abe T., Suzuki T., Lai M.M., Miyamura T., Moriishi K., Matsuura Y.;
RT "Human VAP-B is involved in hepatitis C virus replication through
RT interaction with NS5A and NS5B.";
RL J. Virol. 79:13473-13482(2005).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE, AND
RP CHARACTERIZATION OF VARIANT ALS8 SER-56.
RX PubMed=16891305; DOI=10.1074/jbc.M605049200;
RA Kanekura K., Nishimoto I., Aiso S., Matsuoka M.;
RT "Characterization of amyotrophic lateral sclerosis-linked P56S
RT mutation of vesicle-associated membrane protein-associated protein B
RT (VAPB/ALS8).";
RL J. Biol. Chem. 281:30223-30233(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-150; SER-156 AND
RP SER-160, 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 [12]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [13]
RP INTERACTION WITH ZFYVE27.
RX PubMed=19289470; DOI=10.1074/jbc.M807938200;
RA Saita S., Shirane M., Natume T., Iemura S., Nakayama K.I.;
RT "Promotion of neurite extension by protrudin requires its interaction
RT with vesicle-associated membrane protein-associated protein.";
RL J. Biol. Chem. 284:13766-13777(2009).
RN [14]
RP FUNCTION IN ENDOPLASMIC RETICULUM UNFOLDED PROTEIN RESPONSE, VARIANT
RP ALS8 ILE-46, AND CHARACTERIZATION OF VARIANTS ALS8 ILE-46 AND SER-56.
RX PubMed=20940299; DOI=10.1074/jbc.M110.161398;
RA Chen H.J., Anagnostou G., Chai A., Withers J., Morris A.,
RA Adhikaree J., Pennetta G., de Belleroche J.S.;
RT "Characterization of the properties of a novel mutation in VAPB in
RT familial amyotrophic lateral sclerosis.";
RL J. Biol. Chem. 285:40266-40281(2010).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-150; SER-156 AND
RP SER-160, AND MASS 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 [16]
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 [17]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [18]
RP FUNCTION IN CELLULAR CALCIUM HOMEOSTASIS REGULATION, SUBCELLULAR
RP LOCATION, INTERACTION WITH RMDN3, AND CHARACTERIZATION OF VARIANT ALS8
RP SER-56.
RX PubMed=22131369; DOI=10.1093/hmg/ddr559;
RA De Vos K.J., Morotz G.M., Stoica R., Tudor E.L., Lau K.F.,
RA Ackerley S., Warley A., Shaw C.E., Miller C.C.;
RT "VAPB interacts with the mitochondrial protein PTPIP51 to regulate
RT calcium homeostasis.";
RL Hum. Mol. Genet. 21:1299-1311(2012).
RN [19]
RP VARIANT ALS8 SER-56, AND VARIANT SMAPAD SER-56.
RX PubMed=15372378; DOI=10.1086/425287;
RA Nishimura A.L., Mitne-Neto M., Silva H.C., Richieri-Costa A.,
RA Middleton S., Cascio D., Kok F., Oliveira J.R., Gillingwater T.,
RA Webb J., Skehel P., Zatz M.;
RT "A mutation in the vesicle-trafficking protein VAPB causes late-onset
RT spinal muscular atrophy and amyotrophic lateral sclerosis.";
RL Am. J. Hum. Genet. 75:822-831(2004).
CC -!- FUNCTION: Participates in the endoplasmic reticulum unfolded
CC protein response (UPR) by inducing ERN1/IRE1 activity. Involved in
CC cellular calcium homeostasis regulation.
CC -!- SUBUNIT: Homodimer, and heterodimer with VAPA. Interacts with
CC VAMP1 and VAMP2. Interacts with HCV NS5A and NS5B. Interacts (via
CC MSP domain) with ZFYVE27. Interacts with RMDN3.
CC -!- INTERACTION:
CC Q03463:- (xeno); NbExp=6; IntAct=EBI-1188298, EBI-8803426;
CC Q03137:Epha4 (xeno); NbExp=2; IntAct=EBI-1188298, EBI-1539152;
CC O95070:YIF1A; NbExp=9; IntAct=EBI-1188298, EBI-2799703;
CC Q5T4F4:ZFYVE27; NbExp=2; IntAct=EBI-1188298, EBI-3892947;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass
CC type IV membrane protein (By similarity). Note=Present in
CC mitochondria-associated membranes that are endoplasmic reticulum
CC membrane regions closely apposed to the outer mitochondrial
CC membrane.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=VAP-B;
CC IsoId=O95292-1; Sequence=Displayed;
CC Name=2; Synonyms=VAP-C;
CC IsoId=O95292-2; Sequence=VSP_003277, VSP_003278;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Isoform 1 predominates.
CC -!- DISEASE: Amyotrophic lateral sclerosis 8 (ALS8) [MIM:608627]: A
CC neurodegenerative disorder affecting upper motor neurons in the
CC brain and lower motor neurons in the brain stem and spinal cord,
CC resulting in fatal paralysis. Sensory abnormalities are absent.
CC The pathologic hallmarks of the disease include pallor of the
CC corticospinal tract due to loss of motor neurons, presence of
CC ubiquitin-positive inclusions within surviving motor neurons, and
CC deposition of pathologic aggregates. The etiology of amyotrophic
CC lateral sclerosis is likely to be multifactorial, involving both
CC genetic and environmental factors. The disease is inherited in 5-
CC 10% of the cases. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Spinal muscular atrophy, proximal, adult, autosomal
CC dominant (SMAPAD) [MIM:182980]: A form of spinal muscular atrophy,
CC a neuromuscular disorder characterized by degeneration of the
CC anterior horn cells of the spinal cord, leading to symmetrical
CC muscle weakness and atrophy. SMAPAD is characterized by proximal
CC muscle weakness that begins in the lower limbs and then progresses
CC to upper limbs, onset in late adulthood (after third decade) and a
CC benign course. Most of the patients remain ambulatory 10 to 40
CC years after clinical onset. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the VAMP-associated protein (VAP)
CC (TC 9.B.17) family.
CC -!- SIMILARITY: Contains 1 MSP domain.
CC -!- WEB RESOURCE: Name=Alsod; Note=ALS genetic mutations db;
CC URL="http://alsod.iop.kcl.ac.uk/Als/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/VAPB";
CC -!- WEB RESOURCE: Name=Mendelian genes VAMP (vesicle-associated
CC membrane protein)-associated protein B and C (VAPB); Note=Leiden
CC Open Variation Database (LOVD);
CC URL="http://www.lovd.nl/VAPB";
CC -----------------------------------------------------------------------
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DR EMBL; AF086628; AAD13577.1; -; mRNA.
DR EMBL; AF086629; AAD13578.1; -; mRNA.
DR EMBL; AF160212; AAF67013.1; -; mRNA.
DR EMBL; AY358464; AAQ88829.1; -; mRNA.
DR EMBL; AL035455; CAC15021.1; -; Genomic_DNA.
DR EMBL; AL035455; CAM27023.1; -; Genomic_DNA.
DR EMBL; BC001712; AAH01712.1; -; mRNA.
DR PIR; JG0186; JG0186.
DR RefSeq; NP_001182606.1; NM_001195677.1.
DR RefSeq; NP_004729.1; NM_004738.4.
DR UniGene; Hs.182625; -.
DR PDB; 2MDK; NMR; -; A=1-125.
DR PDB; 3IKK; X-ray; 2.50 A; A/B=1-125.
DR PDBsum; 2MDK; -.
DR PDBsum; 3IKK; -.
DR ProteinModelPortal; O95292; -.
DR SMR; O95292; 1-125.
DR IntAct; O95292; 21.
DR STRING; 9606.ENSP00000417175; -.
DR TCDB; 9.B.17.1.1; the vamp-associated protein (vap) family.
DR PhosphoSite; O95292; -.
DR PaxDb; O95292; -.
DR PRIDE; O95292; -.
DR DNASU; 9217; -.
DR Ensembl; ENST00000395802; ENSP00000379147; ENSG00000124164.
DR Ensembl; ENST00000475243; ENSP00000417175; ENSG00000124164.
DR GeneID; 9217; -.
DR KEGG; hsa:9217; -.
DR UCSC; uc002xza.3; human.
DR CTD; 9217; -.
DR GeneCards; GC20P056964; -.
DR HGNC; HGNC:12649; VAPB.
DR HPA; CAB013722; -.
DR HPA; HPA013144; -.
DR MIM; 182980; phenotype.
DR MIM; 605704; gene.
DR MIM; 608627; phenotype.
DR neXtProt; NX_O95292; -.
DR Orphanet; 209335; Adult-onset proximal spinal muscular atrophy, autosomal dominant.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA37273; -.
DR eggNOG; COG5066; -.
DR HOGENOM; HOG000293182; -.
DR HOVERGEN; HBG028551; -.
DR InParanoid; O95292; -.
DR KO; K10707; -.
DR OMA; GLRMRKA; -.
DR OrthoDB; EOG7CK389; -.
DR PhylomeDB; O95292; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; VAPB; human.
DR EvolutionaryTrace; O95292; -.
DR GeneWiki; VAPB; -.
DR GenomeRNAi; 9217; -.
DR NextBio; 34553; -.
DR PRO; PR:O95292; -.
DR ArrayExpress; O95292; -.
DR Bgee; O95292; -.
DR CleanEx; HS_VAPB; -.
DR Genevestigator; O95292; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0048487; F:beta-tubulin binding; IDA:UniProtKB.
DR GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR GO; GO:0006987; P:activation of signaling protein activity involved in unfolded protein response; IDA:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; IMP:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IDA:UniProtKB.
DR GO; GO:0045070; P:positive regulation of viral genome replication; IMP:UniProtKB.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR GO; GO:0030148; P:sphingolipid biosynthetic process; TAS:Reactome.
DR Gene3D; 2.60.40.360; -; 1.
DR InterPro; IPR000535; MSP_dom.
DR InterPro; IPR008962; PapD-like.
DR InterPro; IPR016763; Vesicle-associated_membrane.
DR Pfam; PF00635; Motile_Sperm; 1.
DR PIRSF; PIRSF019693; VAMP-associated; 1.
DR SUPFAM; SSF49354; SSF49354; 1.
DR PROSITE; PS50202; MSP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Amyotrophic lateral sclerosis; Coiled coil; Complete proteome;
KW Direct protein sequencing; Disease mutation; Endoplasmic reticulum;
KW Host-virus interaction; Membrane; Neurodegeneration; Phosphoprotein;
KW Reference proteome; Transmembrane; Transmembrane helix;
KW Unfolded protein response.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 243 Vesicle-associated membrane protein-
FT associated protein B/C.
FT /FTId=PRO_0000213473.
FT TOPO_DOM 2 222 Cytoplasmic (Potential).
FT TRANSMEM 223 243 Helical; Anchor for type IV membrane
FT protein; (Potential).
FT DOMAIN 7 124 MSP.
FT COILED 159 196 Potential.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 150 150 Phosphothreonine.
FT MOD_RES 156 156 Phosphoserine.
FT MOD_RES 160 160 Phosphoserine.
FT VAR_SEQ 71 99 VMLQPFDYDPNEKSKHKFMVQSMFAPTDT -> GRRWTADE
FT EDSAEQQPHFSISPNWEGRRP (in isoform 2).
FT /FTId=VSP_003277.
FT VAR_SEQ 100 243 Missing (in isoform 2).
FT /FTId=VSP_003278.
FT VARIANT 46 46 T -> I (in ALS8; it forms insoluble
FT cytosolic aggregates; cannot activate the
FT UPR pathway through ERN1/IRE1 induction;
FT results in ubiquitinated aggregates
FT accumulation and cell death;
FT dbSNP:rs281875284).
FT /FTId=VAR_067964.
FT VARIANT 56 56 P -> S (in ALS8 and SMAPAD; it forms
FT insoluble cytosolic aggregates; cannot
FT activate the UPR pathway; affects
FT interaction with RMDN3; affects cellular
FT calcium homeostasis; dbSNP:rs74315431).
FT /FTId=VAR_026743.
FT CONFLICT 60 60 I -> V (in Ref. 2; AAF67013).
FT CONFLICT 67 67 I -> L (in Ref. 2; AAF67013).
FT CONFLICT 97 97 T -> P (in Ref. 2; AAF67013).
FT CONFLICT 103 106 EAVW -> DGTR (in Ref. 2; AAF67013).
FT STRAND 8 20
FT STRAND 26 33
FT STRAND 36 38
FT STRAND 40 47
FT TURN 49 51
FT STRAND 52 61
FT STRAND 66 73
FT STRAND 88 94
FT TURN 104 108
FT STRAND 111 113
FT STRAND 115 124
SQ SEQUENCE 243 AA; 27228 MW; 22AEEF9EC7FC0B3F CRC64;
MAKVEQVLSL EPQHELKFRG PFTDVVTTNL KLGNPTDRNV CFKVKTTAPR RYCVRPNSGI
IDAGASINVS VMLQPFDYDP NEKSKHKFMV QSMFAPTDTS DMEAVWKEAK PEDLMDSKLR
CVFELPAEND KPHDVEINKI ISTTASKTET PIVSKSLSSS LDDTEVKKVM EECKRLQGEV
QRLREENKQF KEEDGLRMRK TVQSNSPISA LAPTGKEEGL STRLLALVVL FFIVGVIIGK
IAL
//
MIM
182980
*RECORD*
*FIELD* NO
182980
*FIELD* TI
#182980 SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE; SMAFK
;;FINKEL LATE-ADULT TYPE SMA;;
read moreSPINAL MUSCULAR ATROPHY, PROXIMAL, ADULT, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because the Finkel type of
late-onset autosomal dominant spinal muscular atrophy (SMAFK) is caused
by heterozygous mutation in the gene encoding vesicle-associated
membrane protein-associated protein B (VAPB; 605704) on chromosome
20q13.
DESCRIPTION
Spinal muscular atrophy is characterized by degeneration of the anterior
horn cells in the spinal cord, leading to symmetric muscle weakness and
wasting.
See also autosomal recessive adult-onset proximal spinal muscular
atrophy (SMA4; 271150), caused by defect in the SMN1 gene (600354), and
autosomal dominant childhood-onset proximal SMA (158600).
CLINICAL FEATURES
Pearn (1978) reported 13 patients from 6 kindreds with autosomal
dominant proximal spinal muscular atrophy. Median age at disease onset
was 37 years. The authors estimated that 30% of adult onset cases of SMA
are due to an autosomal dominant gene. Pearn (1978) suggested that a
separate gene was responsible for autosomal dominant SMA with childhood
onset (birth to 8 years).
Richieri-Costa et al. (1981) studied 2 kindreds in which 80 members were
affected with an autosomal dominant, slowly progressive spinal muscular
atrophy of late onset (average 48.8 years). One of the 2 kindreds was
first described by Finkel (1962); the second was a black family living
in the same region. The neurogenic nature of the disorder was
established by electromyography and muscle biopsy. Unusual findings in
this disorder were slow loss of muscle strength and progressive proximal
atrophy, which started in the legs and later involved the arms;
hypoactive or absent deep tendon reflexes; and generalized
fasciculations. Adult spinal muscular atrophy usually begins after the
third decade of life, and survival for several decades is typical. Emery
(1971) cited cases by Tsukagoshi et al. (1965) and Peters et al. (1968).
In a study on the classification and genetics of proximal SMA, Zerres
(1989) documented the clinical course of 6 families including 20
patients suffering from an autosomal dominant form. Three families were
classified as having the adult-onset form (after age 20 years). The
patients showed a benign course, most of them remaining ambulatory 10 to
40 years after clinical onset (Rietschel et al., 1992). Three patients
of the other 3 families suffered from the childhood-onset form, with
first symptoms before the age of 12 years and walking difficulties
throughout life, whereas other members of these families would have been
classified as the adult-onset form. The latter had an onset between ages
17 and 28 years and were only moderately handicapped when examined at
ages 38 to 60 years. Rietschel et al. (1992) suggested that the great
intrafamilial variability in at least some of the families with
autosomal dominant SMA is not compatible with the distinction of 2
clinically defined genetic entities.
MAPPING
Kausch et al. (1991) performed linkage studies in 4 families with the
autosomal dominant form of proximal spinal muscular atrophy. Three of
the families met the criteria proposed by Pearn (1978). In a fourth
family, affected individuals presented with an unusually mild SMA with
muscle cramps (Ricker and Moxley, 1990); see 158400. For the first 3
families taken together and the fourth family taken alone, close linkage
to D5S6, where the SMN1 gene is located, was excluded. The authors
concluded that autosomal dominant and autosomal recessive forms of SMA
are distinct genetic entities.
MOLECULAR GENETICS
In 3 families with the Finkel type of late-onset spinal muscular
atrophy, Nishimura et al. (2004) found a missense mutation in the VAPB
gene (605704.0001). They identified the same mutation in another 3
families with ALS8 (608627) and in 1 family in which some patients had
typical, and others atypical, ALS. Although it was not possible to link
all these families genealogically, haplotype analysis suggested founder
effect. Members of the vesicle-associated proteins are intracellular
membrane proteins that can associate with microtubules and that have a
function in membrane transport. The data suggested that clinically
variable motor neuron diseases may be caused by a dysfunction in
intracellular membrane trafficking.
*FIELD* SA
Meadows et al. (1969)
*FIELD* RF
1. Emery, A. E. H.: The nosology of the spinal muscular atrophies. J.
Med. Genet. 8: 481-495, 1971.
2. Finkel, N.: A forma pseudomiopatica tardia da atrofia muscular
progressiva heredo-familial. Arquiv. Neuropsiquiatr. 20: 307-322,
1962.
3. Kausch, K.; Muller, C. R.; Grimm, T.; Ricker, K.; Rietschel, M.;
Rudnik-Schoneborn, S.; Zerres, K.: No evidence for linkage of autosomal
dominant proximal spinal muscular atrophies to chromosome 5q markers. Hum.
Genet. 86: 317-318, 1991.
4. Meadows, J. C.; Marsden, C. D.; Harriman, D. G. F.: Chronic spinal
muscular atrophy in adults. I. The Kugelberg-Welander syndrome. J.
Neurol. Sci. 9: 527-550, 1969.
5. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
6. Pearn, J.: Autosomal dominant spinal muscular atrophy: a clinical
and genetic study. J. Neurol. Sci. 38: 263-275, 1978.
7. Peters, H. A.; Opitz, J. M.; Goto, I.; Reese, H. H.: The benign
proximal spinal progressive muscular atrophies: a clinical and genetical
study. Acta Neurol. 44: 542-560, 1968.
8. Richieri-Costa, A.; Rogatko, A.; Levisky, R.; Finkel, N.; Frota-Pessoa,
O.: Autosomal dominant late adult spinal muscular atrophy, type Finkel. Am.
J. Med. Genet. 9: 119-128, 1981.
9. Ricker, K.; Moxley, R. T., III: Autosomal dominant cramping disease. Arch.
Neurol. 47: 810-812, 1990.
10. Rietschel, M.; Rudnik-Schoneborn, S.; Zerres, K.: Clinical variability
of autosomal dominant spinal muscular atrophy. J. Neurol. Sci. 107:
65-73, 1992.
11. Tsukagoshi, H.; Nakanishi, T.; Kondo, K.; Tsubaki, T.: Hereditary
proximal neurogenic muscular atrophy in adults. Arch. Neurol. 12:
597-603, 1965.
12. Zerres, K.: Klassification und Genetik spinaler Muskelatrophien.
Stuttgart: Thieme (pub.) 1989.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal, due to neuronopathy, begins in the lower
limbs and then progresses to upper limbs
NEUROLOGIC:
[Central nervous system];
Muscle weakness, proximal, due to neuronopathy begins in the lower
limbs and then progresses to upper limbs;
Fasciculations;
Hyporeflexia;
EMG shows neurogenic abnormalities
MISCELLANEOUS:
Onset after third decade
MOLECULAR BASIS:
Caused by mutation in the vesicle-associated membrane protein-associated
protein B gene (VAPB, 605704.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 3/29/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 7/2/2013
alopez: 10/25/2004
joanna: 9/2/2004
ckniffin: 3/29/2004
*FIELD* CN
Anne M. Stumpf - updated: 10/25/2004
Cassandra L. Kniffin - reorganized: 3/31/2004
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
ckniffin: 02/13/2013
alopez: 10/25/2004
carol: 3/31/2004
ckniffin: 3/31/2004
ckniffin: 3/29/2004
mgross: 3/17/2004
mimadm: 3/25/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
marie: 12/16/1986
*RECORD*
*FIELD* NO
182980
*FIELD* TI
#182980 SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE; SMAFK
;;FINKEL LATE-ADULT TYPE SMA;;
read moreSPINAL MUSCULAR ATROPHY, PROXIMAL, ADULT, AUTOSOMAL DOMINANT
*FIELD* TX
A number sign (#) is used with this entry because the Finkel type of
late-onset autosomal dominant spinal muscular atrophy (SMAFK) is caused
by heterozygous mutation in the gene encoding vesicle-associated
membrane protein-associated protein B (VAPB; 605704) on chromosome
20q13.
DESCRIPTION
Spinal muscular atrophy is characterized by degeneration of the anterior
horn cells in the spinal cord, leading to symmetric muscle weakness and
wasting.
See also autosomal recessive adult-onset proximal spinal muscular
atrophy (SMA4; 271150), caused by defect in the SMN1 gene (600354), and
autosomal dominant childhood-onset proximal SMA (158600).
CLINICAL FEATURES
Pearn (1978) reported 13 patients from 6 kindreds with autosomal
dominant proximal spinal muscular atrophy. Median age at disease onset
was 37 years. The authors estimated that 30% of adult onset cases of SMA
are due to an autosomal dominant gene. Pearn (1978) suggested that a
separate gene was responsible for autosomal dominant SMA with childhood
onset (birth to 8 years).
Richieri-Costa et al. (1981) studied 2 kindreds in which 80 members were
affected with an autosomal dominant, slowly progressive spinal muscular
atrophy of late onset (average 48.8 years). One of the 2 kindreds was
first described by Finkel (1962); the second was a black family living
in the same region. The neurogenic nature of the disorder was
established by electromyography and muscle biopsy. Unusual findings in
this disorder were slow loss of muscle strength and progressive proximal
atrophy, which started in the legs and later involved the arms;
hypoactive or absent deep tendon reflexes; and generalized
fasciculations. Adult spinal muscular atrophy usually begins after the
third decade of life, and survival for several decades is typical. Emery
(1971) cited cases by Tsukagoshi et al. (1965) and Peters et al. (1968).
In a study on the classification and genetics of proximal SMA, Zerres
(1989) documented the clinical course of 6 families including 20
patients suffering from an autosomal dominant form. Three families were
classified as having the adult-onset form (after age 20 years). The
patients showed a benign course, most of them remaining ambulatory 10 to
40 years after clinical onset (Rietschel et al., 1992). Three patients
of the other 3 families suffered from the childhood-onset form, with
first symptoms before the age of 12 years and walking difficulties
throughout life, whereas other members of these families would have been
classified as the adult-onset form. The latter had an onset between ages
17 and 28 years and were only moderately handicapped when examined at
ages 38 to 60 years. Rietschel et al. (1992) suggested that the great
intrafamilial variability in at least some of the families with
autosomal dominant SMA is not compatible with the distinction of 2
clinically defined genetic entities.
MAPPING
Kausch et al. (1991) performed linkage studies in 4 families with the
autosomal dominant form of proximal spinal muscular atrophy. Three of
the families met the criteria proposed by Pearn (1978). In a fourth
family, affected individuals presented with an unusually mild SMA with
muscle cramps (Ricker and Moxley, 1990); see 158400. For the first 3
families taken together and the fourth family taken alone, close linkage
to D5S6, where the SMN1 gene is located, was excluded. The authors
concluded that autosomal dominant and autosomal recessive forms of SMA
are distinct genetic entities.
MOLECULAR GENETICS
In 3 families with the Finkel type of late-onset spinal muscular
atrophy, Nishimura et al. (2004) found a missense mutation in the VAPB
gene (605704.0001). They identified the same mutation in another 3
families with ALS8 (608627) and in 1 family in which some patients had
typical, and others atypical, ALS. Although it was not possible to link
all these families genealogically, haplotype analysis suggested founder
effect. Members of the vesicle-associated proteins are intracellular
membrane proteins that can associate with microtubules and that have a
function in membrane transport. The data suggested that clinically
variable motor neuron diseases may be caused by a dysfunction in
intracellular membrane trafficking.
*FIELD* SA
Meadows et al. (1969)
*FIELD* RF
1. Emery, A. E. H.: The nosology of the spinal muscular atrophies. J.
Med. Genet. 8: 481-495, 1971.
2. Finkel, N.: A forma pseudomiopatica tardia da atrofia muscular
progressiva heredo-familial. Arquiv. Neuropsiquiatr. 20: 307-322,
1962.
3. Kausch, K.; Muller, C. R.; Grimm, T.; Ricker, K.; Rietschel, M.;
Rudnik-Schoneborn, S.; Zerres, K.: No evidence for linkage of autosomal
dominant proximal spinal muscular atrophies to chromosome 5q markers. Hum.
Genet. 86: 317-318, 1991.
4. Meadows, J. C.; Marsden, C. D.; Harriman, D. G. F.: Chronic spinal
muscular atrophy in adults. I. The Kugelberg-Welander syndrome. J.
Neurol. Sci. 9: 527-550, 1969.
5. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
6. Pearn, J.: Autosomal dominant spinal muscular atrophy: a clinical
and genetic study. J. Neurol. Sci. 38: 263-275, 1978.
7. Peters, H. A.; Opitz, J. M.; Goto, I.; Reese, H. H.: The benign
proximal spinal progressive muscular atrophies: a clinical and genetical
study. Acta Neurol. 44: 542-560, 1968.
8. Richieri-Costa, A.; Rogatko, A.; Levisky, R.; Finkel, N.; Frota-Pessoa,
O.: Autosomal dominant late adult spinal muscular atrophy, type Finkel. Am.
J. Med. Genet. 9: 119-128, 1981.
9. Ricker, K.; Moxley, R. T., III: Autosomal dominant cramping disease. Arch.
Neurol. 47: 810-812, 1990.
10. Rietschel, M.; Rudnik-Schoneborn, S.; Zerres, K.: Clinical variability
of autosomal dominant spinal muscular atrophy. J. Neurol. Sci. 107:
65-73, 1992.
11. Tsukagoshi, H.; Nakanishi, T.; Kondo, K.; Tsubaki, T.: Hereditary
proximal neurogenic muscular atrophy in adults. Arch. Neurol. 12:
597-603, 1965.
12. Zerres, K.: Klassification und Genetik spinaler Muskelatrophien.
Stuttgart: Thieme (pub.) 1989.
*FIELD* CS
INHERITANCE:
Autosomal dominant
MUSCLE, SOFT TISSUE:
Muscle weakness, proximal, due to neuronopathy, begins in the lower
limbs and then progresses to upper limbs
NEUROLOGIC:
[Central nervous system];
Muscle weakness, proximal, due to neuronopathy begins in the lower
limbs and then progresses to upper limbs;
Fasciculations;
Hyporeflexia;
EMG shows neurogenic abnormalities
MISCELLANEOUS:
Onset after third decade
MOLECULAR BASIS:
Caused by mutation in the vesicle-associated membrane protein-associated
protein B gene (VAPB, 605704.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 3/29/2004
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/02/2013
joanna: 7/2/2013
alopez: 10/25/2004
joanna: 9/2/2004
ckniffin: 3/29/2004
*FIELD* CN
Anne M. Stumpf - updated: 10/25/2004
Cassandra L. Kniffin - reorganized: 3/31/2004
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
ckniffin: 02/13/2013
alopez: 10/25/2004
carol: 3/31/2004
ckniffin: 3/31/2004
ckniffin: 3/29/2004
mgross: 3/17/2004
mimadm: 3/25/1995
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
marie: 12/16/1986
MIM
605704
*RECORD*
*FIELD* NO
605704
*FIELD* TI
*605704 VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B; VAPB
;;VAMP-ASSOCIATED PROTEIN B;;
read moreDVAP33A, DROSOPHILA, HOMOLOG OF
VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN C, INCLUDED;
VAPC, INCLUDED;;
VAMP-ASSOCIATED PROTEIN C, INCLUDED
*FIELD* TX
DESCRIPTION
The VAPB gene encodes a protein that is a member of the
vesicle-associated membrane protein (VAMP)-associated protein (VAP)
family. VAPB plays a role in the unfolded protein response (UPR), a
process that suppresses the accumulation of unfolded proteins in the
endoplasmic reticulum (Kanekura et al., 2006).
CLONING
By searching an EST database for human homologs of the Aplysia 33-kD
VAMP-associated protein (Vap33), Nishimura et al. (1999) identified
cDNAs encoding VAPA (605703), VAPB, and VAPC. Sequence analysis
predicted that the 243-amino acid VAPB protein, which is 60% homologous
to VAPA, contains a conserved N-terminal domain, an alpha-helical
coiled-coil domain, and a C-terminal transmembrane domain. The 99-amino
acid VAPC protein is a splice variant of VAPB that retains the
N-terminal 70 residues but lacks the coiled-coil and transmembrane
domains. Northern blot analysis detected a major 2.5-kb VAPB transcript
and 1.1- and 8.7-kb minor VAPB transcripts in all tissues tested.
Expression of VAPB was less intense than that of VAPA or the 1.9-kb VAPC
transcript. SDS-PAGE analysis demonstrated that the transmembrane domain
of recombinant VAPA interacted with VAPA and VAPB fusion proteins.
De Vos et al. (2012) found that a portion of VAPB localized to
mitochondria-associated membranes, a specialized ER domain in close
apposition with mitochondria.
GENE STRUCTURE
Chen et al. (2010) noted that the VAPB gene contains 6 exons.
MAPPING
The finding by Nishimura et al. (2004) of a missense mutation in the
VAPB gene as the cause of a form of amyotrophic lateral sclerosis (ALS8;
608627), which had been mapped to 20q13.3, demonstrated this as the
localization of the VAPB gene.
GENE FUNCTION
In COS-7 cells and mouse NSC34 cells, Kanekura et al. (2006)
demonstrated that wildtype human VABP localized to the endoplasmic
reticulum and that its overexpression promoted the unfolded protein
response. In contrast, mutant VAPB (P56S; 605704.0001) was insoluble,
shifted to non-ER subcellular locations, and did not induce UPR.
Although the studies indicated that mutant VAPB was a loss of function
mutation, cotransfection experiments showed that mutant VAPB inhibited
the ability of wildtype VAPB to mediate UPR, consistent with a
dominant-negative effect.
Using immunohistochemistry and Western blot analysis, Teuling et al.
(2007) found that VABP was widely expressed in both neuronal and
nonneuronal human and mouse cell lines. The protein localized to the
endoplasmic reticulum. In the CNS, the highest levels of VABP expression
were found in mouse and human spinal cord motor neurons.
Using yeast 2-hybrid and coimmunoprecipitation analyses, De Vos et al.
(2012) found that endogenous human VAPB interacted with the outer
mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). The
cytoplasmic N-terminal domain of VAPB specifically interacted with the
cytoplasmic C-terminal domain of PTPIP51. Knockdown of either VAPB or
PTPIP51 in HEK293 cells delayed mitochondrial calcium uptake following
IP3R (ITPR1; 147265)-induced calcium release from ER stores, resulting
in increased peak cytosolic calcium concentration. De Vos et al. (2012)
concluded that PTPIP51 directs VAPB localization to
mitochondria-associated membranes and that both VAPB and PTPIP51 are
involved in calcium exchange between the ER and mitochondria.
MOLECULAR GENETICS
By the study of candidate genes within the region of 20q13.3 that showed
linkage to an atypical form of ALS called ALS8 (608627), Nishimura et
al. (2004) identified a novel mutation in the VAPB gene (P56S;
605704.0001). Subsequently, they identified the same mutation in
patients from 6 additional kindreds but with different clinical courses,
such as ALS8, late-onset spinal muscular atrophy (182980), and a typical
severe ALS with rapid progression. Although it was not possible to link
all of these families, haplotype analysis suggested a founder effect.
Members of the vesicle-associated proteins are intracellular membrane
proteins that can associate with microtubules and have been shown to
have a function in membrane transport. The data suggested that
clinically variable motor neuron diseases may be caused by dysfunction
in intracellular membrane trafficking.
Kirby et al. (2007) did not identify mutations in the VAPB gene in 301
cases of ALS from the United Kingdom, including 23 familial and 278
sporadic cases.
Landers et al. (2008) identified a P56S mutation in the VAPB gene in 1
of 80 families with ALS. The family with the mutation was of Brazilian
origin. No other clearly pathogenic mutations were identified. In 1
other family, they identified a 3-bp in-frame deletion (478delCTT),
resulting in loss of ser160, that was also found in 0.45% of controls.
In vitro expression studies of del-ser160 VAPB showed wildtype
cytoplasmic localization. Landers et al. (2008) concluded that VAPB
mutations are not a common cause of ALS and that the 3-bp deletion they
identified in 1 family was not causative for the disorder.
In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010)
identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002).
In vitro functional expression studies in COS-7 and neuronal cells
showed that the T46I mutation formed intracellular protein aggregates
and ubiquitin aggregates, ultimately resulting in cell death.
ANIMAL MODEL
Chai et al. (2008) demonstrated that the Drosophila Dvap33a gene is the
structural and functional homolog of the human VAPB gene. Hypomorphic
and null Dvap33a alleles expressed in neurons caused a severe decrease
in bouton number and an increase in bouton size. Conversely,
overexpression of Dvap33a in neurons induced a highly significant
increase in the number of boutons with a concomitant decrease in their
size. Electrophysiologic and electron microscopic studies showed that
these structural alterations were associated with compensatory changes
in the physiology and ultrastructure of synapses, which maintained
evoked responses within normal boundaries. These compensatory changes
were determined by changes in expression of glutamate receptor subunits.
Targeted expression of human VAPB in Drosophila neurons with hypomorphic
or null Dvap33a alleles rescued the morphologic and electrophysiologic
mutant phenotype. Transgenic expression of mutant Dvap33a in Drosophila
recapitulated major hallmarks of human neuronal diseases, including
locomotion defects and neuronal death with aggregate formation. The
findings implicated a role for human VAPB in synaptic homeostasis.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 8
SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE, INCLUDED;;
AMYOTROPHIC LATERAL SCLEROSIS, TYPICAL, INCLUDED
VAPB, PRO56SER
In a large white Brazilian family with atypical ALS (ALS8; 608627),
Nishimura et al. (2004) found a heterozygous 166C-T transition in exon 2
of the VAPB gene, leading to a pro56-to-ser (P56S) mutation.
Subsequently the authors demonstrated the same mutation in patients from
6 additional kindreds in which the clinical course varied, including
some with late-onset spinal muscular atrophy (Finkel type; 182980) and
some with typical severe ALS with rapid progression (see 105400).
Although it was not possible to link all of these families, haplotype
analysis suggested founder effect. In vitro functional expression
studies in rat hippocampal neurons and HEK293 cells showed that the P56S
mutation disrupted the normal subcellular distribution of the VAPB
protein and caused intracellular aggregates. Unlike the wildtype
protein, the mutant P56S protein did not colocalize with either the
Golgi apparatus or the endoplasmic reticulum (ER).
Nishimura et al. (2005) analyzed 7 polymorphic markers around the VAPB
gene in an index case from each of the Brazilian families with P56S
mutation previously reported by Nishimura et al. (2004) and in 9
Brazilian Portuguese controls. They found evidence for a common founder
for all families regardless of ancestry, with a founding event 23
generations ago, consistent with the Portuguese colonization of Brazil.
Teuling et al. (2007) found that the P56S mutant protein formed
cytosolic aggregates in all cell types examined, including mouse and
human nonneuronal cells. These aggregates did not colocalize with
markers for the ER. Further studies showed that the mutant protein acted
in a dominant-negative manner by recruiting wildtype VAPB to the
aggregates and disrupting normal protein and cellular function.
Landers et al. (2008) identified the P56S mutation in affected members
of a Brazilian family with ALS. The mean age at onset was between 45 and
55 years with survival varying from 5 to 18 years. The mutation was not
identified in 79 additional ALS families.
Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162
French probands with familial ALS. The patient was of Japanese descent,
representing the first non-Brazilian reported to carry this mutation.
Three other family members had motor neuron disease, suggesting
autosomal dominant inheritance. The patient had long disease duration
with onset in the legs during the sixth decade. Millecamps et al. (2010)
suggested that the finding of the P56S mutation in a Japanese patient
may reflect the Portuguese trading connection with the Far East and
Brazil in the mid-16th century.
De Vos et al. (2012) found that VAPB with the P56S mutation showed
significantly higher affinity than wildtype for the outer mitochondrial
membrane protein PTPIP51 (FAM82A2; 611873). Increased binding with
PTPIP51 resulted in accumulation of VAPB at mitochondria-associated
membranes in the ER and elevated calcium uptake by mitochondria
following release of calcium from ER stores. Expression of human VAPB
with the P56S mutation also disturbed calcium handling in cultured rat
cortical neurons following depolarization.
Using cultured embryonic rat cortical neurons, Morotz et al. (2012)
found that expression of human VAPB with the P56S mutation (VAPB-P56S)
significantly slowed anterograde axonal transport of mitochondria.
Studies in rat neurons and HEK293 cells showed that expression of
VAPB-P56S increased resting intracellular Ca(2+) concentration and
disrupted the interaction between tubulin (see 191130) and the
mitochondrial membrane Rho GTPase MIRO1 (RHOT1; 613888). Expression of
VAPB-P56S had no effect on the amount of TRAK1 (608112) or kinesin-1
(see 602809) associated with MIRO1.
.0002
AMYOTROPHIC LATERAL SCLEROSIS 8
VAPB, THR46ILE
In a non-Brazilian patient with ALS8 (608627), Chen et al. (2010)
identified a heterozygous 137C-T transition in the VAPB gene, resulting
in a thr46-to-ile (T46I) substitution in a highly conserved residue
important for the interaction with lipid-binding proteins. The mutation
was found in 1 of 107 probands with familial ALS and was not found in
257 controls. The 73-year-old male patient presented with wasting of the
small muscles of the hands. He also had fasciculations of the leg, and
later developed speech and swallowing difficulties. The diagnosis was
confirmed by nerve conduction studies. The patient had a brother with
ALS who died within 4 months of diagnosis from pneumonia, but DNA was
not available for testing. In vitro functional expression studies in
COS-7 cells and neuronal showed that the T46I mutation formed
intracellular protein aggregates and ubiquitin aggregates, ultimately
resulting in cell death. The mutant protein was unable to activate the
unfolded protein response pathway, as measured by lack of activation of
IRE1 (ERN1; 604033), and the effect was dominant-negative. Expression of
the equivalent T48I mutation in Drosophila resulted in aggregate
formation in neurons and nerve fibers, cell degeneration, fragmentation
of the endoplasmic reticulum, and upregulation of chaperone proteins.
Muscle was also adversely affected. Chen et al. (2010) also postulated
that disturbances in lipid metabolism may play a role in the
pathogenesis of ALS.
*FIELD* RF
1. Chai, A.; Withers, J.; Koh, Y. H.; Parry, K.; Bao, H.; Zhang, B.;
Budnik, V.; Pennetta, G.: hVAPB, the causative gene of a heterogeneous
group of motor neuron diseases in humans, is functionally interchangeable
with its Drosophila homologue DVAP-33A at the neuromuscular junction. Hum.
Molec. Genet. 17: 266-280, 2008.
2. Chen, H.-J.; Anagnostou, G.; Chai, A.; Withers, J.; Morris, A.;
Adhikaree, J.; Pennetta, G.; de Belleroche, J. S.: Characterization
of the properties of a novel mutation in VAPB in familial amyotrophic
lateral sclerosis. J. Biol. Chem. 285: 40266-40281, 2010.
3. De Vos, K. J.; Morotz, G. M.; Stoica, R.; Tudor, E. L.; Lau, K.-F.;
Ackerly, S.; Warley, A.; Shaw, C. E.; Miller, C. C. J.: VAPB interacts
with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum.
Molec. Genet. 21: 1299-1311, 2012.
4. Kanekura, K.; Nishimoto, I.; Aiso, S.; Matsuoka, M.: Characterization
of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated
membrane protein-associated protein B (VAPB/ALS8). J. Biol. Chem. 281:
30223-30233, 2006.
5. Kirby, J.; Hewamadduma, C. A. A.; Hartley, J. A.; Nixon, H. C.;
Evans, H.; Wadhwa, R. R.; Kershaw, C.; Ince, P. G.; Shaw, P. J.:
Mutations in VAPB are not associated with sporadic ALS. Neurology 68:
1951-1953, 2007.
6. Landers, J. E.; Leclerc, A. L.; Shi, L.; Virkud, A.; Cho, T.; Maxwell,
M. M.; Henry, A. F.; Polak, N.; Glass, J. D.; Kwiatkowski, T. J.;
Al-Chalabi, A.; Shaw, C. E.; Leigh, P. N.; Rodriguez-Leyza, I.; McKenna-Yasek,
D.; Sapp, P. C.; Brown, R. H., Jr.: New VAPB deletion variant and
exclusion of VAPB mutations in familial ALS. Neurology 70: 1179-1185,
2008.
7. Millecamps, S.; Salachas, F.; Cazeneuve, C.; Gordon, P.; Bricka,
B.; Camuzat, A.; Guillot-Noel, L.; Russaouen, O.; Bruneteau, G.; Pradat,
P.-F.; Le Forestier, N.; Vandenberghe, N.; and 14 others: SOD1,
ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral
sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560,
2010.
8. Morotz, G. M.; De Vos, K. J.; Vagnoni, A.; Ackerley, S.; Shaw,
C. E.; Miller, C. C. J.: Amyotrophic lateral sclerosis-associated
mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport
of mitochondria. Hum. Molec. Genet. 21: 1979-1988, 2012.
9. Nishimura, A. L.; Al-Chalabi, A.; Zatz, M.: A common founder for
amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Hum.
Genet. 118: 499-500, 2005.
10. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
11. Nishimura, Y.; Hayashi, M.; Inada, H.; Tanaka, T.: Molecular
cloning and characterization of mammalian homologues of vesicle-associated
membrane protein-associated (VAMP-associated) proteins. Biochem.
Biophys. Res. Commun. 254: 21-26, 1999.
12. Teuling, E.; Ahmed, S.; Haasdijk, E.; Demmers, J.; Steinmetz,
M. O.; Akhmanova, A.; Jaarsma, D.; Hoogenraad, C. C.: Motor neuron
disease-associated mutant vesicle-associated membrane protein-associated
protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived
tubular aggregates. J. Neurosci. 27: 9801-9815, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 07/26/2013
Patricia A. Hartz - updated: 7/16/2013
Cassandra L. Kniffin - updated: 12/22/2010
Cassandra L. Kniffin - updated: 9/27/2010
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 10/17/2008
Cassandra L. Kniffin - updated: 11/29/2007
Cassandra L. Kniffin - updated: 2/20/2007
Marla J. F. O'Neill - updated: 2/15/2006
Victor A. McKusick - updated: 10/21/2004
*FIELD* CD
Paul J. Converse: 2/28/2001
*FIELD* ED
mgross: 07/26/2013
mgross: 7/16/2013
wwang: 1/5/2011
ckniffin: 12/22/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
wwang: 5/19/2009
ckniffin: 4/29/2009
wwang: 10/20/2008
ckniffin: 10/17/2008
wwang: 12/6/2007
ckniffin: 11/29/2007
wwang: 2/22/2007
ckniffin: 2/20/2007
wwang: 2/23/2006
terry: 2/15/2006
alopez: 10/25/2004
terry: 10/21/2004
mgross: 2/28/2001
*RECORD*
*FIELD* NO
605704
*FIELD* TI
*605704 VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN B; VAPB
;;VAMP-ASSOCIATED PROTEIN B;;
read moreDVAP33A, DROSOPHILA, HOMOLOG OF
VESICLE-ASSOCIATED MEMBRANE PROTEIN-ASSOCIATED PROTEIN C, INCLUDED;
VAPC, INCLUDED;;
VAMP-ASSOCIATED PROTEIN C, INCLUDED
*FIELD* TX
DESCRIPTION
The VAPB gene encodes a protein that is a member of the
vesicle-associated membrane protein (VAMP)-associated protein (VAP)
family. VAPB plays a role in the unfolded protein response (UPR), a
process that suppresses the accumulation of unfolded proteins in the
endoplasmic reticulum (Kanekura et al., 2006).
CLONING
By searching an EST database for human homologs of the Aplysia 33-kD
VAMP-associated protein (Vap33), Nishimura et al. (1999) identified
cDNAs encoding VAPA (605703), VAPB, and VAPC. Sequence analysis
predicted that the 243-amino acid VAPB protein, which is 60% homologous
to VAPA, contains a conserved N-terminal domain, an alpha-helical
coiled-coil domain, and a C-terminal transmembrane domain. The 99-amino
acid VAPC protein is a splice variant of VAPB that retains the
N-terminal 70 residues but lacks the coiled-coil and transmembrane
domains. Northern blot analysis detected a major 2.5-kb VAPB transcript
and 1.1- and 8.7-kb minor VAPB transcripts in all tissues tested.
Expression of VAPB was less intense than that of VAPA or the 1.9-kb VAPC
transcript. SDS-PAGE analysis demonstrated that the transmembrane domain
of recombinant VAPA interacted with VAPA and VAPB fusion proteins.
De Vos et al. (2012) found that a portion of VAPB localized to
mitochondria-associated membranes, a specialized ER domain in close
apposition with mitochondria.
GENE STRUCTURE
Chen et al. (2010) noted that the VAPB gene contains 6 exons.
MAPPING
The finding by Nishimura et al. (2004) of a missense mutation in the
VAPB gene as the cause of a form of amyotrophic lateral sclerosis (ALS8;
608627), which had been mapped to 20q13.3, demonstrated this as the
localization of the VAPB gene.
GENE FUNCTION
In COS-7 cells and mouse NSC34 cells, Kanekura et al. (2006)
demonstrated that wildtype human VABP localized to the endoplasmic
reticulum and that its overexpression promoted the unfolded protein
response. In contrast, mutant VAPB (P56S; 605704.0001) was insoluble,
shifted to non-ER subcellular locations, and did not induce UPR.
Although the studies indicated that mutant VAPB was a loss of function
mutation, cotransfection experiments showed that mutant VAPB inhibited
the ability of wildtype VAPB to mediate UPR, consistent with a
dominant-negative effect.
Using immunohistochemistry and Western blot analysis, Teuling et al.
(2007) found that VABP was widely expressed in both neuronal and
nonneuronal human and mouse cell lines. The protein localized to the
endoplasmic reticulum. In the CNS, the highest levels of VABP expression
were found in mouse and human spinal cord motor neurons.
Using yeast 2-hybrid and coimmunoprecipitation analyses, De Vos et al.
(2012) found that endogenous human VAPB interacted with the outer
mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). The
cytoplasmic N-terminal domain of VAPB specifically interacted with the
cytoplasmic C-terminal domain of PTPIP51. Knockdown of either VAPB or
PTPIP51 in HEK293 cells delayed mitochondrial calcium uptake following
IP3R (ITPR1; 147265)-induced calcium release from ER stores, resulting
in increased peak cytosolic calcium concentration. De Vos et al. (2012)
concluded that PTPIP51 directs VAPB localization to
mitochondria-associated membranes and that both VAPB and PTPIP51 are
involved in calcium exchange between the ER and mitochondria.
MOLECULAR GENETICS
By the study of candidate genes within the region of 20q13.3 that showed
linkage to an atypical form of ALS called ALS8 (608627), Nishimura et
al. (2004) identified a novel mutation in the VAPB gene (P56S;
605704.0001). Subsequently, they identified the same mutation in
patients from 6 additional kindreds but with different clinical courses,
such as ALS8, late-onset spinal muscular atrophy (182980), and a typical
severe ALS with rapid progression. Although it was not possible to link
all of these families, haplotype analysis suggested a founder effect.
Members of the vesicle-associated proteins are intracellular membrane
proteins that can associate with microtubules and have been shown to
have a function in membrane transport. The data suggested that
clinically variable motor neuron diseases may be caused by dysfunction
in intracellular membrane trafficking.
Kirby et al. (2007) did not identify mutations in the VAPB gene in 301
cases of ALS from the United Kingdom, including 23 familial and 278
sporadic cases.
Landers et al. (2008) identified a P56S mutation in the VAPB gene in 1
of 80 families with ALS. The family with the mutation was of Brazilian
origin. No other clearly pathogenic mutations were identified. In 1
other family, they identified a 3-bp in-frame deletion (478delCTT),
resulting in loss of ser160, that was also found in 0.45% of controls.
In vitro expression studies of del-ser160 VAPB showed wildtype
cytoplasmic localization. Landers et al. (2008) concluded that VAPB
mutations are not a common cause of ALS and that the 3-bp deletion they
identified in 1 family was not causative for the disorder.
In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010)
identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002).
In vitro functional expression studies in COS-7 and neuronal cells
showed that the T46I mutation formed intracellular protein aggregates
and ubiquitin aggregates, ultimately resulting in cell death.
ANIMAL MODEL
Chai et al. (2008) demonstrated that the Drosophila Dvap33a gene is the
structural and functional homolog of the human VAPB gene. Hypomorphic
and null Dvap33a alleles expressed in neurons caused a severe decrease
in bouton number and an increase in bouton size. Conversely,
overexpression of Dvap33a in neurons induced a highly significant
increase in the number of boutons with a concomitant decrease in their
size. Electrophysiologic and electron microscopic studies showed that
these structural alterations were associated with compensatory changes
in the physiology and ultrastructure of synapses, which maintained
evoked responses within normal boundaries. These compensatory changes
were determined by changes in expression of glutamate receptor subunits.
Targeted expression of human VAPB in Drosophila neurons with hypomorphic
or null Dvap33a alleles rescued the morphologic and electrophysiologic
mutant phenotype. Transgenic expression of mutant Dvap33a in Drosophila
recapitulated major hallmarks of human neuronal diseases, including
locomotion defects and neuronal death with aggregate formation. The
findings implicated a role for human VAPB in synaptic homeostasis.
*FIELD* AV
.0001
AMYOTROPHIC LATERAL SCLEROSIS 8
SPINAL MUSCULAR ATROPHY, LATE-ONSET, FINKEL TYPE, INCLUDED;;
AMYOTROPHIC LATERAL SCLEROSIS, TYPICAL, INCLUDED
VAPB, PRO56SER
In a large white Brazilian family with atypical ALS (ALS8; 608627),
Nishimura et al. (2004) found a heterozygous 166C-T transition in exon 2
of the VAPB gene, leading to a pro56-to-ser (P56S) mutation.
Subsequently the authors demonstrated the same mutation in patients from
6 additional kindreds in which the clinical course varied, including
some with late-onset spinal muscular atrophy (Finkel type; 182980) and
some with typical severe ALS with rapid progression (see 105400).
Although it was not possible to link all of these families, haplotype
analysis suggested founder effect. In vitro functional expression
studies in rat hippocampal neurons and HEK293 cells showed that the P56S
mutation disrupted the normal subcellular distribution of the VAPB
protein and caused intracellular aggregates. Unlike the wildtype
protein, the mutant P56S protein did not colocalize with either the
Golgi apparatus or the endoplasmic reticulum (ER).
Nishimura et al. (2005) analyzed 7 polymorphic markers around the VAPB
gene in an index case from each of the Brazilian families with P56S
mutation previously reported by Nishimura et al. (2004) and in 9
Brazilian Portuguese controls. They found evidence for a common founder
for all families regardless of ancestry, with a founding event 23
generations ago, consistent with the Portuguese colonization of Brazil.
Teuling et al. (2007) found that the P56S mutant protein formed
cytosolic aggregates in all cell types examined, including mouse and
human nonneuronal cells. These aggregates did not colocalize with
markers for the ER. Further studies showed that the mutant protein acted
in a dominant-negative manner by recruiting wildtype VAPB to the
aggregates and disrupting normal protein and cellular function.
Landers et al. (2008) identified the P56S mutation in affected members
of a Brazilian family with ALS. The mean age at onset was between 45 and
55 years with survival varying from 5 to 18 years. The mutation was not
identified in 79 additional ALS families.
Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162
French probands with familial ALS. The patient was of Japanese descent,
representing the first non-Brazilian reported to carry this mutation.
Three other family members had motor neuron disease, suggesting
autosomal dominant inheritance. The patient had long disease duration
with onset in the legs during the sixth decade. Millecamps et al. (2010)
suggested that the finding of the P56S mutation in a Japanese patient
may reflect the Portuguese trading connection with the Far East and
Brazil in the mid-16th century.
De Vos et al. (2012) found that VAPB with the P56S mutation showed
significantly higher affinity than wildtype for the outer mitochondrial
membrane protein PTPIP51 (FAM82A2; 611873). Increased binding with
PTPIP51 resulted in accumulation of VAPB at mitochondria-associated
membranes in the ER and elevated calcium uptake by mitochondria
following release of calcium from ER stores. Expression of human VAPB
with the P56S mutation also disturbed calcium handling in cultured rat
cortical neurons following depolarization.
Using cultured embryonic rat cortical neurons, Morotz et al. (2012)
found that expression of human VAPB with the P56S mutation (VAPB-P56S)
significantly slowed anterograde axonal transport of mitochondria.
Studies in rat neurons and HEK293 cells showed that expression of
VAPB-P56S increased resting intracellular Ca(2+) concentration and
disrupted the interaction between tubulin (see 191130) and the
mitochondrial membrane Rho GTPase MIRO1 (RHOT1; 613888). Expression of
VAPB-P56S had no effect on the amount of TRAK1 (608112) or kinesin-1
(see 602809) associated with MIRO1.
.0002
AMYOTROPHIC LATERAL SCLEROSIS 8
VAPB, THR46ILE
In a non-Brazilian patient with ALS8 (608627), Chen et al. (2010)
identified a heterozygous 137C-T transition in the VAPB gene, resulting
in a thr46-to-ile (T46I) substitution in a highly conserved residue
important for the interaction with lipid-binding proteins. The mutation
was found in 1 of 107 probands with familial ALS and was not found in
257 controls. The 73-year-old male patient presented with wasting of the
small muscles of the hands. He also had fasciculations of the leg, and
later developed speech and swallowing difficulties. The diagnosis was
confirmed by nerve conduction studies. The patient had a brother with
ALS who died within 4 months of diagnosis from pneumonia, but DNA was
not available for testing. In vitro functional expression studies in
COS-7 cells and neuronal showed that the T46I mutation formed
intracellular protein aggregates and ubiquitin aggregates, ultimately
resulting in cell death. The mutant protein was unable to activate the
unfolded protein response pathway, as measured by lack of activation of
IRE1 (ERN1; 604033), and the effect was dominant-negative. Expression of
the equivalent T48I mutation in Drosophila resulted in aggregate
formation in neurons and nerve fibers, cell degeneration, fragmentation
of the endoplasmic reticulum, and upregulation of chaperone proteins.
Muscle was also adversely affected. Chen et al. (2010) also postulated
that disturbances in lipid metabolism may play a role in the
pathogenesis of ALS.
*FIELD* RF
1. Chai, A.; Withers, J.; Koh, Y. H.; Parry, K.; Bao, H.; Zhang, B.;
Budnik, V.; Pennetta, G.: hVAPB, the causative gene of a heterogeneous
group of motor neuron diseases in humans, is functionally interchangeable
with its Drosophila homologue DVAP-33A at the neuromuscular junction. Hum.
Molec. Genet. 17: 266-280, 2008.
2. Chen, H.-J.; Anagnostou, G.; Chai, A.; Withers, J.; Morris, A.;
Adhikaree, J.; Pennetta, G.; de Belleroche, J. S.: Characterization
of the properties of a novel mutation in VAPB in familial amyotrophic
lateral sclerosis. J. Biol. Chem. 285: 40266-40281, 2010.
3. De Vos, K. J.; Morotz, G. M.; Stoica, R.; Tudor, E. L.; Lau, K.-F.;
Ackerly, S.; Warley, A.; Shaw, C. E.; Miller, C. C. J.: VAPB interacts
with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum.
Molec. Genet. 21: 1299-1311, 2012.
4. Kanekura, K.; Nishimoto, I.; Aiso, S.; Matsuoka, M.: Characterization
of amyotrophic lateral sclerosis-linked P56S mutation of vesicle-associated
membrane protein-associated protein B (VAPB/ALS8). J. Biol. Chem. 281:
30223-30233, 2006.
5. Kirby, J.; Hewamadduma, C. A. A.; Hartley, J. A.; Nixon, H. C.;
Evans, H.; Wadhwa, R. R.; Kershaw, C.; Ince, P. G.; Shaw, P. J.:
Mutations in VAPB are not associated with sporadic ALS. Neurology 68:
1951-1953, 2007.
6. Landers, J. E.; Leclerc, A. L.; Shi, L.; Virkud, A.; Cho, T.; Maxwell,
M. M.; Henry, A. F.; Polak, N.; Glass, J. D.; Kwiatkowski, T. J.;
Al-Chalabi, A.; Shaw, C. E.; Leigh, P. N.; Rodriguez-Leyza, I.; McKenna-Yasek,
D.; Sapp, P. C.; Brown, R. H., Jr.: New VAPB deletion variant and
exclusion of VAPB mutations in familial ALS. Neurology 70: 1179-1185,
2008.
7. Millecamps, S.; Salachas, F.; Cazeneuve, C.; Gordon, P.; Bricka,
B.; Camuzat, A.; Guillot-Noel, L.; Russaouen, O.; Bruneteau, G.; Pradat,
P.-F.; Le Forestier, N.; Vandenberghe, N.; and 14 others: SOD1,
ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral
sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560,
2010.
8. Morotz, G. M.; De Vos, K. J.; Vagnoni, A.; Ackerley, S.; Shaw,
C. E.; Miller, C. C. J.: Amyotrophic lateral sclerosis-associated
mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport
of mitochondria. Hum. Molec. Genet. 21: 1979-1988, 2012.
9. Nishimura, A. L.; Al-Chalabi, A.; Zatz, M.: A common founder for
amyotrophic lateral sclerosis type 8 (ALS8) in the Brazilian population. Hum.
Genet. 118: 499-500, 2005.
10. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
11. Nishimura, Y.; Hayashi, M.; Inada, H.; Tanaka, T.: Molecular
cloning and characterization of mammalian homologues of vesicle-associated
membrane protein-associated (VAMP-associated) proteins. Biochem.
Biophys. Res. Commun. 254: 21-26, 1999.
12. Teuling, E.; Ahmed, S.; Haasdijk, E.; Demmers, J.; Steinmetz,
M. O.; Akhmanova, A.; Jaarsma, D.; Hoogenraad, C. C.: Motor neuron
disease-associated mutant vesicle-associated membrane protein-associated
protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived
tubular aggregates. J. Neurosci. 27: 9801-9815, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 07/26/2013
Patricia A. Hartz - updated: 7/16/2013
Cassandra L. Kniffin - updated: 12/22/2010
Cassandra L. Kniffin - updated: 9/27/2010
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 10/17/2008
Cassandra L. Kniffin - updated: 11/29/2007
Cassandra L. Kniffin - updated: 2/20/2007
Marla J. F. O'Neill - updated: 2/15/2006
Victor A. McKusick - updated: 10/21/2004
*FIELD* CD
Paul J. Converse: 2/28/2001
*FIELD* ED
mgross: 07/26/2013
mgross: 7/16/2013
wwang: 1/5/2011
ckniffin: 12/22/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
wwang: 5/19/2009
ckniffin: 4/29/2009
wwang: 10/20/2008
ckniffin: 10/17/2008
wwang: 12/6/2007
ckniffin: 11/29/2007
wwang: 2/22/2007
ckniffin: 2/20/2007
wwang: 2/23/2006
terry: 2/15/2006
alopez: 10/25/2004
terry: 10/21/2004
mgross: 2/28/2001
MIM
608627
*RECORD*
*FIELD* NO
608627
*FIELD* TI
#608627 AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8
*FIELD* TX
A number sign (#) is used with this entry because of evidence that ALS8
read moreis caused by heterozygous mutation in the VAPB gene (605704) on
chromosome 20q13.3.
For a phenotypic description and a discussion of genetic heterogeneity
of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Nishimura et al. (2004) described a Caucasian Brazilian family in which
26 members spanning 3 generations presented with clinical and neurologic
signs compatible with the diagnosis of ALS with slow progression. The
disorder affected both sexes equally, with no evidence of clinical
anticipation. Clinical onset occurred between ages 31 and 45 years, and
the cause of death was respiratory failure. Twelve family members were
examined. All patients had lower motor neuron symptoms, and 5 also had
bulbar involvement.
Chen et al. (2010) reported a 73-year-old man with ALS8, who was not of
Brazilian descent. He presented with wasting of the small muscles of the
hands. He also had fasciculations of the leg, and later developed speech
and swallowing difficulties. The diagnosis was confirmed by nerve
conduction studies. The patient had a brother with ALS who died within 4
months of diagnosis from pneumonia, but DNA was not available for
testing.
MAPPING
Nishimura et al. (2004) performed linkage analysis in the large
Brazilian family with atypical ALS and excluded all previously reported
ALS loci. They identified a novel locus, here designated ALS8, spanning
2.7 Mb between markers D20S430 and D20S173 on chromosome 20q13.33.
Two-point linkage analysis showed a maximum lod score of 6.02 at theta =
0.0 for marker D20S171; multipoint linkage analysis showed a maximum lod
score of 7.45 for marker D20S164. No mutations were identified in 3
genes mapping to the ALS8 interval: TUBB1 (612901), CTSZ (603169), and
ATP5E (606153). ALS8 is presumably distinct from the form of ALS mapping
to chromosome 20p, here designated ALS7 (608031).
MOLECULAR GENETICS
Nishimura et al. (2004) found that the autosomal dominant slowly
progressive disorder in the large Brazilian family described by
Nishimura et al. (2004), characterized by fasciculations, cramps, and
postural tremor, was caused by a P56S mutation in the VAPB gene
(605704.0001). Subsequently, the same mutation was identified in
patients from 6 additional kindreds in which, however, patients
demonstrated different clinical courses, such as ALS8, late-onset spinal
muscular atrophy (182980), and typical severe ALS with rapid
progression. Although it was not possible to link all these families
genealogically, haplotype analysis suggested founder effect. Members of
the vesicle-associated proteins are intracellular membrane proteins that
can associate with microtubules and that have a function in membrane
transport. The data suggested that clinically variable motor neuron
diseases may be caused by a dysfunction in intracellular membrane
trafficking.
Landers et al. (2008) identified the P56S mutation in affected members
of a Brazilian family with ALS. The mean age at onset was between 45 and
55 years with survival varying from 5 to 18 years. Mutations in the VAPB
gene were not identified in 79 other ALS families. Landers et al. (2008)
concluded that VAPB mutations are not a common cause of ALS.
Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162
French probands with familial ALS. The patient was of Japanese descent,
representing the first non-Brazilian reported to carry this mutation.
Three other family members had motor neuron disease, suggesting
autosomal dominant inheritance. The patient had long disease duration
with onset in the legs during the sixth decade. Millecamps et al. (2010)
suggested that the finding of the P56S mutation in a Japanese patient
may reflect the Portuguese trading connection with the Far East and
Brazil in the mid-16th century.
In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010)
identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002).
In vitro functional expression studies in COS-7 and neuronal cells
showed that the T46I mutation formed intracellular protein aggregates
and ubiquitin aggregates, ultimately resulting in cell death. Chen et
al. (2010) also postulated that disturbances in lipid metabolism may
play a role in the pathogenesis of ALS.
*FIELD* RF
1. Chen, H.-J.; Anagnostou, G.; Chai, A.; Withers, J.; Morris, A.;
Adhikaree, J.; Pennetta, G.; de Belleroche, J. S.: Characterization
of the properties of a novel mutation in VAPB in familial amyotrophic
lateral sclerosis. J. Biol. Chem. 285: 40266-40281, 2010.
2. Landers, J. E.; Leclerc, A. L.; Shi, L.; Virkud, A.; Cho, T.; Maxwell,
M. M.; Henry, A. F.; Polak, N.; Glass, J. D.; Kwiatkowski, T. J.;
Al-Chalabi, A.; Shaw, C. E.; Leigh, P. N.; Rodriguez-Leyza, I.; McKenna-Yasek,
D.; Sapp, P. C.; Brown, R. H., Jr.: New VAPB deletion variant and
exclusion of VAPB mutations in familial ALS. Neurology 70: 1179-1185,
2008.
3. Millecamps, S.; Salachas, F.; Cazeneuve, C.; Gordon, P.; Bricka,
B.; Camuzat, A.; Guillot-Noel, L.; Russaouen, O.; Bruneteau, G.; Pradat,
P.-F.; Le Forestier, N.; Vandenberghe, N.; and 14 others: SOD1,
ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral
sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560,
2010.
4. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Oliveira, J.
R. M.; Vainzof, M.; Zatz, M.: A novel locus for late onset amyotrophic
lateral sclerosis/motor neurone disease variant at 20q13. J. Med.
Genet. 41: 315-320, 2004.
5. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/22/2010
Cassandra L. Kniffin - updated: 9/27/2010
Cassandra L. Kniffin - updated: 10/17/2008
Victor A. McKusick - updated: 10/21/2004
*FIELD* CD
Victor A. McKusick: 4/29/2004
*FIELD* ED
wwang: 01/05/2011
ckniffin: 12/22/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
wwang: 9/1/2009
mgross: 7/9/2009
wwang: 10/20/2008
ckniffin: 10/17/2008
alopez: 10/25/2004
terry: 10/21/2004
tkritzer: 4/30/2004
*RECORD*
*FIELD* NO
608627
*FIELD* TI
#608627 AMYOTROPHIC LATERAL SCLEROSIS 8; ALS8
*FIELD* TX
A number sign (#) is used with this entry because of evidence that ALS8
read moreis caused by heterozygous mutation in the VAPB gene (605704) on
chromosome 20q13.3.
For a phenotypic description and a discussion of genetic heterogeneity
of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).
CLINICAL FEATURES
Nishimura et al. (2004) described a Caucasian Brazilian family in which
26 members spanning 3 generations presented with clinical and neurologic
signs compatible with the diagnosis of ALS with slow progression. The
disorder affected both sexes equally, with no evidence of clinical
anticipation. Clinical onset occurred between ages 31 and 45 years, and
the cause of death was respiratory failure. Twelve family members were
examined. All patients had lower motor neuron symptoms, and 5 also had
bulbar involvement.
Chen et al. (2010) reported a 73-year-old man with ALS8, who was not of
Brazilian descent. He presented with wasting of the small muscles of the
hands. He also had fasciculations of the leg, and later developed speech
and swallowing difficulties. The diagnosis was confirmed by nerve
conduction studies. The patient had a brother with ALS who died within 4
months of diagnosis from pneumonia, but DNA was not available for
testing.
MAPPING
Nishimura et al. (2004) performed linkage analysis in the large
Brazilian family with atypical ALS and excluded all previously reported
ALS loci. They identified a novel locus, here designated ALS8, spanning
2.7 Mb between markers D20S430 and D20S173 on chromosome 20q13.33.
Two-point linkage analysis showed a maximum lod score of 6.02 at theta =
0.0 for marker D20S171; multipoint linkage analysis showed a maximum lod
score of 7.45 for marker D20S164. No mutations were identified in 3
genes mapping to the ALS8 interval: TUBB1 (612901), CTSZ (603169), and
ATP5E (606153). ALS8 is presumably distinct from the form of ALS mapping
to chromosome 20p, here designated ALS7 (608031).
MOLECULAR GENETICS
Nishimura et al. (2004) found that the autosomal dominant slowly
progressive disorder in the large Brazilian family described by
Nishimura et al. (2004), characterized by fasciculations, cramps, and
postural tremor, was caused by a P56S mutation in the VAPB gene
(605704.0001). Subsequently, the same mutation was identified in
patients from 6 additional kindreds in which, however, patients
demonstrated different clinical courses, such as ALS8, late-onset spinal
muscular atrophy (182980), and typical severe ALS with rapid
progression. Although it was not possible to link all these families
genealogically, haplotype analysis suggested founder effect. Members of
the vesicle-associated proteins are intracellular membrane proteins that
can associate with microtubules and that have a function in membrane
transport. The data suggested that clinically variable motor neuron
diseases may be caused by a dysfunction in intracellular membrane
trafficking.
Landers et al. (2008) identified the P56S mutation in affected members
of a Brazilian family with ALS. The mean age at onset was between 45 and
55 years with survival varying from 5 to 18 years. Mutations in the VAPB
gene were not identified in 79 other ALS families. Landers et al. (2008)
concluded that VAPB mutations are not a common cause of ALS.
Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162
French probands with familial ALS. The patient was of Japanese descent,
representing the first non-Brazilian reported to carry this mutation.
Three other family members had motor neuron disease, suggesting
autosomal dominant inheritance. The patient had long disease duration
with onset in the legs during the sixth decade. Millecamps et al. (2010)
suggested that the finding of the P56S mutation in a Japanese patient
may reflect the Portuguese trading connection with the Far East and
Brazil in the mid-16th century.
In 1 of 107 non-Brazilian probands with ALS, Chen et al. (2010)
identified a heterozygous mutation in the VAPB gene (T46I; 605704.0002).
In vitro functional expression studies in COS-7 and neuronal cells
showed that the T46I mutation formed intracellular protein aggregates
and ubiquitin aggregates, ultimately resulting in cell death. Chen et
al. (2010) also postulated that disturbances in lipid metabolism may
play a role in the pathogenesis of ALS.
*FIELD* RF
1. Chen, H.-J.; Anagnostou, G.; Chai, A.; Withers, J.; Morris, A.;
Adhikaree, J.; Pennetta, G.; de Belleroche, J. S.: Characterization
of the properties of a novel mutation in VAPB in familial amyotrophic
lateral sclerosis. J. Biol. Chem. 285: 40266-40281, 2010.
2. Landers, J. E.; Leclerc, A. L.; Shi, L.; Virkud, A.; Cho, T.; Maxwell,
M. M.; Henry, A. F.; Polak, N.; Glass, J. D.; Kwiatkowski, T. J.;
Al-Chalabi, A.; Shaw, C. E.; Leigh, P. N.; Rodriguez-Leyza, I.; McKenna-Yasek,
D.; Sapp, P. C.; Brown, R. H., Jr.: New VAPB deletion variant and
exclusion of VAPB mutations in familial ALS. Neurology 70: 1179-1185,
2008.
3. Millecamps, S.; Salachas, F.; Cazeneuve, C.; Gordon, P.; Bricka,
B.; Camuzat, A.; Guillot-Noel, L.; Russaouen, O.; Bruneteau, G.; Pradat,
P.-F.; Le Forestier, N.; Vandenberghe, N.; and 14 others: SOD1,
ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral
sclerosis: genotype-phenotype correlations. J. Med. Genet. 47: 554-560,
2010.
4. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Oliveira, J.
R. M.; Vainzof, M.; Zatz, M.: A novel locus for late onset amyotrophic
lateral sclerosis/motor neurone disease variant at 20q13. J. Med.
Genet. 41: 315-320, 2004.
5. Nishimura, A. L.; Mitne-Neto, M.; Silva, H. C. A.; Richieri-Costa,
A.; Middleton, S.; Cascio, D.; Kok, F.; Oliveira, J. R. M.; Gillingwater,
T.; Webb, J.; Skehel, P.; Zatz, M.: A mutation in the vesicle-trafficking
protein VAPB causes late-onset spinal muscular atrophy and amyotrophic
lateral sclerosis. Am. J. Hum. Genet. 75: 822-831, 2004.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/22/2010
Cassandra L. Kniffin - updated: 9/27/2010
Cassandra L. Kniffin - updated: 10/17/2008
Victor A. McKusick - updated: 10/21/2004
*FIELD* CD
Victor A. McKusick: 4/29/2004
*FIELD* ED
wwang: 01/05/2011
ckniffin: 12/22/2010
wwang: 9/29/2010
ckniffin: 9/27/2010
wwang: 9/1/2009
mgross: 7/9/2009
wwang: 10/20/2008
ckniffin: 10/17/2008
alopez: 10/25/2004
terry: 10/21/2004
tkritzer: 4/30/2004