Full text data of CHMP1A
CHMP1A
(CHMP1, KIAA0047, PCOLN3, PRSM1)
[Confidence: low (only semi-automatic identification from reviews)]
Charged multivesicular body protein 1a (Chromatin-modifying protein 1a; CHMP1a; Vacuolar protein sorting-associated protein 46-1; Vps46-1; hVps46-1)
Charged multivesicular body protein 1a (Chromatin-modifying protein 1a; CHMP1a; Vacuolar protein sorting-associated protein 46-1; Vps46-1; hVps46-1)
UniProt
Q9HD42
ID CHM1A_HUMAN Reviewed; 196 AA.
AC Q9HD42; A2RU09; Q14468; Q15779; Q96G31;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Charged multivesicular body protein 1a;
DE AltName: Full=Chromatin-modifying protein 1a;
DE Short=CHMP1a;
DE AltName: Full=Vacuolar protein sorting-associated protein 46-1;
DE Short=Vps46-1;
DE Short=hVps46-1;
GN Name=CHMP1A; Synonyms=CHMP1, KIAA0047, PCOLN3, PRSM1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PRELIMINARY FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Fibroblast, and Placenta;
RX PubMed=8863740; DOI=10.1016/0378-1119(96)00510-0;
RA Scott I.C., Halila R., Jenkins J.M., Mehan S., Apostolou S.,
RA Winqvist R., Callen D.F., Prockop D.J., Peltonen L., Kadler K.E.;
RT "Molecular cloning, expression and chromosomal localization of a human
RT gene encoding a 33 kDa putative metallopeptidase (PRSM1).";
RL Gene 174:135-143(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
RP LOCATION, AND INDUCTION.
RC TISSUE=Placenta;
RX PubMed=11559747;
RA Stauffer D.R., Howard T.L., Nyun T., Hollenberg S.M.;
RT "CHMP1 is a novel nuclear matrix protein affecting chromatin structure
RT and cell-cycle progression.";
RL J. Cell Sci. 114:2383-2393(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Kidney;
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 [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VPS4A.
RX PubMed=11559748;
RA Howard T.L., Stauffer D.R., Degnin C.R., Hollenberg S.M.;
RT "CHMP1 functions as a member of a newly defined family of vesicle
RT trafficking proteins.";
RL J. Cell Sci. 114:2395-2404(2001).
RN [8]
RP INTERACTION WITH CHMP1B; VPS4A AND VPS4B.
RX PubMed=14505570; DOI=10.1016/S0092-8674(03)00714-1;
RA von Schwedler U.K., Stuchell M., Mueller B., Ward D.M., Chung H.-Y.,
RA Morita E., Wang H.E., Davis T., He G.P., Cimbora D.M., Scott A.,
RA Kraeusslich H.-G., Kaplan J., Morham S.G., Sundquist W.I.;
RT "The protein network of HIV budding.";
RL Cell 114:701-713(2003).
RN [9]
RP SELF-ASSOCIATION, AND INTERACTION WITH CHMP1B AND VPS4A.
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 [10]
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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [12]
RP INTERACTION WITH IST1.
RX PubMed=19129480; DOI=10.1091/mbc.E08-05-0474;
RA Agromayor M., Carlton J.G., Phelan J.P., Matthews D.R., Carlin L.M.,
RA Ameer-Beg S., Bowers K., Martin-Serrano J.;
RT "Essential role of hIST1 in cytokinesis.";
RL Mol. Biol. Cell 20:1374-1387(2009).
RN [13]
RP FUNCTION, INTERACTION WITH IST1, AND MUTAGENESIS OF LEU-191 AND
RP LEU-194.
RX PubMed=19129479; DOI=10.1091/mbc.E08-05-0475;
RA Bajorek M., Morita E., Skalicky J.J., Morham S.G., Babst M.,
RA Sundquist W.I.;
RT "Biochemical analyses of human IST1 and its function in cytokinesis.";
RL Mol. Biol. Cell 20:1360-1373(2009).
RN [14]
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 [15]
RP INVOLVEMENT IN PCH8.
RX PubMed=23023333; DOI=10.1038/ng.2425;
RA Mochida G.H., Ganesh V.S., de Michelena M.I., Dias H., Atabay K.D.,
RA Kathrein K.L., Huang H.T., Hill R.S., Felie J.M., Rakiec D.,
RA Gleason D., Hill A.D., Malik A.N., Barry B.J., Partlow J.N., Tan W.H.,
RA Glader L.J., Barkovich A.J., Dobyns W.B., Zon L.I., Walsh C.A.;
RT "CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar
RT development.";
RL Nat. Genet. 44:1260-1264(2012).
RN [16]
RP STRUCTURE BY NMR OF 180-196 IN COMPLEX 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 [17]
RP X-RAY CRYSTALLOGRAPHY (1.91 ANGSTROMS) OF 184-196 IN COMPLEX WITH
RP MITD1, FUNCTION, AND INTERACTION WITH MITD1.
RX PubMed=23045692; DOI=10.1073/pnas.1206839109;
RA Hadders M.A., Agromayor M., Obita T., Perisic O., Caballe A., Kloc M.,
RA Lamers M.H., Williams R.L., Martin-Serrano J.;
RT "ESCRT-III binding protein MITD1 is involved in cytokinesis and has an
RT unanticipated PLD fold that binds membranes.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:17424-17429(2012).
CC -!- FUNCTION: Probable peripherally associated component of the
CC endosomal sorting required for transport complex III (ESCRT-III)
CC which is involved in multivesicular bodies (MVBs) formation and
CC sorting of endosomal cargo proteins into MVBs. MVBs contain
CC intraluminal vesicles (ILVs) that are generated by invagination
CC and scission from the limiting membrane of the endosome and mostly
CC are delivered to lysosomes enabling degradation of membrane
CC proteins, such as stimulated growth factor receptors, lysosomal
CC enzymes and lipids. The MVB pathway appears to require the
CC sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-
CC III proteins mostly dissociate from the invaginating membrane
CC before the ILV is released. The ESCRT machinery also functions in
CC topologically equivalent membrane fission events, such as the
CC terminal stages of cytokinesis and the budding of enveloped
CC viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are
CC believed to mediate the necessary vesicle extrusion and/or
CC membrane fission activities, possibly in conjunction with the AAA
CC ATPase VPS4. Involved in cytokinesis. Involved in recruiting VPS4A
CC and/or VPS4B to the midbody of dividing cells. May also be
CC involved in chromosome condensation. Targets the Polycomb group
CC (PcG) protein BMI1/PCGF4 to regions of condensed chromatin. May
CC play a role in stable cell cycle progression and in PcG gene
CC silencing.
CC -!- SUBUNIT: Probable peripherally associated component of the
CC endosomal sorting required for transport complex III (ESCRT-III).
CC ESCRT-III components are thought to multimerize to form a flat
CC lattice on the perimeter membrane of the endosome. Several
CC assembly forms of ESCRT-III may exist that interact and act
CC sequentally. Self-associates. Interacts with CHMP1B. Interacts
CC with VPS4A. Interacts with VPS4B. Interacts with PHF1. Interacts
CC with IST1. Interacts with MITD1.
CC -!- INTERACTION:
CC O95630:STAMBP; NbExp=3; IntAct=EBI-1057156, EBI-396676;
CC P40818:USP8; NbExp=3; IntAct=EBI-1057156, EBI-1050865;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Endosome membrane; Peripheral
CC membrane protein. Nucleus matrix. Note=The cytoplasmic form is
CC partially membrane-associated and localizes to early endosomes.
CC The nuclear form remains associated with the chromosome scaffold
CC during mitosis. On overexpression, it localizes to nuclear bodies
CC characterized by nuclease-resistant condensed chromatin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9HD42-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9HD42-2; Sequence=VSP_051716;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in placenta, cultured skin
CC fibroblasts and in osteoblast cell line MG-63.
CC -!- INDUCTION: By muristerone.
CC -!- DISEASE: Pontocerebellar hypoplasia 8 (PCH8) [MIM:614961]: An
CC autosomal recessive neurodevelopmental disorder characterized by
CC severe psychomotor retardation, abnormal movements, hypotonia,
CC spasticity, and variable visual defects. Brain MRI shows
CC pontocerebellar hypoplasia, decreased cerebral white matter, and a
CC thin corpus callosum. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SNF7 family.
CC -!- CAUTION: Was originally (PubMed:8863740) thought to be a
CC metalloprotease (PRSM1). This was based on a wrong translation of
CC the ORF which gave rise to a putative protein of 318 AA containing
CC a pattern reminiscent of zinc metalloproteases.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC50775.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=BAA07557.1; Type=Erroneous translation; Note=Wrong choice of frame;
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DR EMBL; U58048; AAC50775.1; ALT_SEQ; mRNA.
DR EMBL; AF281063; AAG01448.1; -; mRNA.
DR EMBL; D38554; BAA07557.1; ALT_SEQ; mRNA.
DR EMBL; BT006841; AAP35487.1; -; mRNA.
DR EMBL; AC010538; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007527; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC010000; AAH10000.2; -; mRNA.
DR EMBL; BC132711; AAI32712.1; -; mRNA.
DR EMBL; BC132713; AAI32714.1; -; mRNA.
DR PIR; JC4963; JC4963.
DR RefSeq; NP_002759.2; NM_002768.4.
DR UniGene; Hs.589427; -.
DR PDB; 2JQ9; NMR; -; B=180-196.
DR PDB; 2YMB; X-ray; 3.40 A; F/H=184-196.
DR PDB; 4A5X; X-ray; 1.91 A; C/D=184-196.
DR PDBsum; 2JQ9; -.
DR PDBsum; 2YMB; -.
DR PDBsum; 4A5X; -.
DR ProteinModelPortal; Q9HD42; -.
DR DIP; DIP-50647N; -.
DR IntAct; Q9HD42; 4.
DR MINT; MINT-6946738; -.
DR STRING; 9606.ENSP00000253475; -.
DR PhosphoSite; Q9HD42; -.
DR DMDM; 62510514; -.
DR PaxDb; Q9HD42; -.
DR PRIDE; Q9HD42; -.
DR DNASU; 5119; -.
DR Ensembl; ENST00000397901; ENSP00000380998; ENSG00000131165.
DR GeneID; 5119; -.
DR KEGG; hsa:5119; -.
DR UCSC; uc002fnu.4; human.
DR CTD; 5119; -.
DR GeneCards; GC16M089710; -.
DR H-InvDB; HIX0013363; -.
DR HGNC; HGNC:8740; CHMP1A.
DR MIM; 164010; gene.
DR MIM; 614961; phenotype.
DR neXtProt; NX_Q9HD42; -.
DR Orphanet; 324569; Pontocerebellar hypoplasia type 8.
DR PharmGKB; PA33085; -.
DR eggNOG; NOG331649; -.
DR HOGENOM; HOG000241980; -.
DR HOVERGEN; HBG080200; -.
DR OrthoDB; EOG7BP843; -.
DR ChiTaRS; CHMP1A; human.
DR EvolutionaryTrace; Q9HD42; -.
DR GeneWiki; CHMP1A; -.
DR GenomeRNAi; 5119; -.
DR NextBio; 19738; -.
DR PRO; PR:Q9HD42; -.
DR ArrayExpress; Q9HD42; -.
DR Bgee; Q9HD42; -.
DR CleanEx; HS_CHMP1A; -.
DR Genevestigator; Q9HD42; -.
DR GO; GO:0000794; C:condensed nuclear chromosome; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005815; C:microtubule organizing center; IDA:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; TAS:ProtInc.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0016458; P:gene silencing; IDA:UniProtKB.
DR GO; GO:0007076; P:mitotic chromosome condensation; IDA:UniProtKB.
DR GO; GO:0045014; P:negative regulation of transcription by glucose; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0016192; P:vesicle-mediated transport; IDA:UniProtKB.
DR InterPro; IPR005024; Snf7.
DR Pfam; PF03357; Snf7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Cell division; Coiled coil; Complete proteome; Cytoplasm; Endosome;
KW Membrane; Nucleus; Protein transport; Reference proteome; Repressor;
KW Transcription; Transcription regulation; Transport.
FT CHAIN 1 196 Charged multivesicular body protein 1a.
FT /FTId=PRO_0000211448.
FT COILED 5 47 Potential.
FT COILED 102 124 Potential.
FT MOTIF 185 195 MIT-interacting motif.
FT MOD_RES 1 1 N-acetylmethionine.
FT VAR_SEQ 1 128 Missing (in isoform 2).
FT /FTId=VSP_051716.
FT MUTAGEN 191 191 L->A: No effect on interaction with IST1;
FT when associated with L-194.
FT MUTAGEN 194 194 L->A: No effect on interaction with IST1;
FT when associated with L-194.
FT CONFLICT 77 77 Q -> D (in Ref. 1; AAC50775).
FT HELIX 184 195
SQ SEQUENCE 196 AA; 21703 MW; 85D0ED7D10828D60 CRC64;
MDDTLFQLKF TAKQLEKLAK KAEKDSKAEQ AKVKKALLQK NVECARVYAE NAIRKKNEGV
NWLRMASRVD AVASKVQTAV TMKGVTKNMA QVTKALDKAL STMDLQKVSS VMDRFEQQVQ
NLDVHTSVME DSMSSATTLT TPQEQVDSLI MQIAEENGLE VLDQLSQLPE GASAVGESSV
RSQEDQLSRR LAALRN
//
ID CHM1A_HUMAN Reviewed; 196 AA.
AC Q9HD42; A2RU09; Q14468; Q15779; Q96G31;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 103.
DE RecName: Full=Charged multivesicular body protein 1a;
DE AltName: Full=Chromatin-modifying protein 1a;
DE Short=CHMP1a;
DE AltName: Full=Vacuolar protein sorting-associated protein 46-1;
DE Short=Vps46-1;
DE Short=hVps46-1;
GN Name=CHMP1A; Synonyms=CHMP1, KIAA0047, PCOLN3, PRSM1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], PRELIMINARY FUNCTION, AND TISSUE
RP SPECIFICITY.
RC TISSUE=Fibroblast, and Placenta;
RX PubMed=8863740; DOI=10.1016/0378-1119(96)00510-0;
RA Scott I.C., Halila R., Jenkins J.M., Mehan S., Apostolou S.,
RA Winqvist R., Callen D.F., Prockop D.J., Peltonen L., Kadler K.E.;
RT "Molecular cloning, expression and chromosomal localization of a human
RT gene encoding a 33 kDa putative metallopeptidase (PRSM1).";
RL Gene 174:135-143(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR
RP LOCATION, AND INDUCTION.
RC TISSUE=Placenta;
RX PubMed=11559747;
RA Stauffer D.R., Howard T.L., Nyun T., Hollenberg S.M.;
RT "CHMP1 is a novel nuclear matrix protein affecting chromatin structure
RT and cell-cycle progression.";
RL J. Cell Sci. 114:2383-2393(2001).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Bone marrow;
RX PubMed=7584044; DOI=10.1093/dnares/1.5.223;
RA Nomura N., Nagase T., Miyajima N., Sazuka T., Tanaka A., Sato S.,
RA Seki N., Kawarabayasi Y., Ishikawa K., Tabata S.;
RT "Prediction of the coding sequences of unidentified human genes. II.
RT The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by
RT analysis of cDNA clones from human cell line KG-1.";
RL DNA Res. 1:223-229(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15616553; DOI=10.1038/nature03187;
RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X.,
RA Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A.,
RA Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J.,
RA Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L.,
RA Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A.,
RA Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D.,
RA Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J.,
RA Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M.,
RA Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I.,
RA Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W.,
RA Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A.,
RA Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S.,
RA Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J.,
RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D.,
RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L.,
RA Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A.,
RA Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L.,
RA Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N.,
RA Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M.,
RA Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L.,
RA Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D.,
RA Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P.,
RA Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M.,
RA Rubin E.M., Pennacchio L.A.;
RT "The sequence and analysis of duplication-rich human chromosome 16.";
RL Nature 432:988-994(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Kidney;
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 [7]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH VPS4A.
RX PubMed=11559748;
RA Howard T.L., Stauffer D.R., Degnin C.R., Hollenberg S.M.;
RT "CHMP1 functions as a member of a newly defined family of vesicle
RT trafficking proteins.";
RL J. Cell Sci. 114:2395-2404(2001).
RN [8]
RP INTERACTION WITH CHMP1B; VPS4A AND VPS4B.
RX PubMed=14505570; DOI=10.1016/S0092-8674(03)00714-1;
RA von Schwedler U.K., Stuchell M., Mueller B., Ward D.M., Chung H.-Y.,
RA Morita E., Wang H.E., Davis T., He G.P., Cimbora D.M., Scott A.,
RA Kraeusslich H.-G., Kaplan J., Morham S.G., Sundquist W.I.;
RT "The protein network of HIV budding.";
RL Cell 114:701-713(2003).
RN [9]
RP SELF-ASSOCIATION, AND INTERACTION WITH CHMP1B AND VPS4A.
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 [10]
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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [12]
RP INTERACTION WITH IST1.
RX PubMed=19129480; DOI=10.1091/mbc.E08-05-0474;
RA Agromayor M., Carlton J.G., Phelan J.P., Matthews D.R., Carlin L.M.,
RA Ameer-Beg S., Bowers K., Martin-Serrano J.;
RT "Essential role of hIST1 in cytokinesis.";
RL Mol. Biol. Cell 20:1374-1387(2009).
RN [13]
RP FUNCTION, INTERACTION WITH IST1, AND MUTAGENESIS OF LEU-191 AND
RP LEU-194.
RX PubMed=19129479; DOI=10.1091/mbc.E08-05-0475;
RA Bajorek M., Morita E., Skalicky J.J., Morham S.G., Babst M.,
RA Sundquist W.I.;
RT "Biochemical analyses of human IST1 and its function in cytokinesis.";
RL Mol. Biol. Cell 20:1360-1373(2009).
RN [14]
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 [15]
RP INVOLVEMENT IN PCH8.
RX PubMed=23023333; DOI=10.1038/ng.2425;
RA Mochida G.H., Ganesh V.S., de Michelena M.I., Dias H., Atabay K.D.,
RA Kathrein K.L., Huang H.T., Hill R.S., Felie J.M., Rakiec D.,
RA Gleason D., Hill A.D., Malik A.N., Barry B.J., Partlow J.N., Tan W.H.,
RA Glader L.J., Barkovich A.J., Dobyns W.B., Zon L.I., Walsh C.A.;
RT "CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar
RT development.";
RL Nat. Genet. 44:1260-1264(2012).
RN [16]
RP STRUCTURE BY NMR OF 180-196 IN COMPLEX 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 [17]
RP X-RAY CRYSTALLOGRAPHY (1.91 ANGSTROMS) OF 184-196 IN COMPLEX WITH
RP MITD1, FUNCTION, AND INTERACTION WITH MITD1.
RX PubMed=23045692; DOI=10.1073/pnas.1206839109;
RA Hadders M.A., Agromayor M., Obita T., Perisic O., Caballe A., Kloc M.,
RA Lamers M.H., Williams R.L., Martin-Serrano J.;
RT "ESCRT-III binding protein MITD1 is involved in cytokinesis and has an
RT unanticipated PLD fold that binds membranes.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:17424-17429(2012).
CC -!- FUNCTION: Probable peripherally associated component of the
CC endosomal sorting required for transport complex III (ESCRT-III)
CC which is involved in multivesicular bodies (MVBs) formation and
CC sorting of endosomal cargo proteins into MVBs. MVBs contain
CC intraluminal vesicles (ILVs) that are generated by invagination
CC and scission from the limiting membrane of the endosome and mostly
CC are delivered to lysosomes enabling degradation of membrane
CC proteins, such as stimulated growth factor receptors, lysosomal
CC enzymes and lipids. The MVB pathway appears to require the
CC sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-
CC III proteins mostly dissociate from the invaginating membrane
CC before the ILV is released. The ESCRT machinery also functions in
CC topologically equivalent membrane fission events, such as the
CC terminal stages of cytokinesis and the budding of enveloped
CC viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are
CC believed to mediate the necessary vesicle extrusion and/or
CC membrane fission activities, possibly in conjunction with the AAA
CC ATPase VPS4. Involved in cytokinesis. Involved in recruiting VPS4A
CC and/or VPS4B to the midbody of dividing cells. May also be
CC involved in chromosome condensation. Targets the Polycomb group
CC (PcG) protein BMI1/PCGF4 to regions of condensed chromatin. May
CC play a role in stable cell cycle progression and in PcG gene
CC silencing.
CC -!- SUBUNIT: Probable peripherally associated component of the
CC endosomal sorting required for transport complex III (ESCRT-III).
CC ESCRT-III components are thought to multimerize to form a flat
CC lattice on the perimeter membrane of the endosome. Several
CC assembly forms of ESCRT-III may exist that interact and act
CC sequentally. Self-associates. Interacts with CHMP1B. Interacts
CC with VPS4A. Interacts with VPS4B. Interacts with PHF1. Interacts
CC with IST1. Interacts with MITD1.
CC -!- INTERACTION:
CC O95630:STAMBP; NbExp=3; IntAct=EBI-1057156, EBI-396676;
CC P40818:USP8; NbExp=3; IntAct=EBI-1057156, EBI-1050865;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Endosome membrane; Peripheral
CC membrane protein. Nucleus matrix. Note=The cytoplasmic form is
CC partially membrane-associated and localizes to early endosomes.
CC The nuclear form remains associated with the chromosome scaffold
CC during mitosis. On overexpression, it localizes to nuclear bodies
CC characterized by nuclease-resistant condensed chromatin.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9HD42-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9HD42-2; Sequence=VSP_051716;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in placenta, cultured skin
CC fibroblasts and in osteoblast cell line MG-63.
CC -!- INDUCTION: By muristerone.
CC -!- DISEASE: Pontocerebellar hypoplasia 8 (PCH8) [MIM:614961]: An
CC autosomal recessive neurodevelopmental disorder characterized by
CC severe psychomotor retardation, abnormal movements, hypotonia,
CC spasticity, and variable visual defects. Brain MRI shows
CC pontocerebellar hypoplasia, decreased cerebral white matter, and a
CC thin corpus callosum. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the SNF7 family.
CC -!- CAUTION: Was originally (PubMed:8863740) thought to be a
CC metalloprotease (PRSM1). This was based on a wrong translation of
CC the ORF which gave rise to a putative protein of 318 AA containing
CC a pattern reminiscent of zinc metalloproteases.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC50775.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC Sequence=BAA07557.1; Type=Erroneous translation; Note=Wrong choice of frame;
CC -----------------------------------------------------------------------
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DR EMBL; U58048; AAC50775.1; ALT_SEQ; mRNA.
DR EMBL; AF281063; AAG01448.1; -; mRNA.
DR EMBL; D38554; BAA07557.1; ALT_SEQ; mRNA.
DR EMBL; BT006841; AAP35487.1; -; mRNA.
DR EMBL; AC010538; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC007527; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; BC010000; AAH10000.2; -; mRNA.
DR EMBL; BC132711; AAI32712.1; -; mRNA.
DR EMBL; BC132713; AAI32714.1; -; mRNA.
DR PIR; JC4963; JC4963.
DR RefSeq; NP_002759.2; NM_002768.4.
DR UniGene; Hs.589427; -.
DR PDB; 2JQ9; NMR; -; B=180-196.
DR PDB; 2YMB; X-ray; 3.40 A; F/H=184-196.
DR PDB; 4A5X; X-ray; 1.91 A; C/D=184-196.
DR PDBsum; 2JQ9; -.
DR PDBsum; 2YMB; -.
DR PDBsum; 4A5X; -.
DR ProteinModelPortal; Q9HD42; -.
DR DIP; DIP-50647N; -.
DR IntAct; Q9HD42; 4.
DR MINT; MINT-6946738; -.
DR STRING; 9606.ENSP00000253475; -.
DR PhosphoSite; Q9HD42; -.
DR DMDM; 62510514; -.
DR PaxDb; Q9HD42; -.
DR PRIDE; Q9HD42; -.
DR DNASU; 5119; -.
DR Ensembl; ENST00000397901; ENSP00000380998; ENSG00000131165.
DR GeneID; 5119; -.
DR KEGG; hsa:5119; -.
DR UCSC; uc002fnu.4; human.
DR CTD; 5119; -.
DR GeneCards; GC16M089710; -.
DR H-InvDB; HIX0013363; -.
DR HGNC; HGNC:8740; CHMP1A.
DR MIM; 164010; gene.
DR MIM; 614961; phenotype.
DR neXtProt; NX_Q9HD42; -.
DR Orphanet; 324569; Pontocerebellar hypoplasia type 8.
DR PharmGKB; PA33085; -.
DR eggNOG; NOG331649; -.
DR HOGENOM; HOG000241980; -.
DR HOVERGEN; HBG080200; -.
DR OrthoDB; EOG7BP843; -.
DR ChiTaRS; CHMP1A; human.
DR EvolutionaryTrace; Q9HD42; -.
DR GeneWiki; CHMP1A; -.
DR GenomeRNAi; 5119; -.
DR NextBio; 19738; -.
DR PRO; PR:Q9HD42; -.
DR ArrayExpress; Q9HD42; -.
DR Bgee; Q9HD42; -.
DR CleanEx; HS_CHMP1A; -.
DR Genevestigator; Q9HD42; -.
DR GO; GO:0000794; C:condensed nuclear chromosome; IDA:UniProtKB.
DR GO; GO:0005769; C:early endosome; IDA:UniProtKB.
DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB.
DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005815; C:microtubule organizing center; IDA:UniProtKB.
DR GO; GO:0016363; C:nuclear matrix; IDA:UniProtKB.
DR GO; GO:0008237; F:metallopeptidase activity; TAS:ProtInc.
DR GO; GO:0008270; F:zinc ion binding; TAS:ProtInc.
DR GO; GO:0000910; P:cytokinesis; IMP:UniProtKB.
DR GO; GO:0016458; P:gene silencing; IDA:UniProtKB.
DR GO; GO:0007076; P:mitotic chromosome condensation; IDA:UniProtKB.
DR GO; GO:0045014; P:negative regulation of transcription by glucose; IDA:UniProtKB.
DR GO; GO:0015031; P:protein transport; IEA:UniProtKB-KW.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR GO; GO:0016192; P:vesicle-mediated transport; IDA:UniProtKB.
DR InterPro; IPR005024; Snf7.
DR Pfam; PF03357; Snf7; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Cell cycle;
KW Cell division; Coiled coil; Complete proteome; Cytoplasm; Endosome;
KW Membrane; Nucleus; Protein transport; Reference proteome; Repressor;
KW Transcription; Transcription regulation; Transport.
FT CHAIN 1 196 Charged multivesicular body protein 1a.
FT /FTId=PRO_0000211448.
FT COILED 5 47 Potential.
FT COILED 102 124 Potential.
FT MOTIF 185 195 MIT-interacting motif.
FT MOD_RES 1 1 N-acetylmethionine.
FT VAR_SEQ 1 128 Missing (in isoform 2).
FT /FTId=VSP_051716.
FT MUTAGEN 191 191 L->A: No effect on interaction with IST1;
FT when associated with L-194.
FT MUTAGEN 194 194 L->A: No effect on interaction with IST1;
FT when associated with L-194.
FT CONFLICT 77 77 Q -> D (in Ref. 1; AAC50775).
FT HELIX 184 195
SQ SEQUENCE 196 AA; 21703 MW; 85D0ED7D10828D60 CRC64;
MDDTLFQLKF TAKQLEKLAK KAEKDSKAEQ AKVKKALLQK NVECARVYAE NAIRKKNEGV
NWLRMASRVD AVASKVQTAV TMKGVTKNMA QVTKALDKAL STMDLQKVSS VMDRFEQQVQ
NLDVHTSVME DSMSSATTLT TPQEQVDSLI MQIAEENGLE VLDQLSQLPE GASAVGESSV
RSQEDQLSRR LAALRN
//
MIM
164010
*RECORD*
*FIELD* NO
164010
*FIELD* TI
*164010 CHMP FAMILY, MEMBER 1A; CHMP1A
;;CHROMATIN-MODIFYING PROTEIN 1A;;
CHARGED MULTIVESICULAR BODY PROTEIN 1A;;
read moreCHMP1;;
PROCOLLAGEN, TYPE III, N-ENDOPEPTIDASE; PCOLN3;;
METALLOPROTEASE 1; PRSM1;;
METALLOPROTEASE, 33-KD
*FIELD* TX
DESCRIPTION
CHMP1A 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, including CHMP1A,
have both nuclear and cytoplasmic/vesicular distributions, and CHMP1A is
required for both MVB formation and regulation of cell cycle progression
(Tsang et al., 2006).
CLONING
Halila et al. (1989) isolated a cDNA for PCOLN3 from a human placenta
cDNA library. By screening a human placenta cDNA library with polyclonal
antibodies raised against human PCOLN3 and using 5-prime RACE and primer
extension strategies on the isolated cDNAs, Scott et al. (1996) cloned
PCOLN3, which they called PRSM1. PRSM1 belongs to the gluzincin
subfamily of metallopeptidases. The zincin superfamily comprises
metallopeptidases that contain an HEXXH zinc-binding consensus sequence,
and gluzincins have glutamic acid as a third zinc ligand. The
full-length sequence of PRSM1 encodes a deduced 318-amino acid protein
with an HELGH pentapeptide fitting the consensus sequence characteristic
of zincins, and a glutamic acid 25 residues C-terminal of the first
histidine, fitting the pattern of gluzincins for a third zinc-binding
ligand. PRSM1 contains 3 clusters of cysteine residues: 1 cluster of 4
residues and 1 cluster of 6 residues at the N terminus, and a cluster of
6 residues at the C terminus. However, the predicted sequence lacks
potential glycosylation sites. Immunoblot analysis of placenta revealed
an approximately 30-kD protein. Northern blot analysis of human
fibroblast culture mRNA detected a transcript of approximately 2.5 kb.
By Northern blot analysis, Nomura et al. (1994) found that PRSM1, which
they designated KIAA0047, was expressed ubiquitously, with highest
levels in lung and kidney and in HeLa and KG-1 cell lines.
By yeast 2-hybrid screening of a mouse embryo cDNA library using the
mouse Polycomb group (PcG) protein Pcl1 (PHF1; 602881) as bait, followed
by RT-PCR of human placenta RNA, Stauffer et al. (2001) cloned a variant
of PRSM1 that they called CHMP1. CHMP1 uses an alternative reading frame
distinct from that of PRSM1. The deduced 196-amino acid CHMP1 protein
contains an N-terminal nuclear localization signal. CHMP1 is most
closely related to CHMP1B (606486) and BC2 (CHMP2A; 610893), and more
distantly related to S. cerevisiae proteins involved in vesicle
trafficking. Western blot analysis of HEK293 human embryonic kidney
cells showed a doublet of 32- and 35-kD CHMP1 proteins. Subcellular
fractionation of HEK293 cells and several other human cell lines
revealed that the 35-kD protein was exclusively nuclear, whereas the
32-kD protein was predominantly cytoplasmic, with a detectable level
present in the nuclear fraction. Analysis of mouse whole tissue extracts
showed that both Chmp1 proteins were widely expressed, with increased
levels of the 35-kD form in heart, kidney, and liver.
Mochida et al. (2012) found that the subcellular localization of CHMP1A
appears to vary depending on cell type. In mouse embryonic 3T3 cells,
Chmp1a was excluded from the nucleus where Bmi1 (164831) was detected.
In human HEK 293T cells, CHMP1A showed prominent cytoplasmic and some
nuclear immunoreactivity. Primary cultures of cerebellar granule cells
from mice showed predominantly cytoplasmic localization of Chmp1a along
with a speckled nuclear pattern. Chmp1a and Bmi1 did not prominently
colocalize within the nucleus. In the developing mouse cerebellum and
cortex, variable expression of Chmp1a was seen in the cytoplasm and
nucleus of dividing and postmitotic cells, including Purkinje, granule,
and neuroepithelial cells. These findings, combined with other data (see
MOLECULAR GENETICS and ANIMAL MODEL), suggested that CHMP1A is an
essential central nervous system regulator of BMI1, which is a key
regulator of stem cell self-renewal.
GENE FUNCTION
By Western blot analysis of synchronized HEK293 cells, Stauffer et al.
(2001) showed that the ratio of cytoplasmic to nuclear CHMP1 was largely
invariant throughout interphase. In mitotic cells, nuclear CHMP1
localized to the chromosome scaffold fraction. Immunocytochemical
analysis detected CHMP1 in a punctate arrangement on condensed
chromosomes during telophase. The cytoplasmic CHMP1 form exhibited a
perinuclear localization. Overexpression of CHMP1 altered the cell
cycle, producing an increase in the number of cells in late S phase.
Overexpression of CHMP1 also resulted in altered chromatin structure,
with modified histones at the periphery of nuclear bodies, and
nuclease-resistant condensed chromatin within. CHMP1 recruited the PcG
protein BMI1 to these regions of condensed chromatin, and it cooperated
with coexpressed Pcl in a Xenopus embryo PcG assay. Stauffer et al.
(2001) concluded that CHMP1 plays a role in stable gene silencing within
the nucleus.
Howard et al. (2001) found that the cytoplasmic form of CHMP1 localized
in a punctate asymmetrical pattern centered over the microtubule
organizing center and colocalized with an early endosomal marker.
Differential extraction showed that cytoplasmic CHMP1 associated with
membranes through ionic interactions. Yeast 2-hybrid screening and in
vitro binding assays demonstrated that cytoplasmic CHMP1 interacted with
SKD1 (VPS4B; 609983). Overexpression of CHMP1 dilated endosomal
compartments and disrupted the normal distribution of several endosomal
markers. Deletion of S. cerevisiae Chm1, the homolog of CHMP1, resulted
in defective sorting of carboxypeptidases S and Y and production of
abnormal, multilamellar prevacuolar compartments. Howard et al. (2001)
concluded that CHMP1 is involved in vesicle trafficking.
Tsang et al. (2006) performed a systematic yeast 2-hybrid analysis of
human ESCRT-III components, including CHMP1A. Like most CHMPs, CHMP1A
interacted with VPS4A (609982). CHMP1A also interacted with the SUMO
(see SUMO1; 601912)-conjugating enzyme UBE2I (601661) and appeared to be
part of a network connecting CHMP1A, CHMP4B (610897), and CHMP5 (610900)
with UBE2I, SUMO1, PIAS2 (603567), and HIPK2 (606868), all of which are
involved in nuclear sumoylation processes.
GENE STRUCTURE
Scott et al. (1996) found that the first exon of the PRSM1 gene is 72%
GC rich, contains 34 CpG dinucleotides, and appears to lie within a CpG
island.
MAPPING
By analysis of somatic cell hybrids, Halila et al. (1992) mapped the
CHMP1 gene to the telomeric region of the long arm of chromosome 16. By
the same method, Scott et al. (1996) mapped the CHMP1 gene to chromosome
16q24.3.
MOLECULAR GENETICS
By linkage analysis followed by candidate gene sequencing in families
with autosomal recessive pontocerebellar hypoplasia type 8 (PCH8;
614961), Mochida et al. (2012) identified 2 different homozygous
mutations in the CHMP1A gene (164010.0001 and 164010.0002). The
phenotype was characterized by severe psychomotor retardation, abnormal
movements, hypotonia, spasticity, and variable visual defects. Brain MRI
showed pontocerebellar hypoplasia with relative preservation of the
cerebellar folia, decreased cerebral white matter, and a thin corpus
callosum. Patient-derived cell lines showed severely impaired doubling
times compared to control, suggesting a defect in cell proliferation.
Quantitative PCR analysis of patient cells showed abnormally high
expression of the BMI1 target INK4A (see CDKN2A, 600160) and decreased
BMI1 binding to the INK4A promoter compared to control, suggesting
derepression of this CDKN2A isoform. INK4A is a negative regulator of
stem cell proliferation. Binding of BMI1 to the ARF promoter was
unaffected. Mochida et al. (2012) noted the parallels in brain
morphology between individuals with CHMP1A mutations and Bmi1-deficient
mice, which show cerebellar hypoplasia. The findings suggested that
CHMP1A serves as a link between cytoplasmic signals and BMI1-mediated
chromatin modification that regulates proliferation of central nervous
system progenitor cells.
ANIMAL MODEL
Mochida et al. (2012) found that morpholino-based knockdown of Chmp1a in
zebrafish resulted in reduced cerebellar and forebrain volume compared
to control that could be partially rescued by expression of wildtype
Chmp1a. The phenotype of these zebrafish resembled that seen in those
after Bmi1 knockdown, supporting a link between Chmp1a and Bmi1. In
Chmp1a knockdown models, the internal granule and molecular layers were
more severely affected than the Purkinje cells, which was consistent
with the relatively preserved folia observed in humans with CHMP1A
mutations.
*FIELD* AV
.0001
PONTOCEREBELLAR HYPOPLASIA, TYPE 8
CHMP1A, GLN30TER
In affected members of 2 Puerto Rican families with pontocerebellar
hypoplasia type 8 (PCH8; 614961), Mochida et al. (2012) identified a
homozygous 88C-T transition in exon 3 of the CHMP1A gene, resulting in a
gln30-to-ter (Q30X) substitution. The mutation was found by linkage
analysis followed by candidate gene sequencing. Haplotype analysis
indicated a founder effect. No CHMP1A protein was found in
patient-derived cells. Patient-derived cell lines showed severely
impaired doubling times compared to control, suggesting a defect in cell
proliferation. There was also increased expression of INK4A (see CDKN2A;
600160), a negative regulator of stem cell proliferation.
.0002
PONTOCEREBELLAR HYPOPLASIA, TYPE 8
CHMP1A, IVS2AS, G-A, -13
In 3 members of a consanguineous family of Peruvian origin with PCH8
(614961), Mochida et al. (2012) identified a homozygous G-to-A
transition in intron 2 of the CHMP1A gene, creating an aberrant splice
acceptor site leading to an 11-bp insertion in the spliced mRNA product.
The mutation was not seen in 281 normal control samples or in several
large control databases. No normal CHMP1A mRNA transcript or protein was
found in patient-derived cells. Patient-derived cell lines showed
severely impaired doubling times compared to control, suggesting a
defect in cell proliferation. There was also increased expression of
INK4A (see CDKN2A, 600160), a negative regulator of stem cell
proliferation.
*FIELD* RF
1. Halila, R.; Apostolou, S.; Winqvist, R.; Callen, D.; Prockop, D.
J.; Peltonen, L.: Isolation and genomic assignment of a candidate
cDNA clone for type III procollagen N-proteinase. (Abstract) Am.
J. Hum. Genet. 51 (suppl.): A128 only, 1992.
2. Halila, R.; Peltonen, L.; Prockop, D. J.: Isolation of a candidate
cDNA clone for type III procollagen N-proteinase from human placental
cDNA library. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A192 only,
1989.
3. Howard, T. L.; Stauffer, D. R.; Degnin, C. R.; Hollenberg, S. M.
: CHMP1 functions as a member of a newly defined family of vesicle
trafficking proteins. J. Cell Sci. 114: 2395-2404, 2001.
4. Mochida, G. H.; Ganesh, V. S.; de Michelena, M. I.; Dias, H.; Atabay,
K. D.; Kathrein, K. L.; Huang, H.-T.; Hill, R. S.; Felie, J. M.; Rakiec,
D.; Gleason, D.; Hill, A. D.; and 9 others: CHMP1A encodes an essential
regulator of BMI1-INK4A in cerebellar development. Nature Genet. 44:
1260-1264, 2012.
5. Nomura, N.; Nagase, T.; Miyajima, N.; Sazuka, T.; Tanaka, A.; Sato,
S.; Seki, N.; Kawarabayasi, Y.; Ishikawa, K.; Tabata, S.: Prediction
of the coding sequences of unidentified human genes. II. The coding
sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994.
6. Scott, I. C.; Halila, R.; Jenkins, J. M.; Mehan, S.; Apostolou,
S.; Winqvist, R.; Callen, D. F.; Prockop, D. J.; Peltonen, L.; Kadler,
K. E.: Molecular cloning, expression and chromosomal localization
of a human gene encoding a 33 kDa putative metallopeptidase (PRSM1). Gene 174:
135-143, 1996.
7. Stauffer, D. R.; Howard, T. L.; Nyun, T.; Hollenberg, S. M.: CHMP1
is a novel nuclear matrix protein affecting chromatin structure and
cell-cycle progression. J. Cell Sci. 114: 2383-2393, 2001.
8. 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.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2012
Victor A. McKusick - updated: 3/1/2000
Paul J. Converse - updated: 1/18/2000
Victor A. McKusick - updated: 1/11/2000
*FIELD* CD
Victor A. McKusick: 11/6/1989
*FIELD* ED
terry: 12/06/2012
carol: 12/5/2012
ckniffin: 12/5/2012
ckniffin: 12/4/2012
mgross: 3/29/2007
mgross: 3/28/2007
mgross: 3/27/2007
carol: 8/4/2000
carol: 3/15/2000
carol: 3/2/2000
terry: 3/1/2000
mgross: 2/4/2000
terry: 1/11/2000
carol: 1/3/1995
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/6/1989
*RECORD*
*FIELD* NO
164010
*FIELD* TI
*164010 CHMP FAMILY, MEMBER 1A; CHMP1A
;;CHROMATIN-MODIFYING PROTEIN 1A;;
CHARGED MULTIVESICULAR BODY PROTEIN 1A;;
read moreCHMP1;;
PROCOLLAGEN, TYPE III, N-ENDOPEPTIDASE; PCOLN3;;
METALLOPROTEASE 1; PRSM1;;
METALLOPROTEASE, 33-KD
*FIELD* TX
DESCRIPTION
CHMP1A 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, including CHMP1A,
have both nuclear and cytoplasmic/vesicular distributions, and CHMP1A is
required for both MVB formation and regulation of cell cycle progression
(Tsang et al., 2006).
CLONING
Halila et al. (1989) isolated a cDNA for PCOLN3 from a human placenta
cDNA library. By screening a human placenta cDNA library with polyclonal
antibodies raised against human PCOLN3 and using 5-prime RACE and primer
extension strategies on the isolated cDNAs, Scott et al. (1996) cloned
PCOLN3, which they called PRSM1. PRSM1 belongs to the gluzincin
subfamily of metallopeptidases. The zincin superfamily comprises
metallopeptidases that contain an HEXXH zinc-binding consensus sequence,
and gluzincins have glutamic acid as a third zinc ligand. The
full-length sequence of PRSM1 encodes a deduced 318-amino acid protein
with an HELGH pentapeptide fitting the consensus sequence characteristic
of zincins, and a glutamic acid 25 residues C-terminal of the first
histidine, fitting the pattern of gluzincins for a third zinc-binding
ligand. PRSM1 contains 3 clusters of cysteine residues: 1 cluster of 4
residues and 1 cluster of 6 residues at the N terminus, and a cluster of
6 residues at the C terminus. However, the predicted sequence lacks
potential glycosylation sites. Immunoblot analysis of placenta revealed
an approximately 30-kD protein. Northern blot analysis of human
fibroblast culture mRNA detected a transcript of approximately 2.5 kb.
By Northern blot analysis, Nomura et al. (1994) found that PRSM1, which
they designated KIAA0047, was expressed ubiquitously, with highest
levels in lung and kidney and in HeLa and KG-1 cell lines.
By yeast 2-hybrid screening of a mouse embryo cDNA library using the
mouse Polycomb group (PcG) protein Pcl1 (PHF1; 602881) as bait, followed
by RT-PCR of human placenta RNA, Stauffer et al. (2001) cloned a variant
of PRSM1 that they called CHMP1. CHMP1 uses an alternative reading frame
distinct from that of PRSM1. The deduced 196-amino acid CHMP1 protein
contains an N-terminal nuclear localization signal. CHMP1 is most
closely related to CHMP1B (606486) and BC2 (CHMP2A; 610893), and more
distantly related to S. cerevisiae proteins involved in vesicle
trafficking. Western blot analysis of HEK293 human embryonic kidney
cells showed a doublet of 32- and 35-kD CHMP1 proteins. Subcellular
fractionation of HEK293 cells and several other human cell lines
revealed that the 35-kD protein was exclusively nuclear, whereas the
32-kD protein was predominantly cytoplasmic, with a detectable level
present in the nuclear fraction. Analysis of mouse whole tissue extracts
showed that both Chmp1 proteins were widely expressed, with increased
levels of the 35-kD form in heart, kidney, and liver.
Mochida et al. (2012) found that the subcellular localization of CHMP1A
appears to vary depending on cell type. In mouse embryonic 3T3 cells,
Chmp1a was excluded from the nucleus where Bmi1 (164831) was detected.
In human HEK 293T cells, CHMP1A showed prominent cytoplasmic and some
nuclear immunoreactivity. Primary cultures of cerebellar granule cells
from mice showed predominantly cytoplasmic localization of Chmp1a along
with a speckled nuclear pattern. Chmp1a and Bmi1 did not prominently
colocalize within the nucleus. In the developing mouse cerebellum and
cortex, variable expression of Chmp1a was seen in the cytoplasm and
nucleus of dividing and postmitotic cells, including Purkinje, granule,
and neuroepithelial cells. These findings, combined with other data (see
MOLECULAR GENETICS and ANIMAL MODEL), suggested that CHMP1A is an
essential central nervous system regulator of BMI1, which is a key
regulator of stem cell self-renewal.
GENE FUNCTION
By Western blot analysis of synchronized HEK293 cells, Stauffer et al.
(2001) showed that the ratio of cytoplasmic to nuclear CHMP1 was largely
invariant throughout interphase. In mitotic cells, nuclear CHMP1
localized to the chromosome scaffold fraction. Immunocytochemical
analysis detected CHMP1 in a punctate arrangement on condensed
chromosomes during telophase. The cytoplasmic CHMP1 form exhibited a
perinuclear localization. Overexpression of CHMP1 altered the cell
cycle, producing an increase in the number of cells in late S phase.
Overexpression of CHMP1 also resulted in altered chromatin structure,
with modified histones at the periphery of nuclear bodies, and
nuclease-resistant condensed chromatin within. CHMP1 recruited the PcG
protein BMI1 to these regions of condensed chromatin, and it cooperated
with coexpressed Pcl in a Xenopus embryo PcG assay. Stauffer et al.
(2001) concluded that CHMP1 plays a role in stable gene silencing within
the nucleus.
Howard et al. (2001) found that the cytoplasmic form of CHMP1 localized
in a punctate asymmetrical pattern centered over the microtubule
organizing center and colocalized with an early endosomal marker.
Differential extraction showed that cytoplasmic CHMP1 associated with
membranes through ionic interactions. Yeast 2-hybrid screening and in
vitro binding assays demonstrated that cytoplasmic CHMP1 interacted with
SKD1 (VPS4B; 609983). Overexpression of CHMP1 dilated endosomal
compartments and disrupted the normal distribution of several endosomal
markers. Deletion of S. cerevisiae Chm1, the homolog of CHMP1, resulted
in defective sorting of carboxypeptidases S and Y and production of
abnormal, multilamellar prevacuolar compartments. Howard et al. (2001)
concluded that CHMP1 is involved in vesicle trafficking.
Tsang et al. (2006) performed a systematic yeast 2-hybrid analysis of
human ESCRT-III components, including CHMP1A. Like most CHMPs, CHMP1A
interacted with VPS4A (609982). CHMP1A also interacted with the SUMO
(see SUMO1; 601912)-conjugating enzyme UBE2I (601661) and appeared to be
part of a network connecting CHMP1A, CHMP4B (610897), and CHMP5 (610900)
with UBE2I, SUMO1, PIAS2 (603567), and HIPK2 (606868), all of which are
involved in nuclear sumoylation processes.
GENE STRUCTURE
Scott et al. (1996) found that the first exon of the PRSM1 gene is 72%
GC rich, contains 34 CpG dinucleotides, and appears to lie within a CpG
island.
MAPPING
By analysis of somatic cell hybrids, Halila et al. (1992) mapped the
CHMP1 gene to the telomeric region of the long arm of chromosome 16. By
the same method, Scott et al. (1996) mapped the CHMP1 gene to chromosome
16q24.3.
MOLECULAR GENETICS
By linkage analysis followed by candidate gene sequencing in families
with autosomal recessive pontocerebellar hypoplasia type 8 (PCH8;
614961), Mochida et al. (2012) identified 2 different homozygous
mutations in the CHMP1A gene (164010.0001 and 164010.0002). The
phenotype was characterized by severe psychomotor retardation, abnormal
movements, hypotonia, spasticity, and variable visual defects. Brain MRI
showed pontocerebellar hypoplasia with relative preservation of the
cerebellar folia, decreased cerebral white matter, and a thin corpus
callosum. Patient-derived cell lines showed severely impaired doubling
times compared to control, suggesting a defect in cell proliferation.
Quantitative PCR analysis of patient cells showed abnormally high
expression of the BMI1 target INK4A (see CDKN2A, 600160) and decreased
BMI1 binding to the INK4A promoter compared to control, suggesting
derepression of this CDKN2A isoform. INK4A is a negative regulator of
stem cell proliferation. Binding of BMI1 to the ARF promoter was
unaffected. Mochida et al. (2012) noted the parallels in brain
morphology between individuals with CHMP1A mutations and Bmi1-deficient
mice, which show cerebellar hypoplasia. The findings suggested that
CHMP1A serves as a link between cytoplasmic signals and BMI1-mediated
chromatin modification that regulates proliferation of central nervous
system progenitor cells.
ANIMAL MODEL
Mochida et al. (2012) found that morpholino-based knockdown of Chmp1a in
zebrafish resulted in reduced cerebellar and forebrain volume compared
to control that could be partially rescued by expression of wildtype
Chmp1a. The phenotype of these zebrafish resembled that seen in those
after Bmi1 knockdown, supporting a link between Chmp1a and Bmi1. In
Chmp1a knockdown models, the internal granule and molecular layers were
more severely affected than the Purkinje cells, which was consistent
with the relatively preserved folia observed in humans with CHMP1A
mutations.
*FIELD* AV
.0001
PONTOCEREBELLAR HYPOPLASIA, TYPE 8
CHMP1A, GLN30TER
In affected members of 2 Puerto Rican families with pontocerebellar
hypoplasia type 8 (PCH8; 614961), Mochida et al. (2012) identified a
homozygous 88C-T transition in exon 3 of the CHMP1A gene, resulting in a
gln30-to-ter (Q30X) substitution. The mutation was found by linkage
analysis followed by candidate gene sequencing. Haplotype analysis
indicated a founder effect. No CHMP1A protein was found in
patient-derived cells. Patient-derived cell lines showed severely
impaired doubling times compared to control, suggesting a defect in cell
proliferation. There was also increased expression of INK4A (see CDKN2A;
600160), a negative regulator of stem cell proliferation.
.0002
PONTOCEREBELLAR HYPOPLASIA, TYPE 8
CHMP1A, IVS2AS, G-A, -13
In 3 members of a consanguineous family of Peruvian origin with PCH8
(614961), Mochida et al. (2012) identified a homozygous G-to-A
transition in intron 2 of the CHMP1A gene, creating an aberrant splice
acceptor site leading to an 11-bp insertion in the spliced mRNA product.
The mutation was not seen in 281 normal control samples or in several
large control databases. No normal CHMP1A mRNA transcript or protein was
found in patient-derived cells. Patient-derived cell lines showed
severely impaired doubling times compared to control, suggesting a
defect in cell proliferation. There was also increased expression of
INK4A (see CDKN2A, 600160), a negative regulator of stem cell
proliferation.
*FIELD* RF
1. Halila, R.; Apostolou, S.; Winqvist, R.; Callen, D.; Prockop, D.
J.; Peltonen, L.: Isolation and genomic assignment of a candidate
cDNA clone for type III procollagen N-proteinase. (Abstract) Am.
J. Hum. Genet. 51 (suppl.): A128 only, 1992.
2. Halila, R.; Peltonen, L.; Prockop, D. J.: Isolation of a candidate
cDNA clone for type III procollagen N-proteinase from human placental
cDNA library. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A192 only,
1989.
3. Howard, T. L.; Stauffer, D. R.; Degnin, C. R.; Hollenberg, S. M.
: CHMP1 functions as a member of a newly defined family of vesicle
trafficking proteins. J. Cell Sci. 114: 2395-2404, 2001.
4. Mochida, G. H.; Ganesh, V. S.; de Michelena, M. I.; Dias, H.; Atabay,
K. D.; Kathrein, K. L.; Huang, H.-T.; Hill, R. S.; Felie, J. M.; Rakiec,
D.; Gleason, D.; Hill, A. D.; and 9 others: CHMP1A encodes an essential
regulator of BMI1-INK4A in cerebellar development. Nature Genet. 44:
1260-1264, 2012.
5. Nomura, N.; Nagase, T.; Miyajima, N.; Sazuka, T.; Tanaka, A.; Sato,
S.; Seki, N.; Kawarabayasi, Y.; Ishikawa, K.; Tabata, S.: Prediction
of the coding sequences of unidentified human genes. II. The coding
sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis
of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994.
6. Scott, I. C.; Halila, R.; Jenkins, J. M.; Mehan, S.; Apostolou,
S.; Winqvist, R.; Callen, D. F.; Prockop, D. J.; Peltonen, L.; Kadler,
K. E.: Molecular cloning, expression and chromosomal localization
of a human gene encoding a 33 kDa putative metallopeptidase (PRSM1). Gene 174:
135-143, 1996.
7. Stauffer, D. R.; Howard, T. L.; Nyun, T.; Hollenberg, S. M.: CHMP1
is a novel nuclear matrix protein affecting chromatin structure and
cell-cycle progression. J. Cell Sci. 114: 2383-2393, 2001.
8. 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.
*FIELD* CN
Cassandra L. Kniffin - updated: 12/4/2012
Victor A. McKusick - updated: 3/1/2000
Paul J. Converse - updated: 1/18/2000
Victor A. McKusick - updated: 1/11/2000
*FIELD* CD
Victor A. McKusick: 11/6/1989
*FIELD* ED
terry: 12/06/2012
carol: 12/5/2012
ckniffin: 12/5/2012
ckniffin: 12/4/2012
mgross: 3/29/2007
mgross: 3/28/2007
mgross: 3/27/2007
carol: 8/4/2000
carol: 3/15/2000
carol: 3/2/2000
terry: 3/1/2000
mgross: 2/4/2000
terry: 1/11/2000
carol: 1/3/1995
supermim: 3/16/1992
supermim: 3/20/1990
carol: 11/6/1989
MIM
614961
*RECORD*
*FIELD* NO
614961
*FIELD* TI
#614961 PONTOCEREBELLAR HYPOPLASIA, TYPE 8; PCH8
*FIELD* TX
A number sign (#) is used with this entry because pontocerebellar
read morehypoplasia type 8 (PCH8) is caused by homozygous mutation in the CHMP1A
gene (164010) on chromosome 16q24.
DESCRIPTION
Pontocerebellar hypoplasia type 8 is an autosomal recessive
neurodevelopmental disorder characterized by severe psychomotor
retardation, abnormal movements, hypotonia, spasticity, and variable
visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased
cerebral white matter, and a thin corpus callosum (summary by Mochida et
al., 2012).
For a general phenotypic description and a discussion of genetic
heterogeneity of PCH, see PCH1 (607596).
CLINICAL FEATURES
Mochida et al. (2012) reported 6 patients from 3 unrelated families with
pontocerebellar hypoplasia. One consanguineous family was of Peruvian
origin and the 2 other families were from Puerto Rico. The patients
showed early developmental delay in motor, speech, and cognition.
Although most were born with a normal head size, all but 1 developed
postnatal microcephaly (-2 to -4.4 SD). Some learned to walk later in
childhood, whereas some did not achieve independent walking or even
sitting. Most had hypotonia with limb spasticity, variable
hyperreflexia, ataxic gait, and involuntary movements, particularly of
the head. Other features included claw foot deformities,
equinovacovarus, and poor overall growth; 2 patients had more severe
joint contractures. Ocular abnormalities ranged from myopia,
astigmatism, esotropia, and nystagmus to cortical visual impairment and
lack of visual tracking. All had poor social interaction and very poor
cognitive development. Two patients had mild dysmorphic features, 2 had
esophageal reflux, and 1 had hypertrichosis. Brain MRI of all patients
showed a small cerebellum, thin brainstem with short pons and long
medulla, decreased cerebral white matter, and a thin corpus callosum.
There was relative preservation of the cerebellar folia. These changes
did not appear to be progressive and were more consistent with a
developmental rather than a degenerative process.
INHERITANCE
The transmission pattern in the families with PCH8 reported by Mochida
et al. (2012) was consistent with autosomal recessive inheritance.
MAPPING
By genomewide linkage analysis of 2 families with autosomal recessive
pontocerebellar hypoplasia, Mochida et al. (2012) found linkage to a
locus on chromosome 16q24.3 (maximum multipoint lod score of 3.68).
MOLECULAR GENETICS
By linkage analysis followed by candidate gene sequencing in families
with pontocerebellar hypoplasia, Mochida et al. (2012) identified 2
different homozygous mutations in the CHMP1A gene (164010.0001 and
164010.0002). Patient-derived cell lines showed severely impaired
doubling times compared to control, suggesting a defect in cell
proliferation. Quantitative PCR analysis of patient cells showed
abnormally high expression of the BMI1 (164831) target INK4A (see
CDKN2A, 600160) and decreased BMI1 binding to the INK4A promoter
compared to control, suggesting derepression of this CDKN2A isoform.
INK4A is a negative regulator of stem cell proliferation. Mochida et al.
(2012) noted the parallels in brain morphology between individuals with
CHMP1A mutations and Bmi1-deficient mice, which show cerebellar
hypoplasia. The overall findings suggested that CHMP1A serves as a link
between cytoplasmic signals and BMI1-mediated chromatin modification
that regulates proliferation of central nervous system progenitor cells.
*FIELD* RF
1. Mochida, G. H.; Ganesh, V. S.; de Michelena, M. I.; Dias, H.; Atabay,
K. D.; Kathrein, K. L.; Huang, H.-T.; Hill, R. S.; Felie, J. M.; Rakiec,
D.; Gleason, D.; Hill, A. D.; and 9 others: CHMP1A encodes an essential
regulator of BMI1-INK4A in cerebellar development. Nature Genet. 44:
1260-1264, 2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor postnatal growth
HEAD AND NECK:
[Head];
Microcephaly, postnatal (-2 to 4.4 SD);
[Face];
Dysmorphic features (in some patients);
[Eyes];
Myopia;
Astigmatism;
Esotropia;
Strabismus;
Hyperopia;
Nystagmus (in some patients);
Cortical visual impairment (in some patients);
Poor visual tracking (in some patients)
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (rare);
Swallowing difficulties (rare)
SKELETAL:
Joint contractures (in some patients);
Arthrogryposis (in some patients);
[Feet];
Claw feet;
Pes cavus;
Equinovarus;
Talipes valgus
SKIN, NAILS, HAIR:
[Hair];
Hypertrichosis (rare)
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, severe;
Mental retardation;
Poor speech;
Lack of speech;
Lack of independent walking (in some patients);
Truncal hypotonia;
Spasticity, usually of the lower limbs;
Hyperreflexia;
Involuntary repetitive movements;
Choreiform movements;
Brain MRI shows cerebellar hypoplasia;
Relative preservation of the cerebellar folia;
Brainstem hypoplasia;
Reduced cerebral white matter;
Thin corpus callosum
MISCELLANEOUS:
Onset at birth
MOLECULAR BASIS:
Caused by mutation in the CHMP family, member 1A gene (CHMP1A, 164010.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/3/2012
*FIELD* ED
joanna: 10/22/2013
joanna: 12/14/2012
ckniffin: 12/4/2012
*FIELD* CD
Cassandra L. Kniffin: 12/3/2012
*FIELD* ED
carol: 12/05/2012
ckniffin: 12/5/2012
ckniffin: 12/4/2012
*RECORD*
*FIELD* NO
614961
*FIELD* TI
#614961 PONTOCEREBELLAR HYPOPLASIA, TYPE 8; PCH8
*FIELD* TX
A number sign (#) is used with this entry because pontocerebellar
read morehypoplasia type 8 (PCH8) is caused by homozygous mutation in the CHMP1A
gene (164010) on chromosome 16q24.
DESCRIPTION
Pontocerebellar hypoplasia type 8 is an autosomal recessive
neurodevelopmental disorder characterized by severe psychomotor
retardation, abnormal movements, hypotonia, spasticity, and variable
visual defects. Brain MRI shows pontocerebellar hypoplasia, decreased
cerebral white matter, and a thin corpus callosum (summary by Mochida et
al., 2012).
For a general phenotypic description and a discussion of genetic
heterogeneity of PCH, see PCH1 (607596).
CLINICAL FEATURES
Mochida et al. (2012) reported 6 patients from 3 unrelated families with
pontocerebellar hypoplasia. One consanguineous family was of Peruvian
origin and the 2 other families were from Puerto Rico. The patients
showed early developmental delay in motor, speech, and cognition.
Although most were born with a normal head size, all but 1 developed
postnatal microcephaly (-2 to -4.4 SD). Some learned to walk later in
childhood, whereas some did not achieve independent walking or even
sitting. Most had hypotonia with limb spasticity, variable
hyperreflexia, ataxic gait, and involuntary movements, particularly of
the head. Other features included claw foot deformities,
equinovacovarus, and poor overall growth; 2 patients had more severe
joint contractures. Ocular abnormalities ranged from myopia,
astigmatism, esotropia, and nystagmus to cortical visual impairment and
lack of visual tracking. All had poor social interaction and very poor
cognitive development. Two patients had mild dysmorphic features, 2 had
esophageal reflux, and 1 had hypertrichosis. Brain MRI of all patients
showed a small cerebellum, thin brainstem with short pons and long
medulla, decreased cerebral white matter, and a thin corpus callosum.
There was relative preservation of the cerebellar folia. These changes
did not appear to be progressive and were more consistent with a
developmental rather than a degenerative process.
INHERITANCE
The transmission pattern in the families with PCH8 reported by Mochida
et al. (2012) was consistent with autosomal recessive inheritance.
MAPPING
By genomewide linkage analysis of 2 families with autosomal recessive
pontocerebellar hypoplasia, Mochida et al. (2012) found linkage to a
locus on chromosome 16q24.3 (maximum multipoint lod score of 3.68).
MOLECULAR GENETICS
By linkage analysis followed by candidate gene sequencing in families
with pontocerebellar hypoplasia, Mochida et al. (2012) identified 2
different homozygous mutations in the CHMP1A gene (164010.0001 and
164010.0002). Patient-derived cell lines showed severely impaired
doubling times compared to control, suggesting a defect in cell
proliferation. Quantitative PCR analysis of patient cells showed
abnormally high expression of the BMI1 (164831) target INK4A (see
CDKN2A, 600160) and decreased BMI1 binding to the INK4A promoter
compared to control, suggesting derepression of this CDKN2A isoform.
INK4A is a negative regulator of stem cell proliferation. Mochida et al.
(2012) noted the parallels in brain morphology between individuals with
CHMP1A mutations and Bmi1-deficient mice, which show cerebellar
hypoplasia. The overall findings suggested that CHMP1A serves as a link
between cytoplasmic signals and BMI1-mediated chromatin modification
that regulates proliferation of central nervous system progenitor cells.
*FIELD* RF
1. Mochida, G. H.; Ganesh, V. S.; de Michelena, M. I.; Dias, H.; Atabay,
K. D.; Kathrein, K. L.; Huang, H.-T.; Hill, R. S.; Felie, J. M.; Rakiec,
D.; Gleason, D.; Hill, A. D.; and 9 others: CHMP1A encodes an essential
regulator of BMI1-INK4A in cerebellar development. Nature Genet. 44:
1260-1264, 2012.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GROWTH:
[Other];
Poor postnatal growth
HEAD AND NECK:
[Head];
Microcephaly, postnatal (-2 to 4.4 SD);
[Face];
Dysmorphic features (in some patients);
[Eyes];
Myopia;
Astigmatism;
Esotropia;
Strabismus;
Hyperopia;
Nystagmus (in some patients);
Cortical visual impairment (in some patients);
Poor visual tracking (in some patients)
ABDOMEN:
[Gastrointestinal];
Gastroesophageal reflux (rare);
Swallowing difficulties (rare)
SKELETAL:
Joint contractures (in some patients);
Arthrogryposis (in some patients);
[Feet];
Claw feet;
Pes cavus;
Equinovarus;
Talipes valgus
SKIN, NAILS, HAIR:
[Hair];
Hypertrichosis (rare)
MUSCLE, SOFT TISSUE:
Hypotonia
NEUROLOGIC:
[Central nervous system];
Delayed psychomotor development, severe;
Mental retardation;
Poor speech;
Lack of speech;
Lack of independent walking (in some patients);
Truncal hypotonia;
Spasticity, usually of the lower limbs;
Hyperreflexia;
Involuntary repetitive movements;
Choreiform movements;
Brain MRI shows cerebellar hypoplasia;
Relative preservation of the cerebellar folia;
Brainstem hypoplasia;
Reduced cerebral white matter;
Thin corpus callosum
MISCELLANEOUS:
Onset at birth
MOLECULAR BASIS:
Caused by mutation in the CHMP family, member 1A gene (CHMP1A, 164010.0001)
*FIELD* CD
Cassandra L. Kniffin: 12/3/2012
*FIELD* ED
joanna: 10/22/2013
joanna: 12/14/2012
ckniffin: 12/4/2012
*FIELD* CD
Cassandra L. Kniffin: 12/3/2012
*FIELD* ED
carol: 12/05/2012
ckniffin: 12/5/2012
ckniffin: 12/4/2012