Full text data of CHMP2B
CHMP2B
[Confidence: low (only semi-automatic identification from reviews)]
Charged multivesicular body protein 2b (CHMP2.5; Chromatin-modifying protein 2b; CHMP2b; Vacuolar protein sorting-associated protein 2-2; Vps2-2; hVps2-2)
Charged multivesicular body protein 2b (CHMP2.5; Chromatin-modifying protein 2b; CHMP2b; Vacuolar protein sorting-associated protein 2-2; Vps2-2; hVps2-2)
UniProt
Q9UQN3
ID CHM2B_HUMAN Reviewed; 213 AA.
AC Q9UQN3; B4DJG8; Q53HC7; Q9Y4U6;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Charged multivesicular body protein 2b;
DE AltName: Full=CHMP2.5;
DE AltName: Full=Chromatin-modifying protein 2b;
DE Short=CHMP2b;
DE AltName: Full=Vacuolar protein sorting-associated protein 2-2;
DE Short=Vps2-2;
DE Short=hVps2-2;
GN Name=CHMP2B; ORFNames=CGI-84;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=10810093; DOI=10.1101/gr.10.5.703;
RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.;
RT "Identification of novel human genes evolutionarily conserved in
RT Caenorhabditis elegans by comparative proteomics.";
RL Genome Res. 10:703-713(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cervix;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH CHMP2A.
RX PubMed=14519844; DOI=10.1073/pnas.2133846100;
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RT "Divergent retroviral late-budding domains recruit vacuolar protein
RT sorting factors by using alternative adaptor proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:12414-12419(2003).
RN [9]
RP ERRATUM.
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RL Proc. Natl. Acad. Sci. U.S.A. 100:152845-152845(2003).
RN [10]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND VARIANT FTD3 TYR-148.
RX PubMed=16041373; DOI=10.1038/ng1609;
RA Skibinski G., Parkinson N.J., Brown J.M., Chakrabarti L., Lloyd S.L.,
RA Hummerich H., Nielsen J.E., Hodges J.R., Spillantini M.G.,
RA Thusgaard T., Brandner S., Brun A., Rossor M.N., Gade A.,
RA Johannsen P., Soerensen S.A., Gydesen S., Fisher E.M.C., Collinge J.;
RT "Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in
RT frontotemporal dementia.";
RL Nat. Genet. 37:806-808(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [18]
RP STRUCTURE BY NMR OF 195-213 IN COMPLEX WITH VPS4B, AND INTERACTION
RP WITH VPS4A.
RX PubMed=17928862; DOI=10.1038/nature06172;
RA Stuchell-Brereton M.D., Skalicky J.J., Kieffer C., Karren M.A.,
RA Ghaffarian S., Sundquist W.I.;
RT "ESCRT-III recognition by VPS4 ATPases.";
RL Nature 449:740-744(2007).
RN [19]
RP VARIANT ALS17 HIS-206, AND VARIANT VAL-29.
RX PubMed=16807408; DOI=10.1212/01.wnl.0000231510.89311.8b;
RA Parkinson N., Ince P.G., Smith M.O., Highley R., Skibinski G.,
RA Andersen P.M., Morrison K.E., Pall H.S., Hardiman O., Collinge J.,
RA Shaw P.J., Fisher E.M.;
RT "ALS phenotypes with mutations in CHMP2B (charged multivesicular body
RT protein 2B).";
RL Neurology 67:1074-1077(2006).
RN [20]
RP VARIANTS ALS17 VAL-29; ASN-104 AND HIS-206, AND CHARACTERIZATION OF
RP VARIANTS ALS17 VAL-29; ASN-104 AND HIS-206.
RX PubMed=20352044; DOI=10.1371/journal.pone.0009872;
RA Cox L.E., Ferraiuolo L., Goodall E.F., Heath P.R., Higginbottom A.,
RA Mortiboys H., Hollinger H.C., Hartley J.A., Brockington A.,
RA Burness C.E., Morrison K.E., Wharton S.B., Grierson A.J., Ince P.G.,
RA Kirby J., Shaw P.J.;
RT "Mutations in CHMP2B in lower motor neuron predominant amyotrophic
RT lateral sclerosis (ALS).";
RL PLoS ONE 5:E9872-E9872(2010).
CC -!- FUNCTION: Probable core component of the endosomal sorting
CC required for transport complex III (ESCRT-III) which is involved
CC in multivesicular bodies (MVBs) formation and sorting of endosomal
CC cargo proteins into MVBs. MVBs contain intraluminal vesicles
CC (ILVs) that are generated by invagination and scission from the
CC limiting membrane of the endosome and mostly are delivered to
CC lysosomes enabling degradation of membrane proteins, such as
CC stimulated growth factor receptors, lysosomal enzymes and lipids.
CC The MVB pathway appears to require the sequential function of
CC ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly
CC dissociate from the invaginating membrane before the ILV is
CC released. The ESCRT machinery also functions in topologically
CC equivalent membrane fission events, such as the terminal stages of
CC cytokinesis and the budding of enveloped viruses (HIV-1 and other
CC lentiviruses). ESCRT-III proteins are believed to mediate the
CC necessary vesicle extrusion and/or membrane fission activities,
CC possibly in conjunction with the AAA ATPase VPS4.
CC -!- SUBUNIT: Probable core component of the endosomal sorting required
CC for transport complex III (ESCRT-III). ESCRT-III components are
CC thought to multimerize to form a flat lattice on the perimeter
CC membrane of the endosome. Several assembly forms of ESCRT-III may
CC exist that interact and act sequentally. Interacts with CHMP2A.
CC Interacts with VPS4A. Interacts with VPS4B; the interaction is
CC direct.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Late endosome membrane;
CC Peripheral membrane protein (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UQN3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UQN3-2; Sequence=VSP_045142;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in brain, heart,
CC skeletal muscle, spleen, kidney, liver, small intestine, pancreas,
CC lung, placenta and leukocytes. In brain, it is expressed in
CC cerebellum, cerebral cortex, medulla, spinal chord, occipital
CC lobe, frontal lobe, temporal lobe and putamen.
CC -!- DOMAIN: The acidic C-terminus and the basic N-termminus are
CC thought to render the protein in a closed, soluble and inactive
CC conformation through an autoinhibitory intramolecular interaction.
CC The open and active conformation, which enables membrane binding
CC and oligomerization, is achieved by interaction with other
CC cellular binding partners, probably including other ESCRT
CC components (By similarity).
CC -!- DISEASE: Frontotemporal dementia, chromosome 3-linked (FTD3)
CC [MIM:600795]: Characterized by an onset of dementia in the late
CC 50's initially characterized by behavioral and personality changes
CC including apathy, restlessness, disinhibition and hyperorality,
CC progressing to stereotyped behaviors, non-fluent aphasia, mutism
CC and dystonia, with a marked lack of insight. The brains of
CC individuals with FTD3 have no distinctive neuropathological
CC features. They show global cortical and central atrophy, but no
CC beta-amyloid deposits. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 17 (ALS17) [MIM:614696]: An
CC adult-onset progressive neurodegenerative disorder with
CC predominantly lower motor neuron involvement, manifest as muscle
CC weakness and wasting of the upper and lower limbs, bulbar signs,
CC and respiratory insufficiency. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SNF7 family.
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DR EMBL; AF151842; AAD34079.1; -; mRNA.
DR EMBL; AL080122; CAB45721.1; -; mRNA.
DR EMBL; AK296072; BAG58830.1; -; mRNA.
DR EMBL; CR533456; CAG38487.1; -; mRNA.
DR EMBL; AK222654; BAD96374.1; -; mRNA.
DR EMBL; AC123511; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC130885; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001553; AAH01553.1; -; mRNA.
DR PIR; T12468; T12468.
DR RefSeq; NP_001231573.1; NM_001244644.1.
DR RefSeq; NP_054762.2; NM_014043.3.
DR UniGene; Hs.476930; -.
DR PDB; 2JQK; NMR; -; B=195-213.
DR PDBsum; 2JQK; -.
DR ProteinModelPortal; Q9UQN3; -.
DR SMR; Q9UQN3; 7-141.
DR DIP; DIP-50766N; -.
DR IntAct; Q9UQN3; 6.
DR MINT; MINT-1430090; -.
DR STRING; 9606.ENSP00000263780; -.
DR PhosphoSite; Q9UQN3; -.
DR DMDM; 73917746; -.
DR PaxDb; Q9UQN3; -.
DR PRIDE; Q9UQN3; -.
DR DNASU; 25978; -.
DR Ensembl; ENST00000263780; ENSP00000263780; ENSG00000083937.
DR Ensembl; ENST00000471660; ENSP00000419998; ENSG00000083937.
DR GeneID; 25978; -.
DR KEGG; hsa:25978; -.
DR UCSC; uc011bgn.2; human.
DR CTD; 25978; -.
DR GeneCards; GC03P087360; -.
DR HGNC; HGNC:24537; CHMP2B.
DR HPA; HPA035069; -.
DR MIM; 600795; phenotype.
DR MIM; 609512; gene.
DR MIM; 614696; phenotype.
DR neXtProt; NX_Q9UQN3; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR PharmGKB; PA142672112; -.
DR eggNOG; NOG268821; -.
DR HOGENOM; HOG000177218; -.
DR HOVERGEN; HBG102628; -.
DR InParanoid; Q9UQN3; -.
DR KO; K12192; -.
DR OMA; KTMQDFQ; -.
DR OrthoDB; EOG79GT8Q; -.
DR PhylomeDB; Q9UQN3; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; CHMP2B; human.
DR EvolutionaryTrace; Q9UQN3; -.
DR GeneWiki; CHMP2B; -.
DR GenomeRNAi; 25978; -.
DR NextBio; 47630; -.
DR PRO; PR:Q9UQN3; -.
DR ArrayExpress; Q9UQN3; -.
DR Bgee; Q9UQN3; -.
DR CleanEx; HS_CHMP2B; -.
DR Genevestigator; Q9UQN3; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016197; P:endosomal transport; TAS:Reactome.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR005024; Snf7.
DR Pfam; PF03357; Snf7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Amyotrophic lateral sclerosis; Coiled coil; Complete proteome;
KW Cytoplasm; Disease mutation; Endosome; Membrane; Neurodegeneration;
KW Phosphoprotein; Protein transport; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 213 Charged multivesicular body protein 2b.
FT /FTId=PRO_0000211469.
FT COILED 25 55 Potential.
FT MOTIF 201 211 MIT-interacting motif.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 199 199 Phosphoserine.
FT VAR_SEQ 1 42 MASLFKKKTVDDVIKEQNRELRGTQRAIIRDRAALEKQEKQ
FT L -> M (in isoform 2).
FT /FTId=VSP_045142.
FT VARIANT 29 29 I -> V (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A1
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_038373.
FT VARIANT 104 104 T -> N (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_068689.
FT VARIANT 148 148 D -> Y (in FTD3).
FT /FTId=VAR_023383.
FT VARIANT 206 206 Q -> H (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_038374.
FT CONFLICT 8 8 K -> R (in Ref. 2; CAB45721 and 3;
FT CAG38487).
FT CONFLICT 113 113 N -> S (in Ref. 5; BAD96374).
FT CONFLICT 201 201 E -> V (in Ref. 2; CAB45721 and 3;
FT CAG38487).
FT HELIX 201 210
SQ SEQUENCE 213 AA; 23907 MW; BA192A0EAC45C19B CRC64;
MASLFKKKTV DDVIKEQNRE LRGTQRAIIR DRAALEKQEK QLELEIKKMA KIGNKEACKV
LAKQLVHLRK QKTRTFAVSS KVTSMSTQTK VMNSQMKMAG AMSTTAKTMQ AVNKKMDPQK
TLQTMQNFQK ENMKMEMTEE MINDTLDDIF DGSDDEEESQ DIVNQVLDEI GIEISGKMAK
APSAARSLPS ASTSKATISD EEIERQLKAL GVD
//
ID CHM2B_HUMAN Reviewed; 213 AA.
AC Q9UQN3; B4DJG8; Q53HC7; Q9Y4U6;
DT 30-AUG-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 113.
DE RecName: Full=Charged multivesicular body protein 2b;
DE AltName: Full=CHMP2.5;
DE AltName: Full=Chromatin-modifying protein 2b;
DE Short=CHMP2b;
DE AltName: Full=Vacuolar protein sorting-associated protein 2-2;
DE Short=Vps2-2;
DE Short=hVps2-2;
GN Name=CHMP2B; ORFNames=CGI-84;
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 [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=10810093; DOI=10.1101/gr.10.5.703;
RA Lai C.-H., Chou C.-Y., Ch'ang L.-Y., Liu C.-S., Lin W.-C.;
RT "Identification of novel human genes evolutionarily conserved in
RT Caenorhabditis elegans by comparative proteomics.";
RL Genome Res. 10:703-713(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cerebellum;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Cervix;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP INTERACTION WITH CHMP2A.
RX PubMed=14519844; DOI=10.1073/pnas.2133846100;
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RT "Divergent retroviral late-budding domains recruit vacuolar protein
RT sorting factors by using alternative adaptor proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:12414-12419(2003).
RN [9]
RP ERRATUM.
RA Martin-Serrano J., Yarovoy A., Perez-Caballero D., Bieniasz P.D.;
RL Proc. Natl. Acad. Sci. U.S.A. 100:152845-152845(2003).
RN [10]
RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND VARIANT FTD3 TYR-148.
RX PubMed=16041373; DOI=10.1038/ng1609;
RA Skibinski G., Parkinson N.J., Brown J.M., Chakrabarti L., Lloyd S.L.,
RA Hummerich H., Nielsen J.E., Hodges J.R., Spillantini M.G.,
RA Thusgaard T., Brandner S., Brun A., Rossor M.N., Gade A.,
RA Johannsen P., Soerensen S.A., Gydesen S., Fisher E.M.C., Collinge J.;
RT "Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in
RT frontotemporal dementia.";
RL Nat. Genet. 37:806-808(2005).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP 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 [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [15]
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 [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-199, AND MASS
RP SPECTROMETRY.
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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [18]
RP STRUCTURE BY NMR OF 195-213 IN COMPLEX WITH VPS4B, AND INTERACTION
RP WITH VPS4A.
RX PubMed=17928862; DOI=10.1038/nature06172;
RA Stuchell-Brereton M.D., Skalicky J.J., Kieffer C., Karren M.A.,
RA Ghaffarian S., Sundquist W.I.;
RT "ESCRT-III recognition by VPS4 ATPases.";
RL Nature 449:740-744(2007).
RN [19]
RP VARIANT ALS17 HIS-206, AND VARIANT VAL-29.
RX PubMed=16807408; DOI=10.1212/01.wnl.0000231510.89311.8b;
RA Parkinson N., Ince P.G., Smith M.O., Highley R., Skibinski G.,
RA Andersen P.M., Morrison K.E., Pall H.S., Hardiman O., Collinge J.,
RA Shaw P.J., Fisher E.M.;
RT "ALS phenotypes with mutations in CHMP2B (charged multivesicular body
RT protein 2B).";
RL Neurology 67:1074-1077(2006).
RN [20]
RP VARIANTS ALS17 VAL-29; ASN-104 AND HIS-206, AND CHARACTERIZATION OF
RP VARIANTS ALS17 VAL-29; ASN-104 AND HIS-206.
RX PubMed=20352044; DOI=10.1371/journal.pone.0009872;
RA Cox L.E., Ferraiuolo L., Goodall E.F., Heath P.R., Higginbottom A.,
RA Mortiboys H., Hollinger H.C., Hartley J.A., Brockington A.,
RA Burness C.E., Morrison K.E., Wharton S.B., Grierson A.J., Ince P.G.,
RA Kirby J., Shaw P.J.;
RT "Mutations in CHMP2B in lower motor neuron predominant amyotrophic
RT lateral sclerosis (ALS).";
RL PLoS ONE 5:E9872-E9872(2010).
CC -!- FUNCTION: Probable core component of the endosomal sorting
CC required for transport complex III (ESCRT-III) which is involved
CC in multivesicular bodies (MVBs) formation and sorting of endosomal
CC cargo proteins into MVBs. MVBs contain intraluminal vesicles
CC (ILVs) that are generated by invagination and scission from the
CC limiting membrane of the endosome and mostly are delivered to
CC lysosomes enabling degradation of membrane proteins, such as
CC stimulated growth factor receptors, lysosomal enzymes and lipids.
CC The MVB pathway appears to require the sequential function of
CC ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly
CC dissociate from the invaginating membrane before the ILV is
CC released. The ESCRT machinery also functions in topologically
CC equivalent membrane fission events, such as the terminal stages of
CC cytokinesis and the budding of enveloped viruses (HIV-1 and other
CC lentiviruses). ESCRT-III proteins are believed to mediate the
CC necessary vesicle extrusion and/or membrane fission activities,
CC possibly in conjunction with the AAA ATPase VPS4.
CC -!- SUBUNIT: Probable core component of the endosomal sorting required
CC for transport complex III (ESCRT-III). ESCRT-III components are
CC thought to multimerize to form a flat lattice on the perimeter
CC membrane of the endosome. Several assembly forms of ESCRT-III may
CC exist that interact and act sequentally. Interacts with CHMP2A.
CC Interacts with VPS4A. Interacts with VPS4B; the interaction is
CC direct.
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol. Late endosome membrane;
CC Peripheral membrane protein (Probable).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9UQN3-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9UQN3-2; Sequence=VSP_045142;
CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed in brain, heart,
CC skeletal muscle, spleen, kidney, liver, small intestine, pancreas,
CC lung, placenta and leukocytes. In brain, it is expressed in
CC cerebellum, cerebral cortex, medulla, spinal chord, occipital
CC lobe, frontal lobe, temporal lobe and putamen.
CC -!- DOMAIN: The acidic C-terminus and the basic N-termminus are
CC thought to render the protein in a closed, soluble and inactive
CC conformation through an autoinhibitory intramolecular interaction.
CC The open and active conformation, which enables membrane binding
CC and oligomerization, is achieved by interaction with other
CC cellular binding partners, probably including other ESCRT
CC components (By similarity).
CC -!- DISEASE: Frontotemporal dementia, chromosome 3-linked (FTD3)
CC [MIM:600795]: Characterized by an onset of dementia in the late
CC 50's initially characterized by behavioral and personality changes
CC including apathy, restlessness, disinhibition and hyperorality,
CC progressing to stereotyped behaviors, non-fluent aphasia, mutism
CC and dystonia, with a marked lack of insight. The brains of
CC individuals with FTD3 have no distinctive neuropathological
CC features. They show global cortical and central atrophy, but no
CC beta-amyloid deposits. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Amyotrophic lateral sclerosis 17 (ALS17) [MIM:614696]: An
CC adult-onset progressive neurodegenerative disorder with
CC predominantly lower motor neuron involvement, manifest as muscle
CC weakness and wasting of the upper and lower limbs, bulbar signs,
CC and respiratory insufficiency. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SNF7 family.
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DR EMBL; AF151842; AAD34079.1; -; mRNA.
DR EMBL; AL080122; CAB45721.1; -; mRNA.
DR EMBL; AK296072; BAG58830.1; -; mRNA.
DR EMBL; CR533456; CAG38487.1; -; mRNA.
DR EMBL; AK222654; BAD96374.1; -; mRNA.
DR EMBL; AC123511; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC130885; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001553; AAH01553.1; -; mRNA.
DR PIR; T12468; T12468.
DR RefSeq; NP_001231573.1; NM_001244644.1.
DR RefSeq; NP_054762.2; NM_014043.3.
DR UniGene; Hs.476930; -.
DR PDB; 2JQK; NMR; -; B=195-213.
DR PDBsum; 2JQK; -.
DR ProteinModelPortal; Q9UQN3; -.
DR SMR; Q9UQN3; 7-141.
DR DIP; DIP-50766N; -.
DR IntAct; Q9UQN3; 6.
DR MINT; MINT-1430090; -.
DR STRING; 9606.ENSP00000263780; -.
DR PhosphoSite; Q9UQN3; -.
DR DMDM; 73917746; -.
DR PaxDb; Q9UQN3; -.
DR PRIDE; Q9UQN3; -.
DR DNASU; 25978; -.
DR Ensembl; ENST00000263780; ENSP00000263780; ENSG00000083937.
DR Ensembl; ENST00000471660; ENSP00000419998; ENSG00000083937.
DR GeneID; 25978; -.
DR KEGG; hsa:25978; -.
DR UCSC; uc011bgn.2; human.
DR CTD; 25978; -.
DR GeneCards; GC03P087360; -.
DR HGNC; HGNC:24537; CHMP2B.
DR HPA; HPA035069; -.
DR MIM; 600795; phenotype.
DR MIM; 609512; gene.
DR MIM; 614696; phenotype.
DR neXtProt; NX_Q9UQN3; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR PharmGKB; PA142672112; -.
DR eggNOG; NOG268821; -.
DR HOGENOM; HOG000177218; -.
DR HOVERGEN; HBG102628; -.
DR InParanoid; Q9UQN3; -.
DR KO; K12192; -.
DR OMA; KTMQDFQ; -.
DR OrthoDB; EOG79GT8Q; -.
DR PhylomeDB; Q9UQN3; -.
DR Reactome; REACT_11123; Membrane Trafficking.
DR Reactome; REACT_116125; Disease.
DR ChiTaRS; CHMP2B; human.
DR EvolutionaryTrace; Q9UQN3; -.
DR GeneWiki; CHMP2B; -.
DR GenomeRNAi; 25978; -.
DR NextBio; 47630; -.
DR PRO; PR:Q9UQN3; -.
DR ArrayExpress; Q9UQN3; -.
DR Bgee; Q9UQN3; -.
DR CleanEx; HS_CHMP2B; -.
DR Genevestigator; Q9UQN3; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0016197; P:endosomal transport; TAS:Reactome.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR InterPro; IPR005024; Snf7.
DR Pfam; PF03357; Snf7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing;
KW Amyotrophic lateral sclerosis; Coiled coil; Complete proteome;
KW Cytoplasm; Disease mutation; Endosome; Membrane; Neurodegeneration;
KW Phosphoprotein; Protein transport; Reference proteome; Transport.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 213 Charged multivesicular body protein 2b.
FT /FTId=PRO_0000211469.
FT COILED 25 55 Potential.
FT MOTIF 201 211 MIT-interacting motif.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 199 199 Phosphoserine.
FT VAR_SEQ 1 42 MASLFKKKTVDDVIKEQNRELRGTQRAIIRDRAALEKQEKQ
FT L -> M (in isoform 2).
FT /FTId=VSP_045142.
FT VARIANT 29 29 I -> V (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A1
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_038373.
FT VARIANT 104 104 T -> N (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_068689.
FT VARIANT 148 148 D -> Y (in FTD3).
FT /FTId=VAR_023383.
FT VARIANT 206 206 Q -> H (in ALS17; cells expressing the
FT mutant protein have large cytoplasmic
FT vacuoles with an accumulation of the
FT mutant protein on the outer membrane
FT termed halos; cells with the mutant
FT protein also have aberrant localization
FT of CD63 and an increase in MAP1LC3A
FT overall indicating a defect in the
FT autophagic pathway).
FT /FTId=VAR_038374.
FT CONFLICT 8 8 K -> R (in Ref. 2; CAB45721 and 3;
FT CAG38487).
FT CONFLICT 113 113 N -> S (in Ref. 5; BAD96374).
FT CONFLICT 201 201 E -> V (in Ref. 2; CAB45721 and 3;
FT CAG38487).
FT HELIX 201 210
SQ SEQUENCE 213 AA; 23907 MW; BA192A0EAC45C19B CRC64;
MASLFKKKTV DDVIKEQNRE LRGTQRAIIR DRAALEKQEK QLELEIKKMA KIGNKEACKV
LAKQLVHLRK QKTRTFAVSS KVTSMSTQTK VMNSQMKMAG AMSTTAKTMQ AVNKKMDPQK
TLQTMQNFQK ENMKMEMTEE MINDTLDDIF DGSDDEEESQ DIVNQVLDEI GIEISGKMAK
APSAARSLPS ASTSKATISD EEIERQLKAL GVD
//
MIM
600795
*RECORD*
*FIELD* NO
600795
*FIELD* TI
#600795 FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED; FTD3
;;DMT1; DEM;;
DEMENTIA, FAMILIAL NONSPECIFIC
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
frontotemporal dementia mapping to chromosome 3 is caused by
heterozygous mutation in the CHMP2B gene (609512) on chromosome 3p11.
Mutation in the CHMP2B gene can also cause a form of amyotrophic lateral
sclerosis (ALS17; 614696).
DESCRIPTION
A substantial minority of degenerative dementias, perhaps 10%, lack the
distinctive pathologic features that allow subclassification as
Alzheimer disease (see 104300) or other forms of dementia. In perhaps
half of these cases of nonspecific dementia, there is a positive family
history of dementia, with an apparent autosomal dominant mode of
inheritance.
See also frontotemporal lobe dementia (FLDEM; 600274), which maps to
chromosome 17 and is caused by mutation in the microtubule-associated
protein tau gene (MAPT; 157140).
CLINICAL FEATURES
Brown et al. (1995) studied a large kindred from the Jutland region of
Denmark, constituting the largest published pedigree with multiple
members affected by dementia unassociated with distinctive
histopathologic features. The family had previously been described by
Gydesen et al. (1987). Gydesen et al. (2002) provided additional
clinical information on 22 affected individuals spanning 3 generations
of this Danish kindred. The disease presented at an average age of 57
years with an insidious change in personality and behavior, including
memory loss, cognitive decline, apathy, aggressiveness, stereotyped
behavior, and disinhibition. Later in the illness, most patients
developed a motor syndrome with abnormal gait, rigidity, hyperreflexia,
and pyramidal signs. PET scan of 2 affected individuals revealed a
global reduction in cerebral blood flow, and pathologic examination of
several individuals showed generalized cerebral atrophy most prominent
in the frontal and parietal lobes. Microscopic examination revealed
cortical neuronal loss, astrocytosis, and white matter changes due to
loss of myelin, but no plaques, fibrillary tangles, or inclusions. The
authors termed the disorder FTD3 (chromosome 3-linked frontotemporal
dementia). Gydesen et al. (2002) noted that the family reported by Kim
et al. (1981) showed similarities to FTD3.
Poduslo et al. (1999) described a patient with a family history of
dementia who presented with the clinical signs of Alzheimer disease
which lasted for 13 years. At autopsy, brain tissue had
amyloid-containing neuritic plaques, but no fibrillary tangles (i.e.,
the tissue was negative for staining with tau antibody). Furthermore,
genetic analysis of DNA from family members revealed no linkage with
chromosome 17 markers, where another form of frontotemporal dementia
(FLDEM; 600274) had been mapped. Linkage was found with chromosome 3
markers, located, however, somewhat 'downstream' from those linked in
the Danish family reported by Brown et al. (1995) and Brown (1998) (see
MAPPING). Poduslo et al. (1999) may thus have described a distinct
entity; see 604154.
Van der Zee et al. (2008) reported a Belgian woman with onset of
frontotemporal dementia at age 58 years. Initial symptoms included
progressive dysgraphia, memory loss, and mild disinhibition. Two years
later, she had a light disorientation in space and time, severe
dysgraphia, confabulation, dyspraxia, and dyscalculia. Brain CT scan
showed mild frontal cortical atrophy. At the age of 64, she was clearly
disoriented in space and time, her handwriting had become unreadable,
and she was dyslexic with logorrhoea and perseveration. Repeat CT scan
showed generalized cortical atrophy. Her mother and maternal aunt were
reportedly similarly affected.
INHERITANCE
Gydesen et al. (2002) noted that the transmission pattern of dementia in
a large affected Danish family was consistent with autosomal dominant
inheritance.
MAPPING
In a large Danish kindred segregating dementia, Brown et al. (1995)
mapped the disease locus to a 12-cM region of chromosome 3 spanning the
centromere. Haplotype analysis demonstrated a region between markers
D3S1284 and D3S1603 that was shared by all affected individuals. The
disease appeared to present at an earlier age when paternally inherited.
On gathering more information from affected individuals in this family,
however, Gydesen et al. (2002) found that evidence for paternal
anticipation had been weakened.
PATHOGENESIS
Urwin et al. (2010) described endosomal pathology in CHMP2B
mutation-positive patient brains and also identified and characterized
abnormal endosomes in patient fibroblasts. Functional studies
demonstrated a specific disruption of endosome-lysosome fusion but not
protein sorting by the multivesicular body (MVB). The authors proposed a
mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B
constitutively binds to MVBs and prevents recruitment of proteins, such
as Rab7 (602298), that are necessary for fusion to occur.
MOLECULAR GENETICS
In 11 affected members of a large Danish family with frontotemporal
dementia reported by Brown et al. (1995) and Gydesen et al. (2002),
Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2
gene (609512.0001). The authors identified a different CHMPB2 mutation
(609512.0002) in a single unrelated patient with nonspecific dementia.
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2
gene in 128 probands with frontotemporal dementia in whom MAPT mutations
had been excluded. A truncating mutation in the CHMPB2 gene was
identified in 2 middle-aged unaffected Afrikaner individuals from a
large affected family; however, their affected father and 5 affected
paternal relatives did not have the mutation. The maternal side of the
family had no reported dementia. Momeni et al. (2006) noted that the
large Danish family reported by Skibinski et al. (2005) had a similar
truncating mutation in the CHMPB2 gene, which resulted from a different
nucleotide change. The findings raised questions about the pathogenicity
of the CHMPB2 mutation identified by Skibinski et al. (2005) and
suggested that CHMPB2 mutations are not a common cause of frontotemporal
dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141
familial frontotemporal probands from the U.S. and U.K. In addition, the
splice site mutation reported by Skibinski et al. (2005) was not found
in 450 control individuals.
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2
gene (609512.0004) in a Belgian patient with autosomal dominant
frontotemporal lobar degeneration.
NOMENCLATURE
MacKenzie et al. (2010) suggested that the neuropathologic term
'FTLD-UPS' be used for CHMPB2-related FTLD, because the inclusions are
only detectable with immunohistochemistry against proteins of the
ubiquitin proteasome system (UPS).
*FIELD* RF
1. Brown, J.: Chromosome 3-linked frontotemporal dementia. Cell
Molec. Life Sci. 54: 925-927, 1998.
2. Brown, J.; Ashworth, A.; Gydesen, S.; Sorensen, A.; Rossor, M.;
Hardy, J.; Collinge, J.: Familial non-specific dementia maps to chromosome
3. Hum. Molec. Genet. 4: 1625-1628, 1995.
3. Cannon, A.; Baker, M.; Boeve, B.; Josephs, K.; Knopman, D.; Petersen,
R.; Parisi, J.; Dickison, D.; Adamson, J.; Snowden, J.; Neary, D.;
Mann, D.; Hutton, M.; Pickering-Brown, S. M.: CHMP2B mutations are
not a common cause of frontotemporal lobar degeneration. Neurosci.
Lett. 398: 83-84, 2006.
4. Gydesen, S.; Brown, J. M.; Brun, A.; Chakrabarti, L.; Gade, A.;
Johannsen, P.; Rossor, M.; Thusgaard, T.; Grove, A.; Yancopoulou,
D.; Spillantini, M. G.; Fisher, E. M. C.; Collinge, J.; Sorensen,
S. A.: Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 59:
1585-1594, 2002.
5. Gydesen, S.; Hagen, S.; Klinken, L.; Abelskov, J.; Sorensen, S.
A.: Neuropsychiatric studies in a family with presenile dementia
different from Alzheimer and Pick disease. Acta Psychiat. Scand. 76:
276-284, 1987.
6. Kim, R. C.; Collins, G. H.; Parisi, J. E.; Wright, A. W.; Chu,
Y. B.: Familial dementia of adult onset with pathological findings
of a 'non-specific' nature. Brain 104: 61-78, 1981.
7. Mackenzie, I. R. A.; Neumann, M.; Bigio, E. H.; Cairns, N. J.;
Alafuzoff, I.; Kril, J.; Kovacs, G. G.; Ghetti, B.; Halliday, G.;
Holm, I. E.; Ince, P. G.; Kamphorst, W.; and 9 others: Nomenclature
and nosology for neuropathologic subtypes of frontotemporal lobar
degeneration: an update. Acta Neuropath. 119: 1-4, 2010.
8. Momeni, P.; Rogaeva, E.; Van Deerlin, V.; Yuan, W.; Grafman, J.;
Tierney, M.; Huey, E.; Bell, J.; Morris, C. M.; Kalaria, R. N.; van
Rensburg, S. J.; Niehaus, D.; Potocnik, F.; Kawarai, T.; Salehi-Rad,
S.; Sato, C.; St. George-Hyslop, P.; Hardy, J.: Genetic variability
in CHMP2B and frontotemporal dementia. Neurodegener. Dis. 3: 129-133,
2006.
9. Poduslo, S. E.; Yin, X.; Hargis, J.; Brumback, R. A.; Mastrianni,
J. A.; Schwankhaus, J.: A familial case of Alzheimer's disease without
tau pathology may be linked with chromosome 3 markers. Hum. Genet. 105:
32-37, 1999.
10. Skibinski, G.; Parkinson, N. J.; Brown, J. M.; Chakrabarti, L.;
Lloyd, S. L.; Hummerich, H.; Nielsen, J. E.; Hodges, J. R.; Spillantini,
M. G.; Thusgaard, T.; Brandner, S.; Brun, A.; Rossor, M. N.; Gade,
A.; Johannsen, P.; Sorensen, S. A.; Gydesen, S.; Fisher, E. M. C.;
Collinge, J.: Mutations in the endosomal ESCRTIII-complex subunit
CHMP2B in frontotemporal dementia. Nature Genet. 37: 806-808, 2005.
11. Urwin, H.; Authier, A.; Nielsen, J. E.; Metcalf, D.; Powell, C.;
Froud, K.; Malcolm, D. S.; Holm, I.; Johannsen, P.; Brown, J.; Fisher,
E. M. C.; van der Zee, J.; Bruyland, M.; the FReJA Consortium; Collinge,
J.; Brandner, S.; Futter, C.; Isaacs, A. M.: Disruption of endocytic
trafficking in frontotemporal dementia with CHMP2B mutations. Hum.
Molec. Genet. 19: 2228-2238, 2010.
12. van der Zee, J.; Urwin, H.; Engelborghs, S.; Bruyland, M.; Vandenberghe,
R.; Dermaut, B.; De Pooter, T.; Peeters, K.; Santens, P.; De Deyn,
P. P.; Fisher, E. M.; Collinge, J.; Isaacs, A. M.; Van Broeckhoven,
C.: CHMP2B C-truncating mutations in frontotemporal lobar degeneration
are associated with an aberrant endosomal phenotype in vitro. Hum.
Molec. Genet. 17: 313-322, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary incontinence
NEUROLOGIC:
[Central nervous system];
Frontotemporal dementia;
Progressive cognitive decline;
Memory loss;
Loss of speech;
Mutism;
Dyscalculia;
Abnormal gait;
Orofacial dyskinesia;
Rigidity;
Hyperreflexia;
Extensor plantar responses;
Frontal release reflexes;
Pyramidal signs;
Dystonia;
Myoclonus;
Generalized cortical atrophy, most prominent in the frontal and parietal
lobes;
Cortical neuronal loss;
Astrocytosis;
White matter changes;
Global reduction in cerebral blood flow on PET scan;
[Behavioral/psychiatric manifestations];
Personality changes;
Apathy;
Aggressiveness;
Restlessness;
Reclusive;
Stereotyped behavior;
Lack of insight;
Inappropriate behavior;
Disinhibition;
Hyperorality
MISCELLANEOUS:
Average age of onset 57 years;
Average duration of illness 8 years;
Subtle personality and behavioral changes are presenting signs;
Motor symptoms develop later (about 5 years into illness)
MOLECULAR BASIS:
Caused by mutation in the chromatin-modifying protein 2B (CHMP2B,
609512.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 1/23/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
ckniffin: 08/16/2005
ckniffin: 1/23/2003
*FIELD* CN
George E. Tiller - updated: 8/19/2013
Cassandra L. Kniffin - updated: 3/8/2011
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 11/8/2006
Cassandra L. Kniffin - updated: 8/3/2005
Cassandra L. Kniffin - reorganized: 2/11/2003
Cassandra L. Kniffin - updated: 1/23/2003
Victor A. McKusick - updated: 8/23/1999
*FIELD* CD
Victor A. McKusick: 9/23/1995
*FIELD* ED
alopez: 01/10/2014
carol: 1/6/2014
tpirozzi: 8/20/2013
tpirozzi: 8/19/2013
carol: 7/10/2012
ckniffin: 7/2/2012
wwang: 3/11/2011
ckniffin: 3/8/2011
wwang: 5/20/2009
ckniffin: 4/29/2009
wwang: 12/1/2006
wwang: 11/28/2006
ckniffin: 11/8/2006
alopez: 8/3/2005
ckniffin: 8/3/2005
joanna: 3/18/2004
carol: 2/11/2003
ckniffin: 1/23/2003
alopez: 1/8/2001
jlewis: 9/3/1999
terry: 8/23/1999
alopez: 3/10/1998
terry: 1/16/1997
jamie: 1/15/1997
terry: 1/7/1997
mimadm: 11/3/1995
terry: 10/30/1995
mark: 9/23/1995
*RECORD*
*FIELD* NO
600795
*FIELD* TI
#600795 FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED; FTD3
;;DMT1; DEM;;
DEMENTIA, FAMILIAL NONSPECIFIC
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that
frontotemporal dementia mapping to chromosome 3 is caused by
heterozygous mutation in the CHMP2B gene (609512) on chromosome 3p11.
Mutation in the CHMP2B gene can also cause a form of amyotrophic lateral
sclerosis (ALS17; 614696).
DESCRIPTION
A substantial minority of degenerative dementias, perhaps 10%, lack the
distinctive pathologic features that allow subclassification as
Alzheimer disease (see 104300) or other forms of dementia. In perhaps
half of these cases of nonspecific dementia, there is a positive family
history of dementia, with an apparent autosomal dominant mode of
inheritance.
See also frontotemporal lobe dementia (FLDEM; 600274), which maps to
chromosome 17 and is caused by mutation in the microtubule-associated
protein tau gene (MAPT; 157140).
CLINICAL FEATURES
Brown et al. (1995) studied a large kindred from the Jutland region of
Denmark, constituting the largest published pedigree with multiple
members affected by dementia unassociated with distinctive
histopathologic features. The family had previously been described by
Gydesen et al. (1987). Gydesen et al. (2002) provided additional
clinical information on 22 affected individuals spanning 3 generations
of this Danish kindred. The disease presented at an average age of 57
years with an insidious change in personality and behavior, including
memory loss, cognitive decline, apathy, aggressiveness, stereotyped
behavior, and disinhibition. Later in the illness, most patients
developed a motor syndrome with abnormal gait, rigidity, hyperreflexia,
and pyramidal signs. PET scan of 2 affected individuals revealed a
global reduction in cerebral blood flow, and pathologic examination of
several individuals showed generalized cerebral atrophy most prominent
in the frontal and parietal lobes. Microscopic examination revealed
cortical neuronal loss, astrocytosis, and white matter changes due to
loss of myelin, but no plaques, fibrillary tangles, or inclusions. The
authors termed the disorder FTD3 (chromosome 3-linked frontotemporal
dementia). Gydesen et al. (2002) noted that the family reported by Kim
et al. (1981) showed similarities to FTD3.
Poduslo et al. (1999) described a patient with a family history of
dementia who presented with the clinical signs of Alzheimer disease
which lasted for 13 years. At autopsy, brain tissue had
amyloid-containing neuritic plaques, but no fibrillary tangles (i.e.,
the tissue was negative for staining with tau antibody). Furthermore,
genetic analysis of DNA from family members revealed no linkage with
chromosome 17 markers, where another form of frontotemporal dementia
(FLDEM; 600274) had been mapped. Linkage was found with chromosome 3
markers, located, however, somewhat 'downstream' from those linked in
the Danish family reported by Brown et al. (1995) and Brown (1998) (see
MAPPING). Poduslo et al. (1999) may thus have described a distinct
entity; see 604154.
Van der Zee et al. (2008) reported a Belgian woman with onset of
frontotemporal dementia at age 58 years. Initial symptoms included
progressive dysgraphia, memory loss, and mild disinhibition. Two years
later, she had a light disorientation in space and time, severe
dysgraphia, confabulation, dyspraxia, and dyscalculia. Brain CT scan
showed mild frontal cortical atrophy. At the age of 64, she was clearly
disoriented in space and time, her handwriting had become unreadable,
and she was dyslexic with logorrhoea and perseveration. Repeat CT scan
showed generalized cortical atrophy. Her mother and maternal aunt were
reportedly similarly affected.
INHERITANCE
Gydesen et al. (2002) noted that the transmission pattern of dementia in
a large affected Danish family was consistent with autosomal dominant
inheritance.
MAPPING
In a large Danish kindred segregating dementia, Brown et al. (1995)
mapped the disease locus to a 12-cM region of chromosome 3 spanning the
centromere. Haplotype analysis demonstrated a region between markers
D3S1284 and D3S1603 that was shared by all affected individuals. The
disease appeared to present at an earlier age when paternally inherited.
On gathering more information from affected individuals in this family,
however, Gydesen et al. (2002) found that evidence for paternal
anticipation had been weakened.
PATHOGENESIS
Urwin et al. (2010) described endosomal pathology in CHMP2B
mutation-positive patient brains and also identified and characterized
abnormal endosomes in patient fibroblasts. Functional studies
demonstrated a specific disruption of endosome-lysosome fusion but not
protein sorting by the multivesicular body (MVB). The authors proposed a
mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B
constitutively binds to MVBs and prevents recruitment of proteins, such
as Rab7 (602298), that are necessary for fusion to occur.
MOLECULAR GENETICS
In 11 affected members of a large Danish family with frontotemporal
dementia reported by Brown et al. (1995) and Gydesen et al. (2002),
Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2
gene (609512.0001). The authors identified a different CHMPB2 mutation
(609512.0002) in a single unrelated patient with nonspecific dementia.
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2
gene in 128 probands with frontotemporal dementia in whom MAPT mutations
had been excluded. A truncating mutation in the CHMPB2 gene was
identified in 2 middle-aged unaffected Afrikaner individuals from a
large affected family; however, their affected father and 5 affected
paternal relatives did not have the mutation. The maternal side of the
family had no reported dementia. Momeni et al. (2006) noted that the
large Danish family reported by Skibinski et al. (2005) had a similar
truncating mutation in the CHMPB2 gene, which resulted from a different
nucleotide change. The findings raised questions about the pathogenicity
of the CHMPB2 mutation identified by Skibinski et al. (2005) and
suggested that CHMPB2 mutations are not a common cause of frontotemporal
dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141
familial frontotemporal probands from the U.S. and U.K. In addition, the
splice site mutation reported by Skibinski et al. (2005) was not found
in 450 control individuals.
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2
gene (609512.0004) in a Belgian patient with autosomal dominant
frontotemporal lobar degeneration.
NOMENCLATURE
MacKenzie et al. (2010) suggested that the neuropathologic term
'FTLD-UPS' be used for CHMPB2-related FTLD, because the inclusions are
only detectable with immunohistochemistry against proteins of the
ubiquitin proteasome system (UPS).
*FIELD* RF
1. Brown, J.: Chromosome 3-linked frontotemporal dementia. Cell
Molec. Life Sci. 54: 925-927, 1998.
2. Brown, J.; Ashworth, A.; Gydesen, S.; Sorensen, A.; Rossor, M.;
Hardy, J.; Collinge, J.: Familial non-specific dementia maps to chromosome
3. Hum. Molec. Genet. 4: 1625-1628, 1995.
3. Cannon, A.; Baker, M.; Boeve, B.; Josephs, K.; Knopman, D.; Petersen,
R.; Parisi, J.; Dickison, D.; Adamson, J.; Snowden, J.; Neary, D.;
Mann, D.; Hutton, M.; Pickering-Brown, S. M.: CHMP2B mutations are
not a common cause of frontotemporal lobar degeneration. Neurosci.
Lett. 398: 83-84, 2006.
4. Gydesen, S.; Brown, J. M.; Brun, A.; Chakrabarti, L.; Gade, A.;
Johannsen, P.; Rossor, M.; Thusgaard, T.; Grove, A.; Yancopoulou,
D.; Spillantini, M. G.; Fisher, E. M. C.; Collinge, J.; Sorensen,
S. A.: Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 59:
1585-1594, 2002.
5. Gydesen, S.; Hagen, S.; Klinken, L.; Abelskov, J.; Sorensen, S.
A.: Neuropsychiatric studies in a family with presenile dementia
different from Alzheimer and Pick disease. Acta Psychiat. Scand. 76:
276-284, 1987.
6. Kim, R. C.; Collins, G. H.; Parisi, J. E.; Wright, A. W.; Chu,
Y. B.: Familial dementia of adult onset with pathological findings
of a 'non-specific' nature. Brain 104: 61-78, 1981.
7. Mackenzie, I. R. A.; Neumann, M.; Bigio, E. H.; Cairns, N. J.;
Alafuzoff, I.; Kril, J.; Kovacs, G. G.; Ghetti, B.; Halliday, G.;
Holm, I. E.; Ince, P. G.; Kamphorst, W.; and 9 others: Nomenclature
and nosology for neuropathologic subtypes of frontotemporal lobar
degeneration: an update. Acta Neuropath. 119: 1-4, 2010.
8. Momeni, P.; Rogaeva, E.; Van Deerlin, V.; Yuan, W.; Grafman, J.;
Tierney, M.; Huey, E.; Bell, J.; Morris, C. M.; Kalaria, R. N.; van
Rensburg, S. J.; Niehaus, D.; Potocnik, F.; Kawarai, T.; Salehi-Rad,
S.; Sato, C.; St. George-Hyslop, P.; Hardy, J.: Genetic variability
in CHMP2B and frontotemporal dementia. Neurodegener. Dis. 3: 129-133,
2006.
9. Poduslo, S. E.; Yin, X.; Hargis, J.; Brumback, R. A.; Mastrianni,
J. A.; Schwankhaus, J.: A familial case of Alzheimer's disease without
tau pathology may be linked with chromosome 3 markers. Hum. Genet. 105:
32-37, 1999.
10. Skibinski, G.; Parkinson, N. J.; Brown, J. M.; Chakrabarti, L.;
Lloyd, S. L.; Hummerich, H.; Nielsen, J. E.; Hodges, J. R.; Spillantini,
M. G.; Thusgaard, T.; Brandner, S.; Brun, A.; Rossor, M. N.; Gade,
A.; Johannsen, P.; Sorensen, S. A.; Gydesen, S.; Fisher, E. M. C.;
Collinge, J.: Mutations in the endosomal ESCRTIII-complex subunit
CHMP2B in frontotemporal dementia. Nature Genet. 37: 806-808, 2005.
11. Urwin, H.; Authier, A.; Nielsen, J. E.; Metcalf, D.; Powell, C.;
Froud, K.; Malcolm, D. S.; Holm, I.; Johannsen, P.; Brown, J.; Fisher,
E. M. C.; van der Zee, J.; Bruyland, M.; the FReJA Consortium; Collinge,
J.; Brandner, S.; Futter, C.; Isaacs, A. M.: Disruption of endocytic
trafficking in frontotemporal dementia with CHMP2B mutations. Hum.
Molec. Genet. 19: 2228-2238, 2010.
12. van der Zee, J.; Urwin, H.; Engelborghs, S.; Bruyland, M.; Vandenberghe,
R.; Dermaut, B.; De Pooter, T.; Peeters, K.; Santens, P.; De Deyn,
P. P.; Fisher, E. M.; Collinge, J.; Isaacs, A. M.; Van Broeckhoven,
C.: CHMP2B C-truncating mutations in frontotemporal lobar degeneration
are associated with an aberrant endosomal phenotype in vitro. Hum.
Molec. Genet. 17: 313-322, 2008.
*FIELD* CS
INHERITANCE:
Autosomal dominant
GENITOURINARY:
[Bladder];
Urinary incontinence
NEUROLOGIC:
[Central nervous system];
Frontotemporal dementia;
Progressive cognitive decline;
Memory loss;
Loss of speech;
Mutism;
Dyscalculia;
Abnormal gait;
Orofacial dyskinesia;
Rigidity;
Hyperreflexia;
Extensor plantar responses;
Frontal release reflexes;
Pyramidal signs;
Dystonia;
Myoclonus;
Generalized cortical atrophy, most prominent in the frontal and parietal
lobes;
Cortical neuronal loss;
Astrocytosis;
White matter changes;
Global reduction in cerebral blood flow on PET scan;
[Behavioral/psychiatric manifestations];
Personality changes;
Apathy;
Aggressiveness;
Restlessness;
Reclusive;
Stereotyped behavior;
Lack of insight;
Inappropriate behavior;
Disinhibition;
Hyperorality
MISCELLANEOUS:
Average age of onset 57 years;
Average duration of illness 8 years;
Subtle personality and behavioral changes are presenting signs;
Motor symptoms develop later (about 5 years into illness)
MOLECULAR BASIS:
Caused by mutation in the chromatin-modifying protein 2B (CHMP2B,
609512.0001)
*FIELD* CN
Cassandra L. Kniffin - revised: 1/23/2003
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
ckniffin: 08/16/2005
ckniffin: 1/23/2003
*FIELD* CN
George E. Tiller - updated: 8/19/2013
Cassandra L. Kniffin - updated: 3/8/2011
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 11/8/2006
Cassandra L. Kniffin - updated: 8/3/2005
Cassandra L. Kniffin - reorganized: 2/11/2003
Cassandra L. Kniffin - updated: 1/23/2003
Victor A. McKusick - updated: 8/23/1999
*FIELD* CD
Victor A. McKusick: 9/23/1995
*FIELD* ED
alopez: 01/10/2014
carol: 1/6/2014
tpirozzi: 8/20/2013
tpirozzi: 8/19/2013
carol: 7/10/2012
ckniffin: 7/2/2012
wwang: 3/11/2011
ckniffin: 3/8/2011
wwang: 5/20/2009
ckniffin: 4/29/2009
wwang: 12/1/2006
wwang: 11/28/2006
ckniffin: 11/8/2006
alopez: 8/3/2005
ckniffin: 8/3/2005
joanna: 3/18/2004
carol: 2/11/2003
ckniffin: 1/23/2003
alopez: 1/8/2001
jlewis: 9/3/1999
terry: 8/23/1999
alopez: 3/10/1998
terry: 1/16/1997
jamie: 1/15/1997
terry: 1/7/1997
mimadm: 11/3/1995
terry: 10/30/1995
mark: 9/23/1995
MIM
609512
*RECORD*
*FIELD* NO
609512
*FIELD* TI
*609512 CHMP FAMILY, MEMBER 2B; CHMP2B
;;CHROMATIN-MODIFYING PROTEIN 2B;;
CHARGED MULTIVESICULAR BODY PROTEIN 2B;;
read moreVACUOLAR PROTEIN SORTING 2, YEAST, HOMOLOG OF, B; VPS2B
*FIELD* TX
DESCRIPTION
CHMP2B belongs to the chromatin-modifying protein/charged multivesicular
body protein (CHMP) family. These proteins are components of ESCRT-III
(endosomal sorting complex required for transport III), a complex
involved in degradation of surface receptor proteins and formation of
endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and
cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (164010),
is required for both MVB formation and regulation of cell cycle
progression (summary by Tsang et al., 2006).
CLONING
Skibinski et al. (2005) identified the human CHMP2B gene by positional
cloning of a candidate gene region identified for frontotemporal
dementia linked to a 15.5-Mb region on chromosome 3 (FTD3; 600795). The
deduced 213-amino acid protein contains coiled-coil, Snf-7, and acidic
C-terminal domains. Northern blot analysis identified a major 2.4-kb
mRNA transcript in multiple human tissues and all major regions of the
brain. Two minor transcripts of approximately 1.9 and 1.35 kb were also
identified, suggestive of alternative 5-prime and 3-prime untranslated
regions.
GENE STRUCTURE
Skibinski et al. (2005) determined that the CHMP2B gene contains 6
exons.
GENE FUNCTION
By in situ hybridization of mouse brain, Skibinski et al. (2005) found
widespread Chmp2b expression in all neuronal populations, especially in
the hippocampus, frontal and temporal lobes, and cerebellum. No
astrocytes or oligodendrocytes were labeled.
The yeast ortholog of CHMP2B, Vps2, was initially identified in a
mutagenesis screen for unusual vacuolar protein sorting (vps) phenotypes
in S. cerevisiae, and was found to be part of the ESCRTIII complex
(endosomal secretory complex required for transport), which participates
in endosomal trafficking (Babst et al., 2002).
Urwin et al. (2010) described endosomal pathology in CHMP2B
mutation-positive patient brains and also identified and characterized
abnormal endosomes in patient fibroblasts. Functional studies
demonstrated a specific disruption of endosome-lysosome fusion but not
protein sorting by the multivesicular body (MVB). The authors proposed a
mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B
constitutively binds to MVBs and prevents recruitment of proteins, such
as Rab7 (602298), that are necessary for fusion to occur.
MOLECULAR GENETICS
In 11 affected members of a large Danish family with frontotemporal
dementia linked to chromosome 3 (FTD3; 600795) reported by Brown et al.
(1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a
heterozygous mutation in the CHMPB2 gene (609512.0001). The authors
identified a different CHMPB2 mutation (609512.0002) in a single
unrelated patient with nonspecific dementia.
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2
gene in 128 probands with frontotemporal dementia in whom MAPT mutations
had been excluded. A truncating mutation in the CHMPB2 gene was
identified in 2 middle-aged unaffected Afrikaner individuals from a
large affected family; however, their affected father and 5 affected
paternal relatives did not have the mutation. The maternal side of the
family had no reported dementia. Momeni et al. (2006) noted that the
large Danish family reported by Skibinski et al. (2005) had a similar
truncating mutation in the CHMPB2 gene, which resulted from a different
nucleotide change. The findings raised questions about the pathogenicity
of the CHMPB2 mutation identified by Skibinski et al. (2005) and
suggested that CHMPB2 mutations are not a common cause of frontotemporal
dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141
familial frontotemporal probands from the U.S. and U.K.
Parkinson et al. (2006) identified a heterozygous CHMPB2 mutation
(609512.0003) in a patient with rapidly progressive motor deterioration
consistent with a diagnosis of amyotrophic lateral sclerosis (ALS17;
614696). No dementia was present in this patient. A second unrelated man
with FTD and ALS had a different heterozygous mutation (I29V;
609512.0005).
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2
gene (609512.0004) in a Belgian patient with autosomal dominant
frontotemporal lobar degeneration.
Cox et al. (2010) identified heterozygous mutations in the CHMP2B gene
(see, e.g., 609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433
patients with ALS17. However, CHMP2B mutations were found in 10% of
those with the specific lower motor neuron variant of ALS. Microarray
analysis of motor neurons with CHMP2B mutations showed downregulation of
genes involved in axonal transport, autophagy induction, protein
translation, and certain signaling pathways, such as MAPK-related
pathways (see, e.g., 600289). Transfection of mutant CHMP2B into HEK293
and COS-7 cells resulted in the formation of large cytoplasmic vacuoles,
aberrant lysosomal localization, and impaired autophagy. Cox et al.
(2010) hypothesized that CHMP2B mutations may contribute to motor neuron
injury through dysfunction of the autophagic clearance of cellular
proteins.
*FIELD* AV
.0001
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, IVS5AS, G-C
In 11 affected members from a large Danish family with frontotemporal
dementia linked to chromosome 3 (600795), Skibinski et al. (2005)
identified a heterozygous G-to-C transversion in the acceptor splice
site of exon 6 of the CHMP2B gene. RT-PCR analysis showed that the
mutation resulted in either inclusion of the 201-bp intronic sequence
spanning exons 5 and 6 or a short deletion resulting from the use of a
cryptic splice site mapping 10 bp from the 5-prime end of exon 6.
Evidence suggested the presence of a third abnormal product which may
have resulted from a heteroduplex formed between wildtype and mutant
CHMP2B. The G-to-C transversion was not identified in 14 unaffected
family members or 220 control DNA samples. In vitro functional
expression studies in rat PC12 cells showed that the mutant proteins
accumulated on the outer membrane of large aberrant cytoplasmic bodies,
consistent with the formation of dysmorphic organelles of the late
endosomal pathway.
Cannon et al. (2006) did not identify the splice site mutation reported
by Skibinski et al. (2005) in 450 control individuals.
.0002
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, ASP148TYR
In 1 of 400 unrelated European patients with frontotemporal dementia
(600795), Skibinski et al. (2005) identified a 442G-T transversion in
exon 5 of the CHMP2B gene, resulting in an asp148-to-tyr (D148Y)
substitution in the conserved Snf-7 domain.
.0003
AMYOTROPHIC LATERAL SCLEROSIS 17
CHMP2B, GLN206HIS
In a 75-year-old man with rapidly progressive amyotrophic lateral
sclerosis-17 (ALS17; 614696), Parkinson et al. (2006) identified a
heterozygous 694A-C transversion in exon 6 of the CHMP2B gene, resulting
in a gln206-to-his (Q206H) substitution in a highly conserved residue.
The mutation was not identified in 640 control samples. At age 74 years,
the patient developed bulbar-onset weakness with flaccid dysarthria and
tongue fasciculations. He later developed weakness and wasting of the
intrinsic hand muscles and respiratory weakness. Although he had a
previous right leg amputation from trauma, neurophysiologic testing
showed neurogenic changes in all 4 limbs. He had depressed reflexes and
flexor plantar responses, consistent with lower motor neuron
involvement. He died of respiratory failure 15 months after symptom
onset. There was no evidence of dementia or extramotor neurologic
involvement. A cousin reportedly had died of ALS. Neuropathologic
examination showed a predominantly lower motor neuron disease with
intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and
p62/sequestosome (SQSTM1; 601530). SQSTM1-reactive inclusions were also
detected within oligodendroglia in the cerebral motor cortex.
By in vitro functional studies in HEK293 and COS-7 cells, Cox et al.
(2010) showed that cells expressing the Q206H mutant protein had large
cytoplasmic vacuoles with an accumulation of mutant CHMP2B on the outer
membrane, termed halos. Cells with the mutant protein also had aberrant
localization of CD63 (155740) and an increase in LC3-II (601242),
overall indicating a defect in the autophagic pathway.
.0004
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, GLN165TER
In a Belgian woman with onset of frontotemporal dementia (600795) at age
58, van der Zee et al. (2008) identified a heterozygous 493C-T
transition in exon 5 of the CHMP2B gene, resulting in a gln165-to-ter
(Q165X) substitution. Her mother and maternal aunt were reportedly
similarly affected. RT-PCR studies confirmed the presence of a mutant
transcript in patient cells. The mutation was not found in 459 Belgian
control individuals. Overexpression of the Q165X mutant in human
neuroblastoma cells resulted in accumulation of truncated protein in
enlarged vesicular structures. Normally, the C terminal of CHMP2B
functions as an autoinhibitor, allowing the protein to shuttle between
the inactive and active states. The truncation eliminates this
inhibitory effect, resulting in constitutive activation and involvement
in the endosomal complex and accumulation on the endosomal membrane.
.0005
AMYOTROPHIC LATERAL SCLEROSIS 17
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED, INCLUDED
CHMP2B, ILE29VAL
In a man with onset of progressive frontotemporal dementia (600795) in
his late sixties followed by ALS (614696), Parkinson et al. (2006)
identified a heterozygous 161A-G transition in the CHMP3B gene,
resulting in an ile29-to-val (I29V) substitution located between 2
conserved regions of the protein. The mutation was not found in 640
controls or in 400 FTD samples. However, Parkinson et al. (2006) noted
that Cannon et al. (2006) found the I29V variant in 1 of 141 probands
with frontotemporal dementia and at a frequency of 0.5% among 200
control chromosomes, thus suggesting that it may be a benign variant.
The patient reported by Parkinson et al. (2006) had brisk tendon
reflexes and extensor plantar responses. His father reportedly had motor
disturbances and frontal lobe dysfunction.
Cox et al. (2010) identified a heterozygous I29V substitution, which
they stated resulted from an 85A-G transition, in 2 unrelated patients
with onset of ALS at ages 64 and 49 years, respectively. The mutation
was not found in 1,000 control chromosomes. Both patients had
involvement of the upper and lower limbs, as well as bulbar symptoms,
but no signs of upper motor neuron involvement. In vitro functional
studies in HEK293 and COS-7 cells showed that cells expressing the
mutant protein had large cytoplasmic vacuoles with an accumulation of
mutant CHMP2B on the outer membrane, termed halos. Cells with the mutant
protein also had aberrant localization of CD63 (155740) and an increase
in LC3-II (601242), overall indicating a defect in the autophagic
pathway.
.0006
AMYOTROPHIC LATERAL SCLEROSIS 17
CHMP2B, THR104ASN
In a 54-year-old man with ALS17 (614696), Cox et al. (2010) identified a
heterozygous 311C-A transversion in exon 3 of the CHMP2B gene, resulting
in a thr104-to-asn (T104N) substitution in a highly conserved residue.
The mutation was not found in 1,000 control chromosomes. The patient
presented with bulbar and respiratory dysfunction and later developed
wasting and fasciculation in the upper and lower limbs. Reflexes were
normal, suggesting only lower motor neuron involvement. In vitro
functional studies in HEK293 and COS-7 cells showed that cells
expressing the mutant protein had large cytoplasmic vacuoles with an
accumulation of mutant CHMP2B on the outer membrane, termed halos. Cells
with the mutant protein also had aberrant localization of CD63 (155740)
and an increase in LC3-II (601242), overall indicating a defect in the
autophagic pathway.
*FIELD* RF
1. Babst, M.; Katzmann, D. J.; Estepa-Sabal, E. J.; Meerloo, T.; Emr,
S. D.: ESCRT-III: an endosome-associated heterooligomeric protein
complex required for MVB sorting. Dev. Cell 3: 271-282, 2002.
2. Brown, J.; Ashworth, A.; Gydesen, S.; Sorensen, A.; Rossor, M.;
Hardy, J.; Collinge, J.: Familial non-specific dementia maps to chromosome
3. Hum. Molec. Genet. 4: 1625-1628, 1995.
3. Cannon, A.; Baker, M.; Boeve, B.; Josephs, K.; Knopman, D.; Petersen,
R.; Parisi, J.; Dickison, D.; Adamson, J.; Snowden, J.; Neary, D.;
Mann, D.; Hutton, M.; Pickering-Brown, S. M.: CHMP2B mutations are
not a common cause of frontotemporal lobar degeneration. Neurosci.
Lett. 398: 83-84, 2006.
4. Cox, L. E.; Ferraiuolo, L.; Goodall, E. F.; Heath, P. R.; Higginbottom,
A.; Mortiboys, H.; Hollinger, H. C.; Hartley, J. A.; Brockington,
A.; Burness, C. E.; Morrison, K. E.; Wharton, S. B.; Grierson, A.
J.; Ince, P. G.; Kirby, J.; Shaw, P. J.: Mutations in CHMP2B in lower
motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS
One 5: e9872, 2010. Note: Electronic Article.
5. Gydesen, S.; Brown, J. M.; Brun, A.; Chakrabarti, L.; Gade, A.;
Johannsen, P.; Rossor, M.; Thusgaard, T.; Grove, A.; Yancopoulou,
D.; Spillantini, M. G.; Fisher, E. M. C.; Collinge, J.; Sorensen,
S. A.: Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 59:
1585-1594, 2002.
6. Momeni, P.; Rogaeva, E.; Van Deerlin, V.; Yuan, W.; Grafman, J.;
Tierney, M.; Huey, E.; Bell, J.; Morris, C. M.; Kalaria, R. N.; van
Rensburg, S. J.; Niehaus, D.; Potocnik, F.; Kawarai, T.; Salehi-Rad,
S.; Sato, C.; St. George-Hyslop, P.; Hardy, J.: Genetic variability
in CHMP2B and frontotemporal dementia. Neurodegener. Dis. 3: 129-133,
2006.
7. Parkinson, N.; Ince, P. G.; Smith, M. O.; Highley, R.; Skibinski,
G.; Andersen, P. M.; Morrison, K. E.; Pall, H. S.; Hardiman, O.; Collinge,
J.; Shaw, P. J.; Disher, E. M. C.; MRC Proteomics in ALS Study and
the FReJA Consortium: ALS phenotypes with mutations in CHMP2B (charged
multivesicular body protein 2B). Neurology 67: 1074-1077, 2006.
8. Skibinski, G.; Parkinson, N. J.; Brown, J. M.; Chakrabarti, L.;
Lloyd, S. L.; Hummerich, H.; Nielsen, J. E.; Hodges, J. R.; Spillantini,
M. G.; Thusgaard, T.; Brandner, S.; Brun, A.; Rossor, M. N.; Gade,
A.; Johannsen, P.; Sorensen, S. A.; Gydesen, S.; Fisher, E. M. C.;
Collinge, J.: Mutations in the endosomal ESCRTIII-complex subunit
CHMP2B in frontotemporal dementia. Nature Genet. 37: 806-808, 2005.
9. Tsang, H. T. H.; Connell, J. W.; Brown, S. E.; Thompson, A.; Reid,
E.; Sanderson, C. M.: A systematic analysis of human CHMP protein
interactions: additional MIT domain-containing proteins bind to multiple
components of the human ESCRT III complex. Genomics 88: 333-346,
2006.
10. Urwin, H.; Authier, A.; Nielsen, J. E.; Metcalf, D.; Powell, C.;
Froud, K.; Malcolm, D. S.; Holm, I.; Johannsen, P.; Brown, J.; Fisher,
E. M. C.; van der Zee, J.; Bruyland, M.; the FReJA Consortium; Collinge,
J.; Brandner, S.; Futter, C.; Isaacs, A. M.: Disruption of endocytic
trafficking in frontotemporal dementia with CHMP2B mutations. Hum.
Molec. Genet. 19: 2228-2238, 2010.
11. van der Zee, J.; Urwin, H.; Engelborghs, S.; Bruyland, M.; Vandenberghe,
R.; Dermaut, B.; De Pooter, T.; Peeters, K.; Santens, P.; De Deyn,
P. P.; Fisher, E. M.; Collinge, J.; Isaacs, A. M.; Van Broeckhoven,
C.: CHMP2B C-truncating mutations in frontotemporal lobar degeneration
are associated with an aberrant endosomal phenotype in vitro. Hum.
Molec. Genet. 17: 313-322, 2008.
*FIELD* CN
George E. Tiller - updated: 8/19/2013
Cassandra L. Kniffin - updated: 7/2/2012
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 11/8/2006
*FIELD* CD
Cassandra L. Kniffin: 8/3/2005
*FIELD* ED
carol: 08/20/2013
tpirozzi: 8/20/2013
tpirozzi: 8/19/2013
carol: 7/10/2012
terry: 7/10/2012
ckniffin: 7/2/2012
carol: 6/22/2012
wwang: 5/20/2009
ckniffin: 4/29/2009
mgross: 4/2/2007
mgross: 3/28/2007
wwang: 11/29/2006
wwang: 11/28/2006
ckniffin: 11/8/2006
terry: 9/27/2005
alopez: 8/3/2005
ckniffin: 8/3/2005
*RECORD*
*FIELD* NO
609512
*FIELD* TI
*609512 CHMP FAMILY, MEMBER 2B; CHMP2B
;;CHROMATIN-MODIFYING PROTEIN 2B;;
CHARGED MULTIVESICULAR BODY PROTEIN 2B;;
read moreVACUOLAR PROTEIN SORTING 2, YEAST, HOMOLOG OF, B; VPS2B
*FIELD* TX
DESCRIPTION
CHMP2B belongs to the chromatin-modifying protein/charged multivesicular
body protein (CHMP) family. These proteins are components of ESCRT-III
(endosomal sorting complex required for transport III), a complex
involved in degradation of surface receptor proteins and formation of
endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and
cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (164010),
is required for both MVB formation and regulation of cell cycle
progression (summary by Tsang et al., 2006).
CLONING
Skibinski et al. (2005) identified the human CHMP2B gene by positional
cloning of a candidate gene region identified for frontotemporal
dementia linked to a 15.5-Mb region on chromosome 3 (FTD3; 600795). The
deduced 213-amino acid protein contains coiled-coil, Snf-7, and acidic
C-terminal domains. Northern blot analysis identified a major 2.4-kb
mRNA transcript in multiple human tissues and all major regions of the
brain. Two minor transcripts of approximately 1.9 and 1.35 kb were also
identified, suggestive of alternative 5-prime and 3-prime untranslated
regions.
GENE STRUCTURE
Skibinski et al. (2005) determined that the CHMP2B gene contains 6
exons.
GENE FUNCTION
By in situ hybridization of mouse brain, Skibinski et al. (2005) found
widespread Chmp2b expression in all neuronal populations, especially in
the hippocampus, frontal and temporal lobes, and cerebellum. No
astrocytes or oligodendrocytes were labeled.
The yeast ortholog of CHMP2B, Vps2, was initially identified in a
mutagenesis screen for unusual vacuolar protein sorting (vps) phenotypes
in S. cerevisiae, and was found to be part of the ESCRTIII complex
(endosomal secretory complex required for transport), which participates
in endosomal trafficking (Babst et al., 2002).
Urwin et al. (2010) described endosomal pathology in CHMP2B
mutation-positive patient brains and also identified and characterized
abnormal endosomes in patient fibroblasts. Functional studies
demonstrated a specific disruption of endosome-lysosome fusion but not
protein sorting by the multivesicular body (MVB). The authors proposed a
mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B
constitutively binds to MVBs and prevents recruitment of proteins, such
as Rab7 (602298), that are necessary for fusion to occur.
MOLECULAR GENETICS
In 11 affected members of a large Danish family with frontotemporal
dementia linked to chromosome 3 (FTD3; 600795) reported by Brown et al.
(1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a
heterozygous mutation in the CHMPB2 gene (609512.0001). The authors
identified a different CHMPB2 mutation (609512.0002) in a single
unrelated patient with nonspecific dementia.
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2
gene in 128 probands with frontotemporal dementia in whom MAPT mutations
had been excluded. A truncating mutation in the CHMPB2 gene was
identified in 2 middle-aged unaffected Afrikaner individuals from a
large affected family; however, their affected father and 5 affected
paternal relatives did not have the mutation. The maternal side of the
family had no reported dementia. Momeni et al. (2006) noted that the
large Danish family reported by Skibinski et al. (2005) had a similar
truncating mutation in the CHMPB2 gene, which resulted from a different
nucleotide change. The findings raised questions about the pathogenicity
of the CHMPB2 mutation identified by Skibinski et al. (2005) and
suggested that CHMPB2 mutations are not a common cause of frontotemporal
dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141
familial frontotemporal probands from the U.S. and U.K.
Parkinson et al. (2006) identified a heterozygous CHMPB2 mutation
(609512.0003) in a patient with rapidly progressive motor deterioration
consistent with a diagnosis of amyotrophic lateral sclerosis (ALS17;
614696). No dementia was present in this patient. A second unrelated man
with FTD and ALS had a different heterozygous mutation (I29V;
609512.0005).
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2
gene (609512.0004) in a Belgian patient with autosomal dominant
frontotemporal lobar degeneration.
Cox et al. (2010) identified heterozygous mutations in the CHMP2B gene
(see, e.g., 609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433
patients with ALS17. However, CHMP2B mutations were found in 10% of
those with the specific lower motor neuron variant of ALS. Microarray
analysis of motor neurons with CHMP2B mutations showed downregulation of
genes involved in axonal transport, autophagy induction, protein
translation, and certain signaling pathways, such as MAPK-related
pathways (see, e.g., 600289). Transfection of mutant CHMP2B into HEK293
and COS-7 cells resulted in the formation of large cytoplasmic vacuoles,
aberrant lysosomal localization, and impaired autophagy. Cox et al.
(2010) hypothesized that CHMP2B mutations may contribute to motor neuron
injury through dysfunction of the autophagic clearance of cellular
proteins.
*FIELD* AV
.0001
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, IVS5AS, G-C
In 11 affected members from a large Danish family with frontotemporal
dementia linked to chromosome 3 (600795), Skibinski et al. (2005)
identified a heterozygous G-to-C transversion in the acceptor splice
site of exon 6 of the CHMP2B gene. RT-PCR analysis showed that the
mutation resulted in either inclusion of the 201-bp intronic sequence
spanning exons 5 and 6 or a short deletion resulting from the use of a
cryptic splice site mapping 10 bp from the 5-prime end of exon 6.
Evidence suggested the presence of a third abnormal product which may
have resulted from a heteroduplex formed between wildtype and mutant
CHMP2B. The G-to-C transversion was not identified in 14 unaffected
family members or 220 control DNA samples. In vitro functional
expression studies in rat PC12 cells showed that the mutant proteins
accumulated on the outer membrane of large aberrant cytoplasmic bodies,
consistent with the formation of dysmorphic organelles of the late
endosomal pathway.
Cannon et al. (2006) did not identify the splice site mutation reported
by Skibinski et al. (2005) in 450 control individuals.
.0002
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, ASP148TYR
In 1 of 400 unrelated European patients with frontotemporal dementia
(600795), Skibinski et al. (2005) identified a 442G-T transversion in
exon 5 of the CHMP2B gene, resulting in an asp148-to-tyr (D148Y)
substitution in the conserved Snf-7 domain.
.0003
AMYOTROPHIC LATERAL SCLEROSIS 17
CHMP2B, GLN206HIS
In a 75-year-old man with rapidly progressive amyotrophic lateral
sclerosis-17 (ALS17; 614696), Parkinson et al. (2006) identified a
heterozygous 694A-C transversion in exon 6 of the CHMP2B gene, resulting
in a gln206-to-his (Q206H) substitution in a highly conserved residue.
The mutation was not identified in 640 control samples. At age 74 years,
the patient developed bulbar-onset weakness with flaccid dysarthria and
tongue fasciculations. He later developed weakness and wasting of the
intrinsic hand muscles and respiratory weakness. Although he had a
previous right leg amputation from trauma, neurophysiologic testing
showed neurogenic changes in all 4 limbs. He had depressed reflexes and
flexor plantar responses, consistent with lower motor neuron
involvement. He died of respiratory failure 15 months after symptom
onset. There was no evidence of dementia or extramotor neurologic
involvement. A cousin reportedly had died of ALS. Neuropathologic
examination showed a predominantly lower motor neuron disease with
intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and
p62/sequestosome (SQSTM1; 601530). SQSTM1-reactive inclusions were also
detected within oligodendroglia in the cerebral motor cortex.
By in vitro functional studies in HEK293 and COS-7 cells, Cox et al.
(2010) showed that cells expressing the Q206H mutant protein had large
cytoplasmic vacuoles with an accumulation of mutant CHMP2B on the outer
membrane, termed halos. Cells with the mutant protein also had aberrant
localization of CD63 (155740) and an increase in LC3-II (601242),
overall indicating a defect in the autophagic pathway.
.0004
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED
CHMP2B, GLN165TER
In a Belgian woman with onset of frontotemporal dementia (600795) at age
58, van der Zee et al. (2008) identified a heterozygous 493C-T
transition in exon 5 of the CHMP2B gene, resulting in a gln165-to-ter
(Q165X) substitution. Her mother and maternal aunt were reportedly
similarly affected. RT-PCR studies confirmed the presence of a mutant
transcript in patient cells. The mutation was not found in 459 Belgian
control individuals. Overexpression of the Q165X mutant in human
neuroblastoma cells resulted in accumulation of truncated protein in
enlarged vesicular structures. Normally, the C terminal of CHMP2B
functions as an autoinhibitor, allowing the protein to shuttle between
the inactive and active states. The truncation eliminates this
inhibitory effect, resulting in constitutive activation and involvement
in the endosomal complex and accumulation on the endosomal membrane.
.0005
AMYOTROPHIC LATERAL SCLEROSIS 17
FRONTOTEMPORAL DEMENTIA, CHROMOSOME 3-LINKED, INCLUDED
CHMP2B, ILE29VAL
In a man with onset of progressive frontotemporal dementia (600795) in
his late sixties followed by ALS (614696), Parkinson et al. (2006)
identified a heterozygous 161A-G transition in the CHMP3B gene,
resulting in an ile29-to-val (I29V) substitution located between 2
conserved regions of the protein. The mutation was not found in 640
controls or in 400 FTD samples. However, Parkinson et al. (2006) noted
that Cannon et al. (2006) found the I29V variant in 1 of 141 probands
with frontotemporal dementia and at a frequency of 0.5% among 200
control chromosomes, thus suggesting that it may be a benign variant.
The patient reported by Parkinson et al. (2006) had brisk tendon
reflexes and extensor plantar responses. His father reportedly had motor
disturbances and frontal lobe dysfunction.
Cox et al. (2010) identified a heterozygous I29V substitution, which
they stated resulted from an 85A-G transition, in 2 unrelated patients
with onset of ALS at ages 64 and 49 years, respectively. The mutation
was not found in 1,000 control chromosomes. Both patients had
involvement of the upper and lower limbs, as well as bulbar symptoms,
but no signs of upper motor neuron involvement. In vitro functional
studies in HEK293 and COS-7 cells showed that cells expressing the
mutant protein had large cytoplasmic vacuoles with an accumulation of
mutant CHMP2B on the outer membrane, termed halos. Cells with the mutant
protein also had aberrant localization of CD63 (155740) and an increase
in LC3-II (601242), overall indicating a defect in the autophagic
pathway.
.0006
AMYOTROPHIC LATERAL SCLEROSIS 17
CHMP2B, THR104ASN
In a 54-year-old man with ALS17 (614696), Cox et al. (2010) identified a
heterozygous 311C-A transversion in exon 3 of the CHMP2B gene, resulting
in a thr104-to-asn (T104N) substitution in a highly conserved residue.
The mutation was not found in 1,000 control chromosomes. The patient
presented with bulbar and respiratory dysfunction and later developed
wasting and fasciculation in the upper and lower limbs. Reflexes were
normal, suggesting only lower motor neuron involvement. In vitro
functional studies in HEK293 and COS-7 cells showed that cells
expressing the mutant protein had large cytoplasmic vacuoles with an
accumulation of mutant CHMP2B on the outer membrane, termed halos. Cells
with the mutant protein also had aberrant localization of CD63 (155740)
and an increase in LC3-II (601242), overall indicating a defect in the
autophagic pathway.
*FIELD* RF
1. Babst, M.; Katzmann, D. J.; Estepa-Sabal, E. J.; Meerloo, T.; Emr,
S. D.: ESCRT-III: an endosome-associated heterooligomeric protein
complex required for MVB sorting. Dev. Cell 3: 271-282, 2002.
2. Brown, J.; Ashworth, A.; Gydesen, S.; Sorensen, A.; Rossor, M.;
Hardy, J.; Collinge, J.: Familial non-specific dementia maps to chromosome
3. Hum. Molec. Genet. 4: 1625-1628, 1995.
3. Cannon, A.; Baker, M.; Boeve, B.; Josephs, K.; Knopman, D.; Petersen,
R.; Parisi, J.; Dickison, D.; Adamson, J.; Snowden, J.; Neary, D.;
Mann, D.; Hutton, M.; Pickering-Brown, S. M.: CHMP2B mutations are
not a common cause of frontotemporal lobar degeneration. Neurosci.
Lett. 398: 83-84, 2006.
4. Cox, L. E.; Ferraiuolo, L.; Goodall, E. F.; Heath, P. R.; Higginbottom,
A.; Mortiboys, H.; Hollinger, H. C.; Hartley, J. A.; Brockington,
A.; Burness, C. E.; Morrison, K. E.; Wharton, S. B.; Grierson, A.
J.; Ince, P. G.; Kirby, J.; Shaw, P. J.: Mutations in CHMP2B in lower
motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS
One 5: e9872, 2010. Note: Electronic Article.
5. Gydesen, S.; Brown, J. M.; Brun, A.; Chakrabarti, L.; Gade, A.;
Johannsen, P.; Rossor, M.; Thusgaard, T.; Grove, A.; Yancopoulou,
D.; Spillantini, M. G.; Fisher, E. M. C.; Collinge, J.; Sorensen,
S. A.: Chromosome 3 linked frontotemporal dementia (FTD-3). Neurology 59:
1585-1594, 2002.
6. Momeni, P.; Rogaeva, E.; Van Deerlin, V.; Yuan, W.; Grafman, J.;
Tierney, M.; Huey, E.; Bell, J.; Morris, C. M.; Kalaria, R. N.; van
Rensburg, S. J.; Niehaus, D.; Potocnik, F.; Kawarai, T.; Salehi-Rad,
S.; Sato, C.; St. George-Hyslop, P.; Hardy, J.: Genetic variability
in CHMP2B and frontotemporal dementia. Neurodegener. Dis. 3: 129-133,
2006.
7. Parkinson, N.; Ince, P. G.; Smith, M. O.; Highley, R.; Skibinski,
G.; Andersen, P. M.; Morrison, K. E.; Pall, H. S.; Hardiman, O.; Collinge,
J.; Shaw, P. J.; Disher, E. M. C.; MRC Proteomics in ALS Study and
the FReJA Consortium: ALS phenotypes with mutations in CHMP2B (charged
multivesicular body protein 2B). Neurology 67: 1074-1077, 2006.
8. Skibinski, G.; Parkinson, N. J.; Brown, J. M.; Chakrabarti, L.;
Lloyd, S. L.; Hummerich, H.; Nielsen, J. E.; Hodges, J. R.; Spillantini,
M. G.; Thusgaard, T.; Brandner, S.; Brun, A.; Rossor, M. N.; Gade,
A.; Johannsen, P.; Sorensen, S. A.; Gydesen, S.; Fisher, E. M. C.;
Collinge, J.: Mutations in the endosomal ESCRTIII-complex subunit
CHMP2B in frontotemporal dementia. Nature Genet. 37: 806-808, 2005.
9. Tsang, H. T. H.; Connell, J. W.; Brown, S. E.; Thompson, A.; Reid,
E.; Sanderson, C. M.: A systematic analysis of human CHMP protein
interactions: additional MIT domain-containing proteins bind to multiple
components of the human ESCRT III complex. Genomics 88: 333-346,
2006.
10. Urwin, H.; Authier, A.; Nielsen, J. E.; Metcalf, D.; Powell, C.;
Froud, K.; Malcolm, D. S.; Holm, I.; Johannsen, P.; Brown, J.; Fisher,
E. M. C.; van der Zee, J.; Bruyland, M.; the FReJA Consortium; Collinge,
J.; Brandner, S.; Futter, C.; Isaacs, A. M.: Disruption of endocytic
trafficking in frontotemporal dementia with CHMP2B mutations. Hum.
Molec. Genet. 19: 2228-2238, 2010.
11. van der Zee, J.; Urwin, H.; Engelborghs, S.; Bruyland, M.; Vandenberghe,
R.; Dermaut, B.; De Pooter, T.; Peeters, K.; Santens, P.; De Deyn,
P. P.; Fisher, E. M.; Collinge, J.; Isaacs, A. M.; Van Broeckhoven,
C.: CHMP2B C-truncating mutations in frontotemporal lobar degeneration
are associated with an aberrant endosomal phenotype in vitro. Hum.
Molec. Genet. 17: 313-322, 2008.
*FIELD* CN
George E. Tiller - updated: 8/19/2013
Cassandra L. Kniffin - updated: 7/2/2012
Cassandra L. Kniffin - updated: 4/29/2009
Cassandra L. Kniffin - updated: 11/8/2006
*FIELD* CD
Cassandra L. Kniffin: 8/3/2005
*FIELD* ED
carol: 08/20/2013
tpirozzi: 8/20/2013
tpirozzi: 8/19/2013
carol: 7/10/2012
terry: 7/10/2012
ckniffin: 7/2/2012
carol: 6/22/2012
wwang: 5/20/2009
ckniffin: 4/29/2009
mgross: 4/2/2007
mgross: 3/28/2007
wwang: 11/29/2006
wwang: 11/28/2006
ckniffin: 11/8/2006
terry: 9/27/2005
alopez: 8/3/2005
ckniffin: 8/3/2005
MIM
614696
*RECORD*
*FIELD* NO
614696
*FIELD* TI
#614696 AMYOTROPHIC LATERAL SCLEROSIS 17; ALS17
;;AMYOTROPHIC LATERAL SCLEROSIS, CHMP2B-RELATED
read more*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-17 (ALS17) is caused by heterozygous mutation in the CHMP2B
gene (609512) on chromosome 3p.
Mutation in the CHMP2B gene can also cause frontotemporal dementia
(FTD3; 600795).
DESCRIPTION
ALS17 is an adult-onset progressive neurodegenerative disorder with
predominantly lower motor neuron involvement, manifest as muscle
weakness and wasting of the upper and lower limbs, bulbar signs, and
respiratory insufficiency (summary by Cox et al., 2010).
CLINICAL FEATURES
Parkinson et al. (2006) reported a 75-year-old man with rapidly
progressive ALS. At age 74 years, the patient developed bulbar-onset
weakness with flaccid dysarthria and tongue fasciculations. He later
developed weakness and wasting of the intrinsic hand muscles and
respiratory weakness. Although he had a previous right leg amputation
from trauma, neurophysiologic testing showed neurogenic changes in all 4
limbs. Deep tendon reflexes were depressed and plantar responses were
flexor. The patient died of respiratory failure 15 months after symptom
onset. There was no evidence of dementia or extramotor neurologic
involvement. A cousin reportedly died of ALS. Neuropathologic
examination showed a predominantly lower motor neuron disease with
intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and
p62/sequestosome (SQSTM1; 601530) within lower motor neurons in the
ventral horn of the spinal cord. Although initial studies showed no
upper motor neuron pathology in the motor cortex, special repeat studies
showed SQSTM1-reactive inclusions within oligodendroglia in the cerebral
motor cortex. A second unrelated patient developed progressive
frontotemporal dementia in his late sixties. After 5 years, he developed
motor disturbances, including atrophy of the tongue and facial muscles,
spastic dysarthria, pseudobulbar paresis, and progressive paresis of the
limbs, consistent with a diagnosis of ALS. He had brisk tendon reflexes
and extensor plantar responses. His father reportedly had motor
disturbances and frontal lobe dysfunction.
Cox et al. (2010) reported 3 unrelated patients with ALS17. All had
symptoms of predominant lower motor neuron degeneration without upper
motor neuron involvement. One man presented at age 54 years with bulbar
and respiratory dysfunction and later developed wasting and
fasciculation in the upper and lower limbs. Reflexes were normal. A
64-year-old woman presented with leg weakness, with later development of
the upper limb, bulbar, and respiratory muscles. Reflexes were normal
and plantar reflexes were flexor. The third patient was a 49-year-old
man who presented with weakness of the legs and had rapid disease
progression with wasting and fasciculations in the upper limbs and
bulbar involvement. None of the patients had dementia. All patients died
of the disorder. Neuropathologic examination of these 3 patients and 1
of the patients reported by Parkinson et al. (2006) showed no evidence
of corticospinal involvement on conventional stains, consistent with the
lack of upper motor neuron clinical signs. However, 1 patient had some
subcortical microglial activation in the precentral gyrus and mild
changes in the medulla. The lower motor neuron pathology was typical of
the primary muscular atrophy variant of ALS. There was severe loss of
motor neurons at all levels of the spinal cord, and surviving neurons
had UBB-/p62-/TDP43 (605078)-positive inclusion bodies. There did not
appear to be extramotor involvement of the CNS. Skein-like inclusion
bodies and Bunina bodies, which are often found in ALS, were notably
absent in these patients.
MOLECULAR GENETICS
In a 75-year-old man with rapidly progressive ALS, Parkinson et al.
(2006) identified a heterozygous mutation in the CHMP2B gene (Q206H;
609512.0003). A second unrelated patient with frontotemporal dementia
and ALS had a different heterozygous mutation (I29V; 609512.0005).
Cox et al. (2010) identified mutations in the CHMP2B gene (see, e.g.,
609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433 patients
with ALS. However, CHMP2B mutations were found in 10% of those with the
lower motor neuron variant of ALS, suggesting an enrichment of mutations
in patients with that specific disease subtype. Microarray analysis of
motor neurons with CHMP2B mutations showed downregulation of genes
involved in axonal transport, autophagy induction, protein translation,
and certain signaling pathways, such as MAPK-related pathways (see,
e.g., 600289). Transfection of mutant CHMP2B into HEK293 and COS-7 cells
resulted in the formation of large cytoplasmic vacuoles, aberrant
lysosomal localization, and impaired autophagy. Cox et al. (2010)
hypothesized that CHMP2B mutations may contribute to motor neuron injury
through dysfunction of the autophagic clearance of cellular proteins.
*FIELD* RF
1. Cox, L. E.; Ferraiuolo, L.; Goodall, E. F.; Heath, P. R.; Higginbottom,
A.; Mortiboys, H.; Hollinger, H. C.; Hartley, J. A.; Brockington,
A.; Burness, C. E.; Morrison, K. E.; Wharton, S. B.; Grierson, A.
J.; Ince, P. G.; Kirby, J.; Shaw, P. J.: Mutations in CHMP2B in lower
motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS
One 5: e9872, 2010. Note: Electronic Article.
2. Parkinson, N.; Ince, P. G.; Smith, M. O.; Highley, R.; Skibinski,
G.; Andersen, P. M.; Morrison, K. E.; Pall, H. S.; Hardiman, O.; Collinge,
J.; Shaw, P. J.; Disher, E. M. C.; MRC Proteomics in ALS Study and
the FReJA Consortium: ALS phenotypes with mutations in CHMP2B (charged
multivesicular body protein 2B). Neurology 67: 1074-1077, 2006.
*FIELD* CS
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Muscle weakness;
Muscle atrophy
NEUROLOGIC:
[Central nervous system];
Muscle weakness;
Muscle atrophy;
Fasciculations;
Lower motor neuron dysfunction involving Upper and lower limbs;
Bulbar signs;
Dysarthria;
Lack of upper motor neuron signs;
Hyporeflexia;
Areflexia;
Flexor plantar responses;
Extensor plantar responses (1 patient);
Brisk reflexes (1 patient);
Frontotemporal dementia (1 patient);
Loss of motor neurons in the spinal cord;
Intraneuronal inclusions;
Lack of skein-like inclusions;
Lack of Bunina bodies
MISCELLANEOUS:
Onset in adulthood;
Rapidly progressive;
Five unrelated patients have been reported (last curated July 2012)
MOLECULAR BASIS:
Caused by mutation in the CHMP FAMILY, member 2B gene (CHMP2B, 609512.0003)
*FIELD* CD
Cassandra L. Kniffin: 7/2/2012
*FIELD* ED
joanna: 07/18/2012
ckniffin: 7/2/2012
*FIELD* CD
Cassandra L. Kniffin: 6/28/2012
*FIELD* ED
carol: 07/10/2012
terry: 7/10/2012
ckniffin: 7/2/2012
*RECORD*
*FIELD* NO
614696
*FIELD* TI
#614696 AMYOTROPHIC LATERAL SCLEROSIS 17; ALS17
;;AMYOTROPHIC LATERAL SCLEROSIS, CHMP2B-RELATED
read more*FIELD* TX
A number sign (#) is used with this entry because amyotrophic lateral
sclerosis-17 (ALS17) is caused by heterozygous mutation in the CHMP2B
gene (609512) on chromosome 3p.
Mutation in the CHMP2B gene can also cause frontotemporal dementia
(FTD3; 600795).
DESCRIPTION
ALS17 is an adult-onset progressive neurodegenerative disorder with
predominantly lower motor neuron involvement, manifest as muscle
weakness and wasting of the upper and lower limbs, bulbar signs, and
respiratory insufficiency (summary by Cox et al., 2010).
CLINICAL FEATURES
Parkinson et al. (2006) reported a 75-year-old man with rapidly
progressive ALS. At age 74 years, the patient developed bulbar-onset
weakness with flaccid dysarthria and tongue fasciculations. He later
developed weakness and wasting of the intrinsic hand muscles and
respiratory weakness. Although he had a previous right leg amputation
from trauma, neurophysiologic testing showed neurogenic changes in all 4
limbs. Deep tendon reflexes were depressed and plantar responses were
flexor. The patient died of respiratory failure 15 months after symptom
onset. There was no evidence of dementia or extramotor neurologic
involvement. A cousin reportedly died of ALS. Neuropathologic
examination showed a predominantly lower motor neuron disease with
intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and
p62/sequestosome (SQSTM1; 601530) within lower motor neurons in the
ventral horn of the spinal cord. Although initial studies showed no
upper motor neuron pathology in the motor cortex, special repeat studies
showed SQSTM1-reactive inclusions within oligodendroglia in the cerebral
motor cortex. A second unrelated patient developed progressive
frontotemporal dementia in his late sixties. After 5 years, he developed
motor disturbances, including atrophy of the tongue and facial muscles,
spastic dysarthria, pseudobulbar paresis, and progressive paresis of the
limbs, consistent with a diagnosis of ALS. He had brisk tendon reflexes
and extensor plantar responses. His father reportedly had motor
disturbances and frontal lobe dysfunction.
Cox et al. (2010) reported 3 unrelated patients with ALS17. All had
symptoms of predominant lower motor neuron degeneration without upper
motor neuron involvement. One man presented at age 54 years with bulbar
and respiratory dysfunction and later developed wasting and
fasciculation in the upper and lower limbs. Reflexes were normal. A
64-year-old woman presented with leg weakness, with later development of
the upper limb, bulbar, and respiratory muscles. Reflexes were normal
and plantar reflexes were flexor. The third patient was a 49-year-old
man who presented with weakness of the legs and had rapid disease
progression with wasting and fasciculations in the upper limbs and
bulbar involvement. None of the patients had dementia. All patients died
of the disorder. Neuropathologic examination of these 3 patients and 1
of the patients reported by Parkinson et al. (2006) showed no evidence
of corticospinal involvement on conventional stains, consistent with the
lack of upper motor neuron clinical signs. However, 1 patient had some
subcortical microglial activation in the precentral gyrus and mild
changes in the medulla. The lower motor neuron pathology was typical of
the primary muscular atrophy variant of ALS. There was severe loss of
motor neurons at all levels of the spinal cord, and surviving neurons
had UBB-/p62-/TDP43 (605078)-positive inclusion bodies. There did not
appear to be extramotor involvement of the CNS. Skein-like inclusion
bodies and Bunina bodies, which are often found in ALS, were notably
absent in these patients.
MOLECULAR GENETICS
In a 75-year-old man with rapidly progressive ALS, Parkinson et al.
(2006) identified a heterozygous mutation in the CHMP2B gene (Q206H;
609512.0003). A second unrelated patient with frontotemporal dementia
and ALS had a different heterozygous mutation (I29V; 609512.0005).
Cox et al. (2010) identified mutations in the CHMP2B gene (see, e.g.,
609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433 patients
with ALS. However, CHMP2B mutations were found in 10% of those with the
lower motor neuron variant of ALS, suggesting an enrichment of mutations
in patients with that specific disease subtype. Microarray analysis of
motor neurons with CHMP2B mutations showed downregulation of genes
involved in axonal transport, autophagy induction, protein translation,
and certain signaling pathways, such as MAPK-related pathways (see,
e.g., 600289). Transfection of mutant CHMP2B into HEK293 and COS-7 cells
resulted in the formation of large cytoplasmic vacuoles, aberrant
lysosomal localization, and impaired autophagy. Cox et al. (2010)
hypothesized that CHMP2B mutations may contribute to motor neuron injury
through dysfunction of the autophagic clearance of cellular proteins.
*FIELD* RF
1. Cox, L. E.; Ferraiuolo, L.; Goodall, E. F.; Heath, P. R.; Higginbottom,
A.; Mortiboys, H.; Hollinger, H. C.; Hartley, J. A.; Brockington,
A.; Burness, C. E.; Morrison, K. E.; Wharton, S. B.; Grierson, A.
J.; Ince, P. G.; Kirby, J.; Shaw, P. J.: Mutations in CHMP2B in lower
motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS
One 5: e9872, 2010. Note: Electronic Article.
2. Parkinson, N.; Ince, P. G.; Smith, M. O.; Highley, R.; Skibinski,
G.; Andersen, P. M.; Morrison, K. E.; Pall, H. S.; Hardiman, O.; Collinge,
J.; Shaw, P. J.; Disher, E. M. C.; MRC Proteomics in ALS Study and
the FReJA Consortium: ALS phenotypes with mutations in CHMP2B (charged
multivesicular body protein 2B). Neurology 67: 1074-1077, 2006.
*FIELD* CS
INHERITANCE:
Autosomal dominant
RESPIRATORY:
Respiratory insufficiency due to muscle weakness
ABDOMEN:
[Gastrointestinal];
Dysphagia
MUSCLE, SOFT TISSUE:
Muscle weakness;
Muscle atrophy
NEUROLOGIC:
[Central nervous system];
Muscle weakness;
Muscle atrophy;
Fasciculations;
Lower motor neuron dysfunction involving Upper and lower limbs;
Bulbar signs;
Dysarthria;
Lack of upper motor neuron signs;
Hyporeflexia;
Areflexia;
Flexor plantar responses;
Extensor plantar responses (1 patient);
Brisk reflexes (1 patient);
Frontotemporal dementia (1 patient);
Loss of motor neurons in the spinal cord;
Intraneuronal inclusions;
Lack of skein-like inclusions;
Lack of Bunina bodies
MISCELLANEOUS:
Onset in adulthood;
Rapidly progressive;
Five unrelated patients have been reported (last curated July 2012)
MOLECULAR BASIS:
Caused by mutation in the CHMP FAMILY, member 2B gene (CHMP2B, 609512.0003)
*FIELD* CD
Cassandra L. Kniffin: 7/2/2012
*FIELD* ED
joanna: 07/18/2012
ckniffin: 7/2/2012
*FIELD* CD
Cassandra L. Kniffin: 6/28/2012
*FIELD* ED
carol: 07/10/2012
terry: 7/10/2012
ckniffin: 7/2/2012