Full text data of DNAJC5
DNAJC5
(CSP)
[Confidence: high (present in two of the MS resources)]
DnaJ homolog subfamily C member 5 (Cysteine string protein; CSP)
DnaJ homolog subfamily C member 5 (Cysteine string protein; CSP)
hRBCD
IPI00023780
IPI00023780 Splice isoform 2 or 1 of Q9H3Z4 DnaJ homolog subfamily C member 5 Splice isoform 2 or 1 of Q9H3Z4 DnaJ homolog subfamily C member 5 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 2 n/a 2 n/a n/a n/a n/a n/a n/a membrane bound splice isoform 1 and 2 found at its expected molecular weight found at molecular weight
IPI00023780 Splice isoform 2 or 1 of Q9H3Z4 DnaJ homolog subfamily C member 5 Splice isoform 2 or 1 of Q9H3Z4 DnaJ homolog subfamily C member 5 membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 3 2 n/a 2 n/a n/a n/a n/a n/a n/a membrane bound splice isoform 1 and 2 found at its expected molecular weight found at molecular weight
UniProt
Q9H3Z4
ID DNJC5_HUMAN Reviewed; 198 AA.
AC Q9H3Z4; A8K0M0; B3KY68; E1P5G8; Q9H3Z5; Q9H7H2;
DT 14-AUG-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=DnaJ homolog subfamily C member 5;
DE AltName: Full=Cysteine string protein;
DE Short=CSP;
GN Name=DNAJC5; Synonyms=CSP;
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 (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RX PubMed=8764987; DOI=10.1016/0014-5793(96)00750-8;
RA Coppola T., Gundersen C.;
RT "Widespread expression of human cysteine string proteins.";
RL FEBS Lett. 391:269-272(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cerebellum, and Hippocampus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 76-198.
RC TISSUE=Spleen;
RX PubMed=11214971; DOI=10.1093/dnares/7.6.357;
RA Hattori A., Okumura K., Nagase T., Kikuno R., Hirosawa M., Ohara O.;
RT "Characterization of long cDNA clones from human adult spleen.";
RL DNA Res. 7:357-366(2000).
RN [7]
RP PHOSPHORYLATION AT SER-10.
RC TISSUE=Pituitary;
RX PubMed=14997482; DOI=10.1002/pmic.200300584;
RA Giorgianni F., Beranova-Giorgianni S., Desiderio D.M.;
RT "Identification and characterization of phosphorylated proteins in the
RT human pituitary.";
RL Proteomics 4:587-598(2004).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10 AND SER-15, 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=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10, 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 [17]
RP SUBCELLULAR LOCATION, VARIANTS CLN4B ARG-115 AND LEU-116 DEL, AND
RP CHARACTERIZATION OF VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=21820099; DOI=10.1016/j.ajhg.2011.07.003;
RA Noskova L., Stranecky V., Hartmannova H., Pristoupilova A.,
RA Baresova V., Ivanek R., Hulkova H., Jahnova H., van der Zee J.,
RA Staropoli J.F., Sims K.B., Tyynela J., Van Broeckhoven C.,
RA Nijssen P.C., Mole S.E., Elleder M., Kmoch S.;
RT "Mutations in DNAJC5, encoding cysteine-string protein alpha, cause
RT autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.";
RL Am. J. Hum. Genet. 89:241-252(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10, 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 [19]
RP VARIANT CLN4B ARG-115.
RX PubMed=22073189; DOI=10.1371/journal.pone.0026741;
RA Benitez B.A., Alvarado D., Cai Y., Mayo K., Chakraverty S., Norton J.,
RA Morris J.C., Sands M.S., Goate A., Cruchaga C.;
RT "Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal
RT ceroid-lipofuscinosis.";
RL PLoS ONE 6:E26741-E26741(2011).
RN [20]
RP CHARACTERIZATION OF VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22902780; DOI=10.1074/jbc.M112.389098;
RA Greaves J., Lemonidis K., Gorleku O.A., Cruchaga C., Grefen C.,
RA Chamberlain L.H.;
RT "Palmitoylation-induced aggregation of cysteine-string protein mutants
RT that cause neuronal ceroid lipofuscinosis.";
RL J. Biol. Chem. 287:37330-37339(2012).
RN [21]
RP VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22235333; DOI=10.1371/journal.pone.0029729;
RA Velinov M., Dolzhanskaya N., Gonzalez M., Powell E., Konidari I.,
RA Hulme W., Staropoli J.F., Xin W., Wen G.Y., Barone R., Coppel S.H.,
RA Sims K., Brown W.T., Zuchner S.;
RT "Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in
RT a proportion of cases: study of the Parry family and 8 other
RT families.";
RL PLoS ONE 7:E29729-E29729(2012).
RN [22]
RP VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22978711; DOI=10.1111/cge.12020;
RA Cadieux-Dion M., Andermann E., Lachance-Touchette P., Ansorge O.,
RA Meloche C., Barnabe A., Kuzniecky R.I., Andermann F., Faught E.,
RA Leonberg S., Damiano J.A., Berkovic S.F., Rouleau G.A., Cossette P.;
RT "Recurrent mutations in DNAJC5 cause autosomal dominant Kufs
RT disease.";
RL Clin. Genet. 83:571-575(2013).
CC -!- FUNCTION: May have an important role in presynaptic function. May
CC be involved in calcium-dependent neurotransmitter release at nerve
CC endings (By similarity).
CC -!- SUBUNIT: Homodimer (Probable). Interacts with the chaperone
CC complex consisting of HSC70 and SGTA (By similarity).
CC -!- SUBCELLULAR LOCATION: Membrane; Lipid-anchor (By similarity).
CC Melanosome. Cell membrane. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H3Z4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H3Z4-2; Sequence=VSP_001292;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in pancreas, kidney, skeletal
CC muscle, liver, lung, placenta, brain and heart.
CC -!- PTM: Fatty acylated. Heavily palmitoylated in the cysteine string
CC motif (By similarity).
CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 4B (CLN4B) [MIM:162350]:
CC An adult-onset neuronal ceroid lipofuscinosis. Neuronal ceroid
CC lipofuscinoses are progressive neurodegenerative, lysosomal
CC storage diseases characterized by intracellular accumulation of
CC autofluorescent liposomal material, and clinically by seizures,
CC dementia, visual loss, and/or cerebral atrophy. CLN4B has no
CC visual involvement and is characterized by seizures and other
CC neurologic symptoms. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 J domain.
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DR EMBL; AL118506; CAC15495.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75191.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75192.1; -; Genomic_DNA.
DR EMBL; BC053642; AAH53642.1; -; mRNA.
DR EMBL; AK024508; BAB15798.1; -; mRNA.
DR EMBL; AK128776; BAG54730.1; -; mRNA.
DR EMBL; AK289585; BAF82274.1; -; mRNA.
DR PIR; S70515; S70515.
DR RefSeq; NP_079495.1; NM_025219.2.
DR UniGene; Hs.164419; -.
DR ProteinModelPortal; Q9H3Z4; -.
DR SMR; Q9H3Z4; 5-100.
DR IntAct; Q9H3Z4; 1.
DR MINT; MINT-5000726; -.
DR STRING; 9606.ENSP00000354111; -.
DR PhosphoSite; Q9H3Z4; -.
DR DMDM; 15213953; -.
DR PaxDb; Q9H3Z4; -.
DR PRIDE; Q9H3Z4; -.
DR Ensembl; ENST00000360864; ENSP00000354111; ENSG00000101152.
DR Ensembl; ENST00000369911; ENSP00000358927; ENSG00000101152.
DR Ensembl; ENST00000470551; ENSP00000434744; ENSG00000101152.
DR GeneID; 80331; -.
DR KEGG; hsa:80331; -.
DR UCSC; uc002yhf.3; human.
DR CTD; 80331; -.
DR GeneCards; GC20P062526; -.
DR HGNC; HGNC:16235; DNAJC5.
DR HPA; HPA012737; -.
DR HPA; HPA013154; -.
DR MIM; 162350; phenotype.
DR MIM; 611203; gene.
DR neXtProt; NX_Q9H3Z4; -.
DR Orphanet; 228343; CLN4B disease.
DR PharmGKB; PA27422; -.
DR eggNOG; COG0484; -.
DR HOGENOM; HOG000231969; -.
DR HOVERGEN; HBG005414; -.
DR InParanoid; Q9H3Z4; -.
DR KO; K09525; -.
DR OMA; CCCGRCK; -.
DR OrthoDB; EOG7WHHBD; -.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; DNAJC5; human.
DR GeneWiki; DNAJC5; -.
DR GenomeRNAi; 80331; -.
DR NextBio; 70876; -.
DR PRO; PR:Q9H3Z4; -.
DR ArrayExpress; Q9H3Z4; -.
DR Bgee; Q9H3Z4; -.
DR CleanEx; HS_DNAJC5; -.
DR Genevestigator; Q9H3Z4; -.
DR GO; GO:0061202; C:clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome.
DR Gene3D; 1.10.287.110; -; 1.
DR InterPro; IPR001623; DnaJ_domain.
DR InterPro; IPR018253; DnaJ_domain_CS.
DR Pfam; PF00226; DnaJ; 1.
DR PRINTS; PR00625; JDOMAIN.
DR SMART; SM00271; DnaJ; 1.
DR SUPFAM; SSF46565; SSF46565; 1.
DR PROSITE; PS00636; DNAJ_1; 1.
DR PROSITE; PS50076; DNAJ_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell membrane; Chaperone;
KW Complete proteome; Disease mutation; Lipoprotein; Membrane;
KW Neurodegeneration; Neuronal ceroid lipofuscinosis; Palmitate;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 198 DnaJ homolog subfamily C member 5.
FT /FTId=PRO_0000071052.
FT DOMAIN 13 82 J.
FT COMPBIAS 118 128 Poly-Cys.
FT MOD_RES 8 8 Phosphoserine.
FT MOD_RES 10 10 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 56 56 N6-acetyllysine.
FT VAR_SEQ 165 198 EATDTPIVIQPASATETTQLTADSHPSYHTDGFN -> GGH
FT (in isoform 2).
FT /FTId=VSP_001292.
FT VARIANT 115 115 L -> R (in CLN4B; results in near absence
FT of palmitoylated monomeric forms of the
FT protein and formation of high molecular
FT mass aggregates with diffuse
FT intracellular localization).
FT /FTId=VAR_066555.
FT VARIANT 116 116 Missing (in CLN4B; results in near
FT absence of palmitoylated monomeric forms
FT of the protein and formation of high
FT molecular mass aggregates with diffuse
FT intracellular localization).
FT /FTId=VAR_066556.
SQ SEQUENCE 198 AA; 22149 MW; A3F89270EBAD8A25 CRC64;
MADQRQRSLS TSGESLYHVL GLDKNATSDD IKKSYRKLAL KYHPDKNPDN PEAADKFKEI
NNAHAILTDA TKRNIYDKYG SLGLYVAEQF GEENVNTYFV LSSWWAKALF VFCGLLTCCY
CCCCLCCCFN CCCGKCKPKA PEGEETEFYV SPEDLEAQLQ SDEREATDTP IVIQPASATE
TTQLTADSHP SYHTDGFN
//
ID DNJC5_HUMAN Reviewed; 198 AA.
AC Q9H3Z4; A8K0M0; B3KY68; E1P5G8; Q9H3Z5; Q9H7H2;
DT 14-AUG-2001, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAR-2001, sequence version 1.
DT 22-JAN-2014, entry version 117.
DE RecName: Full=DnaJ homolog subfamily C member 5;
DE AltName: Full=Cysteine string protein;
DE Short=CSP;
GN Name=DNAJC5; Synonyms=CSP;
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 (ISOFORMS 1 AND 2), AND TISSUE SPECIFICITY.
RX PubMed=8764987; DOI=10.1016/0014-5793(96)00750-8;
RA Coppola T., Gundersen C.;
RT "Widespread expression of human cysteine string proteins.";
RL FEBS Lett. 391:269-272(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cerebellum, and Hippocampus;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Blood;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 76-198.
RC TISSUE=Spleen;
RX PubMed=11214971; DOI=10.1093/dnares/7.6.357;
RA Hattori A., Okumura K., Nagase T., Kikuno R., Hirosawa M., Ohara O.;
RT "Characterization of long cDNA clones from human adult spleen.";
RL DNA Res. 7:357-366(2000).
RN [7]
RP PHOSPHORYLATION AT SER-10.
RC TISSUE=Pituitary;
RX PubMed=14997482; DOI=10.1002/pmic.200300584;
RA Giorgianni F., Beranova-Giorgianni S., Desiderio D.M.;
RT "Identification and characterization of phosphorylated proteins in the
RT human pituitary.";
RL Proteomics 4:587-598(2004).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-10 AND SER-15, 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=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-56, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10, 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 [17]
RP SUBCELLULAR LOCATION, VARIANTS CLN4B ARG-115 AND LEU-116 DEL, AND
RP CHARACTERIZATION OF VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=21820099; DOI=10.1016/j.ajhg.2011.07.003;
RA Noskova L., Stranecky V., Hartmannova H., Pristoupilova A.,
RA Baresova V., Ivanek R., Hulkova H., Jahnova H., van der Zee J.,
RA Staropoli J.F., Sims K.B., Tyynela J., Van Broeckhoven C.,
RA Nijssen P.C., Mole S.E., Elleder M., Kmoch S.;
RT "Mutations in DNAJC5, encoding cysteine-string protein alpha, cause
RT autosomal-dominant adult-onset neuronal ceroid lipofuscinosis.";
RL Am. J. Hum. Genet. 89:241-252(2011).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-8 AND SER-10, 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 [19]
RP VARIANT CLN4B ARG-115.
RX PubMed=22073189; DOI=10.1371/journal.pone.0026741;
RA Benitez B.A., Alvarado D., Cai Y., Mayo K., Chakraverty S., Norton J.,
RA Morris J.C., Sands M.S., Goate A., Cruchaga C.;
RT "Exome-sequencing confirms DNAJC5 mutations as cause of adult neuronal
RT ceroid-lipofuscinosis.";
RL PLoS ONE 6:E26741-E26741(2011).
RN [20]
RP CHARACTERIZATION OF VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22902780; DOI=10.1074/jbc.M112.389098;
RA Greaves J., Lemonidis K., Gorleku O.A., Cruchaga C., Grefen C.,
RA Chamberlain L.H.;
RT "Palmitoylation-induced aggregation of cysteine-string protein mutants
RT that cause neuronal ceroid lipofuscinosis.";
RL J. Biol. Chem. 287:37330-37339(2012).
RN [21]
RP VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22235333; DOI=10.1371/journal.pone.0029729;
RA Velinov M., Dolzhanskaya N., Gonzalez M., Powell E., Konidari I.,
RA Hulme W., Staropoli J.F., Xin W., Wen G.Y., Barone R., Coppel S.H.,
RA Sims K., Brown W.T., Zuchner S.;
RT "Mutations in the gene DNAJC5 cause autosomal dominant Kufs disease in
RT a proportion of cases: study of the Parry family and 8 other
RT families.";
RL PLoS ONE 7:E29729-E29729(2012).
RN [22]
RP VARIANTS CLN4B ARG-115 AND LEU-116 DEL.
RX PubMed=22978711; DOI=10.1111/cge.12020;
RA Cadieux-Dion M., Andermann E., Lachance-Touchette P., Ansorge O.,
RA Meloche C., Barnabe A., Kuzniecky R.I., Andermann F., Faught E.,
RA Leonberg S., Damiano J.A., Berkovic S.F., Rouleau G.A., Cossette P.;
RT "Recurrent mutations in DNAJC5 cause autosomal dominant Kufs
RT disease.";
RL Clin. Genet. 83:571-575(2013).
CC -!- FUNCTION: May have an important role in presynaptic function. May
CC be involved in calcium-dependent neurotransmitter release at nerve
CC endings (By similarity).
CC -!- SUBUNIT: Homodimer (Probable). Interacts with the chaperone
CC complex consisting of HSC70 and SGTA (By similarity).
CC -!- SUBCELLULAR LOCATION: Membrane; Lipid-anchor (By similarity).
CC Melanosome. Cell membrane. Note=Identified by mass spectrometry in
CC melanosome fractions from stage I to stage IV.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9H3Z4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9H3Z4-2; Sequence=VSP_001292;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in pancreas, kidney, skeletal
CC muscle, liver, lung, placenta, brain and heart.
CC -!- PTM: Fatty acylated. Heavily palmitoylated in the cysteine string
CC motif (By similarity).
CC -!- DISEASE: Ceroid lipofuscinosis, neuronal, 4B (CLN4B) [MIM:162350]:
CC An adult-onset neuronal ceroid lipofuscinosis. Neuronal ceroid
CC lipofuscinoses are progressive neurodegenerative, lysosomal
CC storage diseases characterized by intracellular accumulation of
CC autofluorescent liposomal material, and clinically by seizures,
CC dementia, visual loss, and/or cerebral atrophy. CLN4B has no
CC visual involvement and is characterized by seizures and other
CC neurologic symptoms. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 J domain.
CC -----------------------------------------------------------------------
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DR EMBL; AL118506; CAC15495.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75191.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW75192.1; -; Genomic_DNA.
DR EMBL; BC053642; AAH53642.1; -; mRNA.
DR EMBL; AK024508; BAB15798.1; -; mRNA.
DR EMBL; AK128776; BAG54730.1; -; mRNA.
DR EMBL; AK289585; BAF82274.1; -; mRNA.
DR PIR; S70515; S70515.
DR RefSeq; NP_079495.1; NM_025219.2.
DR UniGene; Hs.164419; -.
DR ProteinModelPortal; Q9H3Z4; -.
DR SMR; Q9H3Z4; 5-100.
DR IntAct; Q9H3Z4; 1.
DR MINT; MINT-5000726; -.
DR STRING; 9606.ENSP00000354111; -.
DR PhosphoSite; Q9H3Z4; -.
DR DMDM; 15213953; -.
DR PaxDb; Q9H3Z4; -.
DR PRIDE; Q9H3Z4; -.
DR Ensembl; ENST00000360864; ENSP00000354111; ENSG00000101152.
DR Ensembl; ENST00000369911; ENSP00000358927; ENSG00000101152.
DR Ensembl; ENST00000470551; ENSP00000434744; ENSG00000101152.
DR GeneID; 80331; -.
DR KEGG; hsa:80331; -.
DR UCSC; uc002yhf.3; human.
DR CTD; 80331; -.
DR GeneCards; GC20P062526; -.
DR HGNC; HGNC:16235; DNAJC5.
DR HPA; HPA012737; -.
DR HPA; HPA013154; -.
DR MIM; 162350; phenotype.
DR MIM; 611203; gene.
DR neXtProt; NX_Q9H3Z4; -.
DR Orphanet; 228343; CLN4B disease.
DR PharmGKB; PA27422; -.
DR eggNOG; COG0484; -.
DR HOGENOM; HOG000231969; -.
DR HOVERGEN; HBG005414; -.
DR InParanoid; Q9H3Z4; -.
DR KO; K09525; -.
DR OMA; CCCGRCK; -.
DR OrthoDB; EOG7WHHBD; -.
DR Reactome; REACT_13685; Neuronal System.
DR ChiTaRS; DNAJC5; human.
DR GeneWiki; DNAJC5; -.
DR GenomeRNAi; 80331; -.
DR NextBio; 70876; -.
DR PRO; PR:Q9H3Z4; -.
DR ArrayExpress; Q9H3Z4; -.
DR Bgee; Q9H3Z4; -.
DR CleanEx; HS_DNAJC5; -.
DR Genevestigator; Q9H3Z4; -.
DR GO; GO:0061202; C:clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane; TAS:Reactome.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0007269; P:neurotransmitter secretion; TAS:Reactome.
DR Gene3D; 1.10.287.110; -; 1.
DR InterPro; IPR001623; DnaJ_domain.
DR InterPro; IPR018253; DnaJ_domain_CS.
DR Pfam; PF00226; DnaJ; 1.
DR PRINTS; PR00625; JDOMAIN.
DR SMART; SM00271; DnaJ; 1.
DR SUPFAM; SSF46565; SSF46565; 1.
DR PROSITE; PS00636; DNAJ_1; 1.
DR PROSITE; PS50076; DNAJ_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Cell membrane; Chaperone;
KW Complete proteome; Disease mutation; Lipoprotein; Membrane;
KW Neurodegeneration; Neuronal ceroid lipofuscinosis; Palmitate;
KW Phosphoprotein; Reference proteome.
FT CHAIN 1 198 DnaJ homolog subfamily C member 5.
FT /FTId=PRO_0000071052.
FT DOMAIN 13 82 J.
FT COMPBIAS 118 128 Poly-Cys.
FT MOD_RES 8 8 Phosphoserine.
FT MOD_RES 10 10 Phosphoserine.
FT MOD_RES 15 15 Phosphoserine.
FT MOD_RES 56 56 N6-acetyllysine.
FT VAR_SEQ 165 198 EATDTPIVIQPASATETTQLTADSHPSYHTDGFN -> GGH
FT (in isoform 2).
FT /FTId=VSP_001292.
FT VARIANT 115 115 L -> R (in CLN4B; results in near absence
FT of palmitoylated monomeric forms of the
FT protein and formation of high molecular
FT mass aggregates with diffuse
FT intracellular localization).
FT /FTId=VAR_066555.
FT VARIANT 116 116 Missing (in CLN4B; results in near
FT absence of palmitoylated monomeric forms
FT of the protein and formation of high
FT molecular mass aggregates with diffuse
FT intracellular localization).
FT /FTId=VAR_066556.
SQ SEQUENCE 198 AA; 22149 MW; A3F89270EBAD8A25 CRC64;
MADQRQRSLS TSGESLYHVL GLDKNATSDD IKKSYRKLAL KYHPDKNPDN PEAADKFKEI
NNAHAILTDA TKRNIYDKYG SLGLYVAEQF GEENVNTYFV LSSWWAKALF VFCGLLTCCY
CCCCLCCCFN CCCGKCKPKA PEGEETEFYV SPEDLEAQLQ SDEREATDTP IVIQPASATE
TTQLTADSHP SYHTDGFN
//
MIM
162350
*RECORD*
*FIELD* NO
162350
*FIELD* TI
#162350 CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B
;;KUFS DISEASE, AUTOSOMAL DOMINANT;;
read moreCEROID LIPOFUSCINOSIS, NEURONAL, PARRY TYPE
*FIELD* TX
A number sign (#) is used with this entry because neuronal
lipofuscinosis-4B (CLN4B) is caused by heterozygous mutation in the
DNAJC5 gene (611203) on chromosome 20q13.
DESCRIPTION
The neuronal ceroid lipofuscinoses are a group of progressive
neurodegenerative diseases characterized by accumulation of
intracellular autofluorescent lipopigment storage material in the brain
and other tissues. Several different forms have been described according
to age of onset (see, e.g., CLN3, 204200). An adult form, sometimes
referred to as Kufs disease, is distinguished clinically by onset of
symptoms in adulthood and by absence of ocular involvement.
For a general phenotypic description and a discussion of genetic
heterogeneity of CLN, see CLN1 (256730).
CLINICAL FEATURES
Boehme et al. (1971) reported a family (named Parry) in which 11
individuals over 4 generations were affected with adult-onset neuronal
ceroid lipofuscinosis (NCL) in an autosomal dominant pattern of
inheritance. The strikingly consistent clinical picture was onset of a
cerebellar syndrome at about age 31 years, followed by seizures,
myoclonic jerks, and progressive dementia. Pathologic features included
neuronal loss and accumulation of lipopigment in remaining neurons. No
curvilinear or fingerprint patterns were apparent on ultrastructural
examination. Armstrong et al. (1974) studied 3 sibs from Boehme's family
and found that all 3 had low peroxidase although only 2 were clinically
affected. Brodner and Noh (1976) studied a 24-year-old man from the
family reported by Boehme et al. (1971). Cortical biopsy at the time of
craniotomy for removal of astrocytoma showed changes indicative of Kufs
disease.
Ferrer et al. (1980) reported a family with autosomal dominant Kufs
disease with 6 affected individuals in 2 generations. Disease onset
ranged from age 33 to 37 years and was characterized by progressive
dementia and involuntary movements of the face and neck. One affected
individual had seizures. Brain biopsy showed mild neuronal loss and the
accumulation of a granular, membrane-bound product resembling lipofuscin
with occasional dense compact rectilinear profiles, but no fingerprint
or curvilinear profiles.
Goebel and Braak (1989) provided a detailed review of adult-onset NCL.
Psychiatric and behavioral changes, mental deterioration, seizures,
extrapyramidal symptoms, and ataxia dominate the clinical picture, while
ocular symptoms are conspicuously absent.
Josephson et al. (2001) reported a family of English ancestry in which
10 members over 5 generations had Kufs disease. Age of onset ranged from
32 to 40 years, with the initial manifestation being new-onset seizures.
Dementia developed in all affected members within 3 years of seizure
onset and was characterized by impaired episodic memory, visual/spatial
abilities, and executive function. Motor symptoms included myoclonus and
extrapyramidal symptoms. Detailed postmortem examination of 1 patient
showed cortical atrophy and autofluorescent granular accumulations in
neurons of the cortex, basal ganglia, thalamus, brainstem, and
cerebellum. Ultrastructural examination of the granular deposits did not
show fingerprint or curvilinear profiles.
Nijssen et al. (2002) reported a Dutch family with autosomal dominant
Kufs disease. There were 6 affected individuals in 3 generations, with
an age of onset ranging from 24 to 46 years. Clinical features were
similar to previously reported cases, including seizures, myoclonus, and
dementia. Parkinsonian features such as rigidity, short-stepped gait,
masked face, and stooped posture were also present in later stages of
the disease. Some individuals also had hearing impairment.
Neuropathologic examination of some affected individuals showed
ballooned cells with autofluorescent and PAS-positive intraneuronal
storage material and granular osmiophilic deposits.
Burneo et al. (2003) reported a family from Alabama with the disorder in
which at least 4 generations were affected. In addition to seizures,
dementia, and myoclonus, several affected individuals also had
parkinsonism. Noskova et al. (2011) had excluded a mutation in the
DNAJC5 gene in the family reported by Burneo et al. (2003), but
Cadieux-Dion et al. (2013) did find a DNAJC5 mutation (611203.0001) in
this family.
Noskova et al. (2011) reported a 3-generation Czech family with
autosomal dominant adult-onset CLN. The proband presented at age 30 with
myoclonic epilepsy, generalized tonic-clonic seizures, and progressive
cognitive deterioration with depression; these symptoms were followed by
progressive motor neurologic symptoms leading to death at age 37 years.
Neuropathologic examination of postmortem brain tissue showed
characteristic neurolysosomal storage of autofluorescent material with
ultrastructural appearance corresponding to granular osmiophilic
deposits (GROD). Other family members showed a similar clinical course.
INHERITANCE
The transmission pattern in the family with adult-onset NCL reported by
Boehme et al. (1971) was consistent with autosomal dominant inheritance.
MAPPING
By linkage analysis of the large family with adult-onset NCL reported by
Boehme et al. (1971), Cadieux-Dion et al. (2013) found linkage to a
3.8-Mb region on chromosome 20q13.33 (maximum multipoint lod score of
5.3 at SNP dbSNP rs11204451).
MOLECULAR GENETICS
In a Czech family with autosomal dominant adult-onset ceroid neuronal
lipofuscinosis-4B, Noskova et al. (2011) identified a heterozygous
mutation in the DNAJC5 gene (leu116del; 611203.0001). The mutation was
found by using a combination of linkage analysis, copy-number analysis,
gene-expression analysis, and exome sequencing of candidate genes.
Screening of this gene in 20 additional families identified pathogenic
mutations in 4 (611203.0001 or L115R, 611203.0002). Two of the families
had been reported by Josephson et al. (2001) and Nijssen et al. (2002).
By linkage analysis combined with exome sequencing in the large family
(Parry) reported by Boehme et al. (1971), Cadieux-Dion et al. (2013)
identified a heterozygous leu116del mutation in the DNAJC5 gene
(611203.0001). The mutation was confirmed by Sanger sequencing, was not
found in 380 control chromosomes, and segregated with the disorder in
the family. The American patient reported by Noskova et al. (2011) who
carried this mutation was found to be from the Parry family.
Cadieux-Dion et al. (2013) also identified the leu116del mutation in
affected members of a family from Alabama reported by Burneo et al.
(2003), even though the mutation in this family had not been found by
Noskova et al. (2011). Haplotype analysis did not show a founder effect
between the 2 families, suggesting that it is a recurrent mutation.
Cadieux-Dion et al. (2013) also identified a heterozygous L115R mutation
in 1 of 6 additional patients with the disorder; this patient had no
family history. Overall, DNAJC5 mutations accounted for 38% of cases
with unexplained adult-onset NCL in their cohort, with the mutations
occurring at mutational hotspots.
*FIELD* SA
Brodner et al. (1976)
*FIELD* RF
1. Armstrong, D.; Dimmitt, S.; Boehme, D. H.; Leonberg, S. C., Jr.;
Vogel, W.: Leukocyte peroxidase deficiency in a family with a dominant
form of Kuf's (sic) disease. (Letter) Science 186: 155-156, 1974.
2. Boehme, D. H.; Cottrell, J. C.; Leonberg, S. C.; Zeman, W.: A
dominant form of neuronal ceroid-lipofuscinosis. Brain 94: 745-760,
1971.
3. Brodner, R. A.; Noh, J. M.: Early diagnosis of Kufs' disease.
(Letter) Lancet 308308308: 1024 only, 1976. Note: Originally Volume
II.
4. Brodner, R. A.; Noh, J. M.; Fine, E. J.: A dominant form of adult
neuronal ceroid-lipofuscinosis (Kufs' disease) with an associated
occipital astrocytoma: early diagnosis by cortical biopsy. J. Neurol.
Neurosurg. Psychiat. 39: 231-238, 1976.
5. Burneo, J. G.; Arnold, T.; Palmer, C. A.; Kuzniecky, R. I.; Oh,
S. J.; Faught, E.: Adult-onset neuronal ceroid lipofuscinosis (Kufs
disease) with autosomal dominant inheritance in Alabama. Epilepsia 44:
841-846, 2003.
6. Cadieux-Dion, M.; Andermann, E.; Lachance-Touchette, P.; Ansorge,
O.; Meloche, C.; Barnabe, A.; Kuzniecky, R. I.; Andermann, F.; Faught,
E.; Leonberg, S.; Damiano, J. A.; Berkovic, S. F.; Rouleau, G. A.;
Cossette, P.: Recurrent mutations in DNAJC5 cause autosomal dominant
Kufs disease. Clin. Genet. 83: 571-575, 2013.
7. Ferrer, I.; Arbizu, T.; Pena, J.; Serra, J. P.: A Golgi and ultrastructural
study of a dominant form of Kufs' disease. J. Neurol. 222: 183-190,
1980.
8. Goebel, H. H.; Braak, H.: Adult neuronal ceroid-lipofuscinosis. Clin.
Neuropath. 8: 109-119, 1989.
9. Josephson, S. A.; Schmidt, R. E.; Millsap, P.; McManus, D. Q.;
Morris, J. C.: Autosomal dominant Kufs' disease: a cause of early
onset dementia. J. Neurol. Sci. 188: 51-60, 2001.
10. Nijssen, P. C. G.; Brusse, E.; Leyten, A. C. M.; Martin, J. J.;
Teepen, J. L. J. M.; Roos, R. A. C.: Autosomal dominant adult neuronal
ceroid lipofuscinosis: parkinsonism due to both striatal and nigral
dysfunction. Mov. Disord. 17: 482-487, 2002.
11. Noskova, L.; Stranecky, V.; Hartmannova, H.; Pristoupilova, A.;
Baresova, V.; Ivanek, R.; Hulkova, H.; Jahnova, H.; van der Zee, J.;
Staropoli, J. F.; Sims, K. B.; Tyynela, J.; Van Broeckhoven, C.; Nijssen,
P. C. G.; Mole, S. E.; Elleder, M.; Kmoch, S.: Mutations in DNAJC5,
encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset
neuronal ceroid lipofuscinosis. Am. J. Hum. Genet. 89: 241-252,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 241-252, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Seizures;
Dementia;
Speech deterioration;
Myoclonus;
Cerebellar signs;
Cerebellar ataxia;
Parkinsonism may occur;
Extrapyramidal signs;
Autofluorescent lipopigment in neurons;
[Behavioral/psychiatric manifestations];
Behavioral changes;
Depression;
Auditory and visual hallucinations
LABORATORY ABNORMALITIES:
'Fingerprint' profiles ultrastructurally;
'Curvilinear' profiles ultrastructurally;
'Rectilinear' profiles ultrastructurally;
Granular osmiophilic deposits (GROD) in cells
MISCELLANEOUS:
Onset in adulthood (third to fourth decade);
Rapidly progressive;
For similar autosomal recessive form, see CLN4 (204300)
MOLECULAR BASIS:
Caused by mutation in the DNAJ/HSP40 homolog, subfamily C, member
5 gene (DNAJC5, 611203.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - revised: 7/23/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/24/2013
ckniffin: 6/3/2013
ckniffin: 9/19/2011
ckniffin: 5/5/2006
joanna: 1/21/2004
ckniffin: 7/30/2003
joanna: 7/16/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - updated: 9/15/2011
Cassandra L. Kniffin - updated: 5/5/2006
Cassandra L. Kniffin - reorganized: 7/31/2003
Cassandra L. Kniffin - updated: 7/30/2003
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 08/14/2013
ckniffin: 8/8/2013
carol: 6/7/2013
ckniffin: 6/3/2013
carol: 10/21/2011
carol: 9/16/2011
ckniffin: 9/15/2011
wwang: 5/17/2011
terry: 1/30/2009
ckniffin: 7/6/2007
wwang: 5/15/2006
ckniffin: 5/5/2006
terry: 2/22/2005
terry: 7/27/2004
alopez: 3/17/2004
tkritzer: 10/14/2003
carol: 7/31/2003
ckniffin: 7/30/2003
carol: 7/9/2003
alopez: 10/29/1999
dkim: 7/23/1998
mimadm: 12/2/1994
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
*RECORD*
*FIELD* NO
162350
*FIELD* TI
#162350 CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT; CLN4B
;;KUFS DISEASE, AUTOSOMAL DOMINANT;;
read moreCEROID LIPOFUSCINOSIS, NEURONAL, PARRY TYPE
*FIELD* TX
A number sign (#) is used with this entry because neuronal
lipofuscinosis-4B (CLN4B) is caused by heterozygous mutation in the
DNAJC5 gene (611203) on chromosome 20q13.
DESCRIPTION
The neuronal ceroid lipofuscinoses are a group of progressive
neurodegenerative diseases characterized by accumulation of
intracellular autofluorescent lipopigment storage material in the brain
and other tissues. Several different forms have been described according
to age of onset (see, e.g., CLN3, 204200). An adult form, sometimes
referred to as Kufs disease, is distinguished clinically by onset of
symptoms in adulthood and by absence of ocular involvement.
For a general phenotypic description and a discussion of genetic
heterogeneity of CLN, see CLN1 (256730).
CLINICAL FEATURES
Boehme et al. (1971) reported a family (named Parry) in which 11
individuals over 4 generations were affected with adult-onset neuronal
ceroid lipofuscinosis (NCL) in an autosomal dominant pattern of
inheritance. The strikingly consistent clinical picture was onset of a
cerebellar syndrome at about age 31 years, followed by seizures,
myoclonic jerks, and progressive dementia. Pathologic features included
neuronal loss and accumulation of lipopigment in remaining neurons. No
curvilinear or fingerprint patterns were apparent on ultrastructural
examination. Armstrong et al. (1974) studied 3 sibs from Boehme's family
and found that all 3 had low peroxidase although only 2 were clinically
affected. Brodner and Noh (1976) studied a 24-year-old man from the
family reported by Boehme et al. (1971). Cortical biopsy at the time of
craniotomy for removal of astrocytoma showed changes indicative of Kufs
disease.
Ferrer et al. (1980) reported a family with autosomal dominant Kufs
disease with 6 affected individuals in 2 generations. Disease onset
ranged from age 33 to 37 years and was characterized by progressive
dementia and involuntary movements of the face and neck. One affected
individual had seizures. Brain biopsy showed mild neuronal loss and the
accumulation of a granular, membrane-bound product resembling lipofuscin
with occasional dense compact rectilinear profiles, but no fingerprint
or curvilinear profiles.
Goebel and Braak (1989) provided a detailed review of adult-onset NCL.
Psychiatric and behavioral changes, mental deterioration, seizures,
extrapyramidal symptoms, and ataxia dominate the clinical picture, while
ocular symptoms are conspicuously absent.
Josephson et al. (2001) reported a family of English ancestry in which
10 members over 5 generations had Kufs disease. Age of onset ranged from
32 to 40 years, with the initial manifestation being new-onset seizures.
Dementia developed in all affected members within 3 years of seizure
onset and was characterized by impaired episodic memory, visual/spatial
abilities, and executive function. Motor symptoms included myoclonus and
extrapyramidal symptoms. Detailed postmortem examination of 1 patient
showed cortical atrophy and autofluorescent granular accumulations in
neurons of the cortex, basal ganglia, thalamus, brainstem, and
cerebellum. Ultrastructural examination of the granular deposits did not
show fingerprint or curvilinear profiles.
Nijssen et al. (2002) reported a Dutch family with autosomal dominant
Kufs disease. There were 6 affected individuals in 3 generations, with
an age of onset ranging from 24 to 46 years. Clinical features were
similar to previously reported cases, including seizures, myoclonus, and
dementia. Parkinsonian features such as rigidity, short-stepped gait,
masked face, and stooped posture were also present in later stages of
the disease. Some individuals also had hearing impairment.
Neuropathologic examination of some affected individuals showed
ballooned cells with autofluorescent and PAS-positive intraneuronal
storage material and granular osmiophilic deposits.
Burneo et al. (2003) reported a family from Alabama with the disorder in
which at least 4 generations were affected. In addition to seizures,
dementia, and myoclonus, several affected individuals also had
parkinsonism. Noskova et al. (2011) had excluded a mutation in the
DNAJC5 gene in the family reported by Burneo et al. (2003), but
Cadieux-Dion et al. (2013) did find a DNAJC5 mutation (611203.0001) in
this family.
Noskova et al. (2011) reported a 3-generation Czech family with
autosomal dominant adult-onset CLN. The proband presented at age 30 with
myoclonic epilepsy, generalized tonic-clonic seizures, and progressive
cognitive deterioration with depression; these symptoms were followed by
progressive motor neurologic symptoms leading to death at age 37 years.
Neuropathologic examination of postmortem brain tissue showed
characteristic neurolysosomal storage of autofluorescent material with
ultrastructural appearance corresponding to granular osmiophilic
deposits (GROD). Other family members showed a similar clinical course.
INHERITANCE
The transmission pattern in the family with adult-onset NCL reported by
Boehme et al. (1971) was consistent with autosomal dominant inheritance.
MAPPING
By linkage analysis of the large family with adult-onset NCL reported by
Boehme et al. (1971), Cadieux-Dion et al. (2013) found linkage to a
3.8-Mb region on chromosome 20q13.33 (maximum multipoint lod score of
5.3 at SNP dbSNP rs11204451).
MOLECULAR GENETICS
In a Czech family with autosomal dominant adult-onset ceroid neuronal
lipofuscinosis-4B, Noskova et al. (2011) identified a heterozygous
mutation in the DNAJC5 gene (leu116del; 611203.0001). The mutation was
found by using a combination of linkage analysis, copy-number analysis,
gene-expression analysis, and exome sequencing of candidate genes.
Screening of this gene in 20 additional families identified pathogenic
mutations in 4 (611203.0001 or L115R, 611203.0002). Two of the families
had been reported by Josephson et al. (2001) and Nijssen et al. (2002).
By linkage analysis combined with exome sequencing in the large family
(Parry) reported by Boehme et al. (1971), Cadieux-Dion et al. (2013)
identified a heterozygous leu116del mutation in the DNAJC5 gene
(611203.0001). The mutation was confirmed by Sanger sequencing, was not
found in 380 control chromosomes, and segregated with the disorder in
the family. The American patient reported by Noskova et al. (2011) who
carried this mutation was found to be from the Parry family.
Cadieux-Dion et al. (2013) also identified the leu116del mutation in
affected members of a family from Alabama reported by Burneo et al.
(2003), even though the mutation in this family had not been found by
Noskova et al. (2011). Haplotype analysis did not show a founder effect
between the 2 families, suggesting that it is a recurrent mutation.
Cadieux-Dion et al. (2013) also identified a heterozygous L115R mutation
in 1 of 6 additional patients with the disorder; this patient had no
family history. Overall, DNAJC5 mutations accounted for 38% of cases
with unexplained adult-onset NCL in their cohort, with the mutations
occurring at mutational hotspots.
*FIELD* SA
Brodner et al. (1976)
*FIELD* RF
1. Armstrong, D.; Dimmitt, S.; Boehme, D. H.; Leonberg, S. C., Jr.;
Vogel, W.: Leukocyte peroxidase deficiency in a family with a dominant
form of Kuf's (sic) disease. (Letter) Science 186: 155-156, 1974.
2. Boehme, D. H.; Cottrell, J. C.; Leonberg, S. C.; Zeman, W.: A
dominant form of neuronal ceroid-lipofuscinosis. Brain 94: 745-760,
1971.
3. Brodner, R. A.; Noh, J. M.: Early diagnosis of Kufs' disease.
(Letter) Lancet 308308308: 1024 only, 1976. Note: Originally Volume
II.
4. Brodner, R. A.; Noh, J. M.; Fine, E. J.: A dominant form of adult
neuronal ceroid-lipofuscinosis (Kufs' disease) with an associated
occipital astrocytoma: early diagnosis by cortical biopsy. J. Neurol.
Neurosurg. Psychiat. 39: 231-238, 1976.
5. Burneo, J. G.; Arnold, T.; Palmer, C. A.; Kuzniecky, R. I.; Oh,
S. J.; Faught, E.: Adult-onset neuronal ceroid lipofuscinosis (Kufs
disease) with autosomal dominant inheritance in Alabama. Epilepsia 44:
841-846, 2003.
6. Cadieux-Dion, M.; Andermann, E.; Lachance-Touchette, P.; Ansorge,
O.; Meloche, C.; Barnabe, A.; Kuzniecky, R. I.; Andermann, F.; Faught,
E.; Leonberg, S.; Damiano, J. A.; Berkovic, S. F.; Rouleau, G. A.;
Cossette, P.: Recurrent mutations in DNAJC5 cause autosomal dominant
Kufs disease. Clin. Genet. 83: 571-575, 2013.
7. Ferrer, I.; Arbizu, T.; Pena, J.; Serra, J. P.: A Golgi and ultrastructural
study of a dominant form of Kufs' disease. J. Neurol. 222: 183-190,
1980.
8. Goebel, H. H.; Braak, H.: Adult neuronal ceroid-lipofuscinosis. Clin.
Neuropath. 8: 109-119, 1989.
9. Josephson, S. A.; Schmidt, R. E.; Millsap, P.; McManus, D. Q.;
Morris, J. C.: Autosomal dominant Kufs' disease: a cause of early
onset dementia. J. Neurol. Sci. 188: 51-60, 2001.
10. Nijssen, P. C. G.; Brusse, E.; Leyten, A. C. M.; Martin, J. J.;
Teepen, J. L. J. M.; Roos, R. A. C.: Autosomal dominant adult neuronal
ceroid lipofuscinosis: parkinsonism due to both striatal and nigral
dysfunction. Mov. Disord. 17: 482-487, 2002.
11. Noskova, L.; Stranecky, V.; Hartmannova, H.; Pristoupilova, A.;
Baresova, V.; Ivanek, R.; Hulkova, H.; Jahnova, H.; van der Zee, J.;
Staropoli, J. F.; Sims, K. B.; Tyynela, J.; Van Broeckhoven, C.; Nijssen,
P. C. G.; Mole, S. E.; Elleder, M.; Kmoch, S.: Mutations in DNAJC5,
encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset
neuronal ceroid lipofuscinosis. Am. J. Hum. Genet. 89: 241-252,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 241-252, 2011.
*FIELD* CS
INHERITANCE:
Autosomal dominant
NEUROLOGIC:
[Central nervous system];
Seizures;
Dementia;
Speech deterioration;
Myoclonus;
Cerebellar signs;
Cerebellar ataxia;
Parkinsonism may occur;
Extrapyramidal signs;
Autofluorescent lipopigment in neurons;
[Behavioral/psychiatric manifestations];
Behavioral changes;
Depression;
Auditory and visual hallucinations
LABORATORY ABNORMALITIES:
'Fingerprint' profiles ultrastructurally;
'Curvilinear' profiles ultrastructurally;
'Rectilinear' profiles ultrastructurally;
Granular osmiophilic deposits (GROD) in cells
MISCELLANEOUS:
Onset in adulthood (third to fourth decade);
Rapidly progressive;
For similar autosomal recessive form, see CLN4 (204300)
MOLECULAR BASIS:
Caused by mutation in the DNAJ/HSP40 homolog, subfamily C, member
5 gene (DNAJC5, 611203.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - revised: 7/23/2002
*FIELD* CD
John F. Jackson: 6/15/1995
*FIELD* ED
joanna: 07/24/2013
ckniffin: 6/3/2013
ckniffin: 9/19/2011
ckniffin: 5/5/2006
joanna: 1/21/2004
ckniffin: 7/30/2003
joanna: 7/16/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - updated: 9/15/2011
Cassandra L. Kniffin - updated: 5/5/2006
Cassandra L. Kniffin - reorganized: 7/31/2003
Cassandra L. Kniffin - updated: 7/30/2003
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 08/14/2013
ckniffin: 8/8/2013
carol: 6/7/2013
ckniffin: 6/3/2013
carol: 10/21/2011
carol: 9/16/2011
ckniffin: 9/15/2011
wwang: 5/17/2011
terry: 1/30/2009
ckniffin: 7/6/2007
wwang: 5/15/2006
ckniffin: 5/5/2006
terry: 2/22/2005
terry: 7/27/2004
alopez: 3/17/2004
tkritzer: 10/14/2003
carol: 7/31/2003
ckniffin: 7/30/2003
carol: 7/9/2003
alopez: 10/29/1999
dkim: 7/23/1998
mimadm: 12/2/1994
supermim: 3/16/1992
carol: 3/3/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
MIM
611203
*RECORD*
*FIELD* NO
611203
*FIELD* TI
*611203 DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5
;;DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5, ALPHA; DNAJC5A;;
read moreCYSTEINE STRING PROTEIN; CSP;;
CSP-ALPHA
*FIELD* TX
DESCRIPTION
The DNAJC5 gene encodes the cysteine string protein, a presynaptic J
protein expressed in neural tissues as well as in synaptic and
clathrin-coated vesicles (summary by Cadieux-Dion et al., 2013).
CLONING
Using antibody directed against rat Csp to screen a brain cDNA
expression library, Coppola and Gundersen (1996) obtained a full-length
human CSP clone. The deduced 198-amino acid protein differs from rat Csp
at only 1 residue. Coppola and Gundersen (1996) also cloned a splice
variant of CSP that contains a 72-nucleotide insertion that introduces
an in-frame stop codon. This variant encodes a deduced 167-amino acid
protein that is identical to the full-length protein for the first 164
amino acids. Northern blot analysis detected at least 3 CSP variants in
all 8 human tissues examined. Western blot analysis of human blood
detected CSP at an apparent molecular mass of 35 kD. Treatment with a
deacylating agent caused a downward shift of 7 kD in apparent mass.
Tobaben et al. (2001) showed that the 198-amino acid rat Csp protein
contains an N-terminal J domain, followed by a cysteine string and a
C-terminal domain. They noted that most of the cysteines are
palmitoylated and are required for membrane targeting of Csp.
Using real-time RT-PCR, Fernandez-Chacon et al. (2004) detected
Csp-alpha in mouse brain and testis.
Natochin et al. (2005) stated that rat Csp has 2 binding sites for G
proteins, one that overlaps the J domain and binds G-alpha subunits (see
GNAS, 139320), and another between the J domain and cysteine string that
binds G-beta (see GNB1, 139380) and/or the G-alpha-beta-gamma (see GNG2,
606981) trimer.
GENE FUNCTION
Tobaben et al. (2001) showed that rat Csp interacted with Sgt (SGTA;
603419) and Hsc70 (HSPA8; 600816) in a complex located on the synaptic
vesicle surface. The complex functioned as an ATP-dependent chaperone
that reactivated a denatured substrate. Sgt overexpression in cultured
rat hippocampal neurons inhibited neurotransmitter release, suggesting
that the Csp/Sgt/Hsc70 complex is important for maintenance of a normal
synapse.
Miller et al. (2003) stated that rat Csp binds both the N-type calcium
channel (see 601012) and G protein beta-gamma subunits in vitro, and
that these associations give rise to tonic G protein inhibition of the
calcium channel. They showed that an N-terminal fragment of human
huntingtin (HTT; 613004) with an expanded polyglutamine tract blocked
association of Csp with G proteins and eliminated Csp's tonic G protein
inhibition of N-type calcium channels. In contrast, an N-terminal
huntingtin fragment without an expanded polyglutamine tract did not
alter association of Csp with G proteins and had no effect on channel
inhibition by Csp.
Natochin et al. (2005) showed that rat Csp stimulated GDP/GTP exchange
on G-alpha-S. Modulation of G proteins by Csp was, in turn, regulated by
Hsc70 and Sgt.
MAPPING
Gross (2011) mapped the DNAJC5 gene to chromosome 20q13.33 based on an
alignment of the DNAJC5 sequence (GenBank GENBANK BC053642) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In a Czech family with autosomal dominant adult-onset ceroid neuronal
lipofuscinosis-4B (CLN4B; 162350), Noskova et al. (2011) identified a
heterozygous mutation 3-bp deletion in the DNAJC5 gene (Leu116del;
611203.0001). The mutation was found by using a combination of linkage
analysis, copy-number analysis, gene-expression analysis, and exome
sequencing of candidate genes. Screening of this gene in 20 additional
families identified pathogenic mutations in 4. Two of the families had
been reported by Josephson et al. (2001) and Nijssen et al. (2002). The
patients had onset of rapidly progressive neurodegenerative disorder
with onset in the third or fourth decades.
By linkage analysis combined with exome sequencing in the large family
(Parry family) with adult-onset CLN reported by Boehme et al. (1971),
Cadieux-Dion et al. (2013) identified heterozygosity for the leu116del
mutation in the DNAJC5 gene (611203.0001). The mutation was confirmed by
Sanger sequencing, was not found in 380 control chromosomes, and
segregated with the disorder in the family. The American patient
reported by Noskova et al. (2011) who carried this mutation was found to
be from the Parry family. Cadieux-Dion et al. (2013) also identified the
leu116del mutation in affected members of a family from Alabama reported
by Burneo et al. (2003). Haplotype analysis did not show a founder
effect between the 2 families, suggesting that it is a recurrent
mutation. Cadieux-Dion et al. (2013) also identified a heterozygous
L115R mutation in the DNAJC5 gene (61103.0002) in 1 of 6 additional
patients with the disorder; this patient had no family history. Overall,
DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset
NCL in their cohort, with the mutations occurring at mutational
hotspots.
ANIMAL MODEL
Fernandez-Chacon et al. (2004) found that Csp-alpha -/- mice appeared
normal at birth but developed a progressive lethal phenotype that
manifested as muscle weakness and a sensorimotor disorder at 2 to 4
weeks of age. Analysis of synaptic transmission in Csp-alpha -/-
neuromuscular junctions and at the Calyx of Held synapse revealed normal
Ca(2+) channel function and Ca(2+)-dependent exocytosis. However,
synapses showed progressively worsening presynaptic degeneration, with
persistent vacuoles, proliferation of multilamellar bodies, and
protrusion of Schwann cell fingers into the neuromuscular nerve
terminal. Coppola and Gundersen (1996) concluded that the degeneration
of Csp-alpha -/- synapses appeared to occur in a use-dependent manner
and that CSP-alpha is required to maintain the integrity of synapses in
the face of use-dependent stress.
*FIELD* AV
.0001
CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT
DNAJC5, 3-BP DEL, 346CTC
In affected members of a Czech family with autosomal dominant
adult-onset neuronal ceroid lipofuscinosis-4B (CLN4B; 162350), Noskova
et al. (2011) identified a heterozygous 3-bp deletion (346delCTC) in the
DNAJC5 gene, resulting in a deletion of leu116 in a conserved region of
the cysteine-string domain of the protein. Screening of this gene in 20
additional families identified this mutation in 1 affected American
patient who had a family history of the disorder. The patients had onset
of rapidly progressive neurodegenerative disorder with onset in the
third or fourth decades. Haplotype analysis did not suggest a common
origin. The mutation was not found in 200 controls. In vitro functional
expression in CAD5 neuronal cells showed that the mutant protein had
abnormal diffuse intracellular localization and abnormal colocalization
with markers for the endoplasmic reticulum and Golgi apparatus.
Immunoblot analysis indicated that the mutant protein was less
efficiently palmitoylated compared to wildtype. Analysis of brain tissue
from affected individuals showed significantly reduced immunostaining
for DNAJC5 in the cerebral cortex compared to controls.
By linkage analysis combined with exome sequencing in the large family
(Parry family) with adult-onset CLN reported by Boehme et al. (1971),
Cadieux-Dion et al. (2013) identified a heterozygous leu116del mutation.
The mutation was confirmed by Sanger sequencing, was not found in 380
control chromosomes, and segregated with the disorder in the family. The
American patient reported by Noskova et al. (2011) who carried this
mutation was found to be from the Parry family. Cadieux-Dion et al.
(2013) also identified the leu116del mutation in affected members of a
family from Alabama reported by Burneo et al. (2003), even though the
mutation in this family had not been found by Noskova et al. (2011).
Haplotype analysis did not show a founder effect between the 2 families,
suggesting that it is a recurrent mutation.
.0002
CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT
DNAJC5, LEU115ARG
In affected members of 2 unrelated families and 1 patient with autosomal
dominant adult-onset neuronal ceroid lipofuscinosis-4B (162350), Noskova
et al. (2011) identified a heterozygous 344T-G transversion in the
DNAJC5 gene, resulting in a leu115-to-arg (L115R) substitution in a
conserved residue in the cysteine-string domain of the protein. Two of
the families had been reported by Josephson et al. (2001) and Nijssen et
al. (2002). The mutation was not found in 200 controls. Haplotype
analysis did not suggest a common origin. In vitro functional expression
in CAD5 neuronal cells showed that the mutant protein had abnormal
diffuse intracellular localization and abnormal colocalization with
markers for the endoplasmic reticulum and Golgi apparatus. Immunoblot
analysis indicated that the mutant protein was less efficiently
palmitoylated compared to wildtype. Analysis of brain tissue from
affected individuals showed absence of immunostaining for DNAJC5 in
synaptic regions in both the cerebral and cerebellar cortex compared to
controls. However, there was some evidence for an insoluble
DNAJC5-containing aggregate in brain lysate.
Cadieux-Dion et al. (2013) identified a heterozygous L115R mutation in a
patient with sporadic occurrence of CLN4B.
*FIELD* RF
1. Boehme, D. H.; Cottrell, J. C.; Leonberg, S. C.; Zeman, W.: A
dominant form of neuronal ceroid-lipofuscinosis. Brain 94: 745-760,
1971.
2. Burneo, J. G.; Arnold, T.; Palmer, C. A.; Kuzniecky, R. I.; Oh,
S. J.; Faught, E.: Adult-onset neuronal ceroid lipofuscinosis (Kufs
disease) with autosomal dominant inheritance in Alabama. Epilepsia 44:
841-846, 2003.
3. Cadieux-Dion, M.; Andermann, E.; Lachance-Touchette, P.; Ansorge,
O.; Meloche, C.; Barnabe, A.; Kuzniecky, R. I.; Andermann, F.; Faught,
E.; Leonberg, S.; Damiano, J. A.; Berkovic, S. F.; Rouleau, G. A.;
Cossette, P.: Recurrent mutations in DNAJC5 cause autosomal dominant
Kufs disease. Clin. Genet. 83: 571-575, 2013.
4. Coppola, T.; Gundersen, C.: Widespread expression of human cysteine
string proteins. FEBS Lett. 391: 269-272, 1996.
5. Fernandez-Chacon, R.; Wolfel, M.; Nishimune, H.; Tabares, L.; Schmitz,
F.; Castellano-Munoz, M.; Rosenmund, C.; Montesinos, M. L.; Sanes,
J. R.; Schneggenburger, R.; Sudhof, T. C.: The synaptic vesicle protein
CSP-alpha prevents presynaptic degeneration. Neuron 42: 237-251,
2004.
6. Gross, M. B.: Personal Communication. Baltimore, Md. 4/28/2011.
7. Josephson, S. A.; Schmidt, R. E.; Millsap, P.; McManus, D. Q.;
Morris, J. C.: Autosomal dominant Kufs' disease: a cause of early
onset dementia. J. Neurol. Sci. 188: 51-60, 2001.
8. Miller, L. C.; Swayne, L. A.; Chen, L.; Feng, Z.-P.; Wacker, J.
L.; Muchowski, P. J.; Zamponi, G. W.; Braun, J. E. A.: Cysteine string
protein (CSP) inhibition of N-type calcium channels is blocked by
mutant huntingtin. J. Biol. Chem. 278: 53072-53081, 2003.
9. Natochin, M.; Campbell, T. N.; Barren, B.; Miller, L. C.; Hameed,
S.; Artemyev, N. O.; Braun, J. E. A.: Characterization of the G-alpha-s
regulator cysteine string protein. J. Biol. Chem. 280: 30236-30241,
2005.
10. Nijssen, P. C. G.; Brusse, E.; Leyten, A. C. M.; Martin, J. J.;
Teepen, J. L. J. M.; Roos, R. A. C.: Autosomal dominant adult neuronal
ceroid lipofuscinosis: parkinsonism due to both striatal and nigral
dysfunction. Mov. Disord. 17: 482-487, 2002.
11. Noskova, L.; Stranecky, V.; Hartmannova, H.; Pristoupilova, A.;
Baresova, V.; Ivanek, R.; Hulkova, H.; Jahnova, H.; van der Zee, J.;
Staropoli, J. F.; Sims, K. B.; Tyynela, J.; Van Broeckhoven, C.; Nijssen,
P. C. G.; Mole, S. E.; Elleder, M.; Kmoch, S.: Mutations in DNAJC5,
encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset
neuronal ceroid lipofuscinosis. Am. J. Hum. Genet. 89: 241-252,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 589 only, 2011.
12. Tobaben, S.; Thakur, P.; Fernandez-Chacon, R.; Sudhof, T. C.;
Rettig, J.; Stahl, B.: A trimeric protein complex functions as a
synaptic chaperone machine. Neuron 31: 987-999, 2001.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - updated: 9/15/2011
Matthew B. Gross - updated: 4/28/2011
Patricia A. Hartz - updated: 4/19/2011
*FIELD* CD
Patricia A. Hartz: 7/16/2007
*FIELD* ED
carol: 06/07/2013
ckniffin: 6/3/2013
carol: 10/21/2011
carol: 9/16/2011
ckniffin: 9/15/2011
mgross: 4/28/2011
terry: 4/19/2011
wwang: 9/15/2009
carol: 8/17/2007
mgross: 7/16/2007
*RECORD*
*FIELD* NO
611203
*FIELD* TI
*611203 DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5; DNAJC5
;;DNAJ/HSP40 HOMOLOG, SUBFAMILY C, MEMBER 5, ALPHA; DNAJC5A;;
read moreCYSTEINE STRING PROTEIN; CSP;;
CSP-ALPHA
*FIELD* TX
DESCRIPTION
The DNAJC5 gene encodes the cysteine string protein, a presynaptic J
protein expressed in neural tissues as well as in synaptic and
clathrin-coated vesicles (summary by Cadieux-Dion et al., 2013).
CLONING
Using antibody directed against rat Csp to screen a brain cDNA
expression library, Coppola and Gundersen (1996) obtained a full-length
human CSP clone. The deduced 198-amino acid protein differs from rat Csp
at only 1 residue. Coppola and Gundersen (1996) also cloned a splice
variant of CSP that contains a 72-nucleotide insertion that introduces
an in-frame stop codon. This variant encodes a deduced 167-amino acid
protein that is identical to the full-length protein for the first 164
amino acids. Northern blot analysis detected at least 3 CSP variants in
all 8 human tissues examined. Western blot analysis of human blood
detected CSP at an apparent molecular mass of 35 kD. Treatment with a
deacylating agent caused a downward shift of 7 kD in apparent mass.
Tobaben et al. (2001) showed that the 198-amino acid rat Csp protein
contains an N-terminal J domain, followed by a cysteine string and a
C-terminal domain. They noted that most of the cysteines are
palmitoylated and are required for membrane targeting of Csp.
Using real-time RT-PCR, Fernandez-Chacon et al. (2004) detected
Csp-alpha in mouse brain and testis.
Natochin et al. (2005) stated that rat Csp has 2 binding sites for G
proteins, one that overlaps the J domain and binds G-alpha subunits (see
GNAS, 139320), and another between the J domain and cysteine string that
binds G-beta (see GNB1, 139380) and/or the G-alpha-beta-gamma (see GNG2,
606981) trimer.
GENE FUNCTION
Tobaben et al. (2001) showed that rat Csp interacted with Sgt (SGTA;
603419) and Hsc70 (HSPA8; 600816) in a complex located on the synaptic
vesicle surface. The complex functioned as an ATP-dependent chaperone
that reactivated a denatured substrate. Sgt overexpression in cultured
rat hippocampal neurons inhibited neurotransmitter release, suggesting
that the Csp/Sgt/Hsc70 complex is important for maintenance of a normal
synapse.
Miller et al. (2003) stated that rat Csp binds both the N-type calcium
channel (see 601012) and G protein beta-gamma subunits in vitro, and
that these associations give rise to tonic G protein inhibition of the
calcium channel. They showed that an N-terminal fragment of human
huntingtin (HTT; 613004) with an expanded polyglutamine tract blocked
association of Csp with G proteins and eliminated Csp's tonic G protein
inhibition of N-type calcium channels. In contrast, an N-terminal
huntingtin fragment without an expanded polyglutamine tract did not
alter association of Csp with G proteins and had no effect on channel
inhibition by Csp.
Natochin et al. (2005) showed that rat Csp stimulated GDP/GTP exchange
on G-alpha-S. Modulation of G proteins by Csp was, in turn, regulated by
Hsc70 and Sgt.
MAPPING
Gross (2011) mapped the DNAJC5 gene to chromosome 20q13.33 based on an
alignment of the DNAJC5 sequence (GenBank GENBANK BC053642) with the
genomic sequence (GRCh37).
MOLECULAR GENETICS
In a Czech family with autosomal dominant adult-onset ceroid neuronal
lipofuscinosis-4B (CLN4B; 162350), Noskova et al. (2011) identified a
heterozygous mutation 3-bp deletion in the DNAJC5 gene (Leu116del;
611203.0001). The mutation was found by using a combination of linkage
analysis, copy-number analysis, gene-expression analysis, and exome
sequencing of candidate genes. Screening of this gene in 20 additional
families identified pathogenic mutations in 4. Two of the families had
been reported by Josephson et al. (2001) and Nijssen et al. (2002). The
patients had onset of rapidly progressive neurodegenerative disorder
with onset in the third or fourth decades.
By linkage analysis combined with exome sequencing in the large family
(Parry family) with adult-onset CLN reported by Boehme et al. (1971),
Cadieux-Dion et al. (2013) identified heterozygosity for the leu116del
mutation in the DNAJC5 gene (611203.0001). The mutation was confirmed by
Sanger sequencing, was not found in 380 control chromosomes, and
segregated with the disorder in the family. The American patient
reported by Noskova et al. (2011) who carried this mutation was found to
be from the Parry family. Cadieux-Dion et al. (2013) also identified the
leu116del mutation in affected members of a family from Alabama reported
by Burneo et al. (2003). Haplotype analysis did not show a founder
effect between the 2 families, suggesting that it is a recurrent
mutation. Cadieux-Dion et al. (2013) also identified a heterozygous
L115R mutation in the DNAJC5 gene (61103.0002) in 1 of 6 additional
patients with the disorder; this patient had no family history. Overall,
DNAJC5 mutations accounted for 38% of cases with unexplained adult-onset
NCL in their cohort, with the mutations occurring at mutational
hotspots.
ANIMAL MODEL
Fernandez-Chacon et al. (2004) found that Csp-alpha -/- mice appeared
normal at birth but developed a progressive lethal phenotype that
manifested as muscle weakness and a sensorimotor disorder at 2 to 4
weeks of age. Analysis of synaptic transmission in Csp-alpha -/-
neuromuscular junctions and at the Calyx of Held synapse revealed normal
Ca(2+) channel function and Ca(2+)-dependent exocytosis. However,
synapses showed progressively worsening presynaptic degeneration, with
persistent vacuoles, proliferation of multilamellar bodies, and
protrusion of Schwann cell fingers into the neuromuscular nerve
terminal. Coppola and Gundersen (1996) concluded that the degeneration
of Csp-alpha -/- synapses appeared to occur in a use-dependent manner
and that CSP-alpha is required to maintain the integrity of synapses in
the face of use-dependent stress.
*FIELD* AV
.0001
CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT
DNAJC5, 3-BP DEL, 346CTC
In affected members of a Czech family with autosomal dominant
adult-onset neuronal ceroid lipofuscinosis-4B (CLN4B; 162350), Noskova
et al. (2011) identified a heterozygous 3-bp deletion (346delCTC) in the
DNAJC5 gene, resulting in a deletion of leu116 in a conserved region of
the cysteine-string domain of the protein. Screening of this gene in 20
additional families identified this mutation in 1 affected American
patient who had a family history of the disorder. The patients had onset
of rapidly progressive neurodegenerative disorder with onset in the
third or fourth decades. Haplotype analysis did not suggest a common
origin. The mutation was not found in 200 controls. In vitro functional
expression in CAD5 neuronal cells showed that the mutant protein had
abnormal diffuse intracellular localization and abnormal colocalization
with markers for the endoplasmic reticulum and Golgi apparatus.
Immunoblot analysis indicated that the mutant protein was less
efficiently palmitoylated compared to wildtype. Analysis of brain tissue
from affected individuals showed significantly reduced immunostaining
for DNAJC5 in the cerebral cortex compared to controls.
By linkage analysis combined with exome sequencing in the large family
(Parry family) with adult-onset CLN reported by Boehme et al. (1971),
Cadieux-Dion et al. (2013) identified a heterozygous leu116del mutation.
The mutation was confirmed by Sanger sequencing, was not found in 380
control chromosomes, and segregated with the disorder in the family. The
American patient reported by Noskova et al. (2011) who carried this
mutation was found to be from the Parry family. Cadieux-Dion et al.
(2013) also identified the leu116del mutation in affected members of a
family from Alabama reported by Burneo et al. (2003), even though the
mutation in this family had not been found by Noskova et al. (2011).
Haplotype analysis did not show a founder effect between the 2 families,
suggesting that it is a recurrent mutation.
.0002
CEROID LIPOFUSCINOSIS, NEURONAL, 4B, AUTOSOMAL DOMINANT
DNAJC5, LEU115ARG
In affected members of 2 unrelated families and 1 patient with autosomal
dominant adult-onset neuronal ceroid lipofuscinosis-4B (162350), Noskova
et al. (2011) identified a heterozygous 344T-G transversion in the
DNAJC5 gene, resulting in a leu115-to-arg (L115R) substitution in a
conserved residue in the cysteine-string domain of the protein. Two of
the families had been reported by Josephson et al. (2001) and Nijssen et
al. (2002). The mutation was not found in 200 controls. Haplotype
analysis did not suggest a common origin. In vitro functional expression
in CAD5 neuronal cells showed that the mutant protein had abnormal
diffuse intracellular localization and abnormal colocalization with
markers for the endoplasmic reticulum and Golgi apparatus. Immunoblot
analysis indicated that the mutant protein was less efficiently
palmitoylated compared to wildtype. Analysis of brain tissue from
affected individuals showed absence of immunostaining for DNAJC5 in
synaptic regions in both the cerebral and cerebellar cortex compared to
controls. However, there was some evidence for an insoluble
DNAJC5-containing aggregate in brain lysate.
Cadieux-Dion et al. (2013) identified a heterozygous L115R mutation in a
patient with sporadic occurrence of CLN4B.
*FIELD* RF
1. Boehme, D. H.; Cottrell, J. C.; Leonberg, S. C.; Zeman, W.: A
dominant form of neuronal ceroid-lipofuscinosis. Brain 94: 745-760,
1971.
2. Burneo, J. G.; Arnold, T.; Palmer, C. A.; Kuzniecky, R. I.; Oh,
S. J.; Faught, E.: Adult-onset neuronal ceroid lipofuscinosis (Kufs
disease) with autosomal dominant inheritance in Alabama. Epilepsia 44:
841-846, 2003.
3. Cadieux-Dion, M.; Andermann, E.; Lachance-Touchette, P.; Ansorge,
O.; Meloche, C.; Barnabe, A.; Kuzniecky, R. I.; Andermann, F.; Faught,
E.; Leonberg, S.; Damiano, J. A.; Berkovic, S. F.; Rouleau, G. A.;
Cossette, P.: Recurrent mutations in DNAJC5 cause autosomal dominant
Kufs disease. Clin. Genet. 83: 571-575, 2013.
4. Coppola, T.; Gundersen, C.: Widespread expression of human cysteine
string proteins. FEBS Lett. 391: 269-272, 1996.
5. Fernandez-Chacon, R.; Wolfel, M.; Nishimune, H.; Tabares, L.; Schmitz,
F.; Castellano-Munoz, M.; Rosenmund, C.; Montesinos, M. L.; Sanes,
J. R.; Schneggenburger, R.; Sudhof, T. C.: The synaptic vesicle protein
CSP-alpha prevents presynaptic degeneration. Neuron 42: 237-251,
2004.
6. Gross, M. B.: Personal Communication. Baltimore, Md. 4/28/2011.
7. Josephson, S. A.; Schmidt, R. E.; Millsap, P.; McManus, D. Q.;
Morris, J. C.: Autosomal dominant Kufs' disease: a cause of early
onset dementia. J. Neurol. Sci. 188: 51-60, 2001.
8. Miller, L. C.; Swayne, L. A.; Chen, L.; Feng, Z.-P.; Wacker, J.
L.; Muchowski, P. J.; Zamponi, G. W.; Braun, J. E. A.: Cysteine string
protein (CSP) inhibition of N-type calcium channels is blocked by
mutant huntingtin. J. Biol. Chem. 278: 53072-53081, 2003.
9. Natochin, M.; Campbell, T. N.; Barren, B.; Miller, L. C.; Hameed,
S.; Artemyev, N. O.; Braun, J. E. A.: Characterization of the G-alpha-s
regulator cysteine string protein. J. Biol. Chem. 280: 30236-30241,
2005.
10. Nijssen, P. C. G.; Brusse, E.; Leyten, A. C. M.; Martin, J. J.;
Teepen, J. L. J. M.; Roos, R. A. C.: Autosomal dominant adult neuronal
ceroid lipofuscinosis: parkinsonism due to both striatal and nigral
dysfunction. Mov. Disord. 17: 482-487, 2002.
11. Noskova, L.; Stranecky, V.; Hartmannova, H.; Pristoupilova, A.;
Baresova, V.; Ivanek, R.; Hulkova, H.; Jahnova, H.; van der Zee, J.;
Staropoli, J. F.; Sims, K. B.; Tyynela, J.; Van Broeckhoven, C.; Nijssen,
P. C. G.; Mole, S. E.; Elleder, M.; Kmoch, S.: Mutations in DNAJC5,
encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset
neuronal ceroid lipofuscinosis. Am. J. Hum. Genet. 89: 241-252,
2011. Note: Erratum: Am. J. Hum. Genet. 89: 589 only, 2011.
12. Tobaben, S.; Thakur, P.; Fernandez-Chacon, R.; Sudhof, T. C.;
Rettig, J.; Stahl, B.: A trimeric protein complex functions as a
synaptic chaperone machine. Neuron 31: 987-999, 2001.
*FIELD* CN
Cassandra L. Kniffin - updated: 6/3/2013
Cassandra L. Kniffin - updated: 9/15/2011
Matthew B. Gross - updated: 4/28/2011
Patricia A. Hartz - updated: 4/19/2011
*FIELD* CD
Patricia A. Hartz: 7/16/2007
*FIELD* ED
carol: 06/07/2013
ckniffin: 6/3/2013
carol: 10/21/2011
carol: 9/16/2011
ckniffin: 9/15/2011
mgross: 4/28/2011
terry: 4/19/2011
wwang: 9/15/2009
carol: 8/17/2007
mgross: 7/16/2007