Full text data of DNAJB6
DNAJB6
(HSJ2, MRJ, MSJ1)
[Confidence: low (only semi-automatic identification from reviews)]
DnaJ homolog subfamily B member 6 (HHDJ1; Heat shock protein J2; HSJ-2; MRJ; MSJ-1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
DnaJ homolog subfamily B member 6 (HHDJ1; Heat shock protein J2; HSJ-2; MRJ; MSJ-1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
O75190
ID DNJB6_HUMAN Reviewed; 326 AA.
AC O75190; A4D232; A8K7D8; O95806; Q53EN8; Q59EF2; Q6FIC8; Q75MA2;
read moreAC Q9UIK6;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 18-OCT-2001, sequence version 2.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=DnaJ homolog subfamily B member 6;
DE AltName: Full=HHDJ1;
DE AltName: Full=Heat shock protein J2;
DE Short=HSJ-2;
DE AltName: Full=MRJ;
DE AltName: Full=MSJ-1;
GN Name=DNAJB6; Synonyms=HSJ2, MRJ, MSJ1;
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] (ISOFORM B), INTERACTION WITH PTTG, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=9915854; DOI=10.1074/jbc.274.5.3151;
RA Pei L.;
RT "Pituitary tumor-transforming gene protein associates with ribosomal
RT protein S10 and a novel human homologue of DnaJ in testicular cells.";
RL J. Biol. Chem. 274:3151-3158(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), FUNCTION, AND TISSUE
RP SPECIFICITY.
RX PubMed=11896048; DOI=10.1074/jbc.M109613200;
RA Chuang J.-Z., Zhou H., Zhu M., Li S.-H., Li X.-J., Sung C.-H.;
RT "Characterization of a brain-enriched chaperone, MRJ, that inhibits
RT Huntingtin aggregation and toxicity independently.";
RL J. Biol. Chem. 277:19831-19838(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
RX PubMed=12974469; DOI=10.1023/A:1024916223616;
RA Hanai R., Mashima K.;
RT "Characterization of two isoforms of a human DnaJ homologue, HSJ2.";
RL Mol. Biol. Rep. 30:149-153(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RC TISSUE=Pancreas;
RA Zhang J.S., Nelson M., Wang L., Smith D.I.;
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=10319584; DOI=10.1007/s100380050139;
RA Seki N., Hattori A., Hayashi A., Kozuma S., Miyajima N., Saito T.;
RT "Cloning, tissue expression, and chromosomal assignment of human MRJ
RT gene for a member of the DNAJ protein family.";
RL J. Hum. Genet. 44:185-189(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RA Zhang W., Wan T., Yuan Z., Cao X.;
RT "HSJ2, a novel human homologue of the bacterial heat-shock protein
RT DnaJ.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND C).
RC TISSUE=Aortic endothelium, and Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
RC TISSUE=Fetal kidney;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [13]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND B).
RC TISSUE=Placenta, and Skin;
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 [15]
RP PROTEIN SEQUENCE OF 2-12; 48-60; 71-101; 208-242 AND 271-287, CLEAVAGE
RP OF INITIATOR METHIONINE, LACK OF N-TERMINAL ACETYLATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [16]
RP FUNCTION, INTERACTION WITH HSP70 AND KRT18, AND SUBCELLULAR LOCATION.
RX PubMed=10954706; DOI=10.1074/jbc.M003492200;
RA Izawa I., Nishizawa M., Ohtakara K., Ohtsuka K., Inada H., Inagaki M.;
RT "Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18
RT filament regulatory protein.";
RL J. Biol. Chem. 275:34521-34527(2000).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-277, AND MASS
RP SPECTROMETRY.
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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [19]
RP FUNCTION AS SUPPRESSOR OF PROTEIN AGGREGATION.
RX PubMed=20159555; DOI=10.1016/j.molcel.2010.01.001;
RA Hageman J., Rujano M.A., van Waarde M.A., Kakkar V., Dirks R.P.,
RA Govorukhina N., Oosterveld-Hut H.M., Lubsen N.H., Kampinga H.H.;
RT "A DNAJB chaperone subfamily with HDAC-dependent activities suppresses
RT toxic protein aggregation.";
RL Mol. Cell 37:355-369(2010).
RN [20]
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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-277, 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 [22]
RP FUNCTION IN INHIBITION OF HUNTINGTIN AGGREGATION, SUBUNIT, INTERACTION
RP WITH BAG3; HSPB8 AND STUB1, TISSUE SPECIFICITY, SUBCELLULAR LOCATION,
RP VARIANTS LGMD1E ILE-89 AND LEU-93, AND CHARACTERIZATION OF VARIANTS
RP LGMD1E ILE-89 AND LEU-93.
RX PubMed=22366786; DOI=10.1038/ng.1103;
RA Sarparanta J., Jonson P.H., Golzio C., Sandell S., Luque H.,
RA Screen M., McDonald K., Stajich J.M., Mahjneh I., Vihola A.,
RA Raheem O., Penttila S., Lehtinen S., Huovinen S., Palmio J., Tasca G.,
RA Ricci E., Hackman P., Hauser M., Katsanis N., Udd B.;
RT "Mutations affecting the cytoplasmic functions of the co-chaperone
RT DNAJB6 cause limb-girdle muscular dystrophy.";
RL Nat. Genet. 44:450-455(2012).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [24]
RP VARIANTS LGMD1E LEU-93 AND ARG-96.
RX PubMed=22334415; DOI=10.1002/ana.22683;
RA Harms M.B., Sommerville R.B., Allred P., Bell S., Ma D., Cooper P.,
RA Lopate G., Pestronk A., Weihl C.C., Baloh R.H.;
RT "Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
RT myopathy.";
RL Ann. Neurol. 71:407-416(2012).
CC -!- FUNCTION: Plays an indispensable role in the organization of
CC KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone
CC for neuronal proteins including huntingtin. Suppresses aggregation
CC and toxicity of polyglutamine-containing, aggregation-prone
CC proteins. Isoform B but not isoform A inhibits huntingtin
CC aggregation. Has a stimulatory effect on the ATPase activity of
CC HSP70 in a dose-dependent and time-dependent manner and hence acts
CC as a co-chaperone of HSP70. Also reduces cellular toxicity and
CC caspase-3 activity.
CC -!- SUBUNIT: Homooligomer. Interacts with BAG3, HSPB8 and STUB1.
CC Interacts with ALKBH1 (By similarity). Interacts with HSP70, KRT18
CC and PTTG. Isoform B interacts with histone deacetylases HDAC4,
CC HDAC6, and SIRT2, HDAC activity is required for antiaggregation.
CC -!- INTERACTION:
CC Q9HCU9:BRMS1; NbExp=2; IntAct=EBI-1053164, EBI-714781;
CC O75923:DYSF; NbExp=2; IntAct=EBI-1053164, EBI-2799016;
CC P05783:KRT18; NbExp=6; IntAct=EBI-1053164, EBI-297888;
CC Q13326:SGCG; NbExp=2; IntAct=EBI-1053164, EBI-5357343;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Nucleus.
CC Cytoplasm, myofibril, sarcomere, Z line.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A;
CC IsoId=O75190-1; Sequence=Displayed;
CC Name=B;
CC IsoId=O75190-2; Sequence=VSP_001289, VSP_001290;
CC Name=C; Synonyms=a;
CC IsoId=O75190-3; Sequence=VSP_026180;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest levels in testis and
CC brain, and lower levels in heart, spleen, intestine, ovary,
CC placenta, lung, kidney, pancreas, thymus, prostate, skeletal
CC muscle, liver and leukocytes. In testis, expressed in germ cells
CC in the earlier stages of differentiation pathway as well as in
CC spermatids. In brain, expressed at a higher level in hippocampus
CC and thalamus and a lower level in amygdala, substantia nigra,
CC corpus callosum and caudate nucleus.
CC -!- DOMAIN: The antiaggregation activity of isoform B resides in the
CC serine-rich region and the C-terminus.
CC -!- DISEASE: Limb-girdle muscular dystrophy 1E (LGMD1E) [MIM:603511]:
CC An autosomal dominant myopathy characterized by adult onset of
CC proximal muscle weakness, beginning in the hip girdle region and
CC later progressing to the shoulder girdle region. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry. There is evidence that LGMD1E is caused by dysfunction of
CC isoform B (PubMed:22366786).
CC -!- SIMILARITY: Contains 1 J domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD16010.1; Type=Frameshift; Positions=197;
CC Sequence=BAD93096.1; Type=Erroneous initiation;
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DR EMBL; AF080569; AAD16010.1; ALT_FRAME; mRNA.
DR EMBL; AB015798; BAA88769.1; -; mRNA.
DR EMBL; AB015799; BAA88770.1; -; mRNA.
DR EMBL; AF060703; AAF21257.1; -; mRNA.
DR EMBL; AB014888; BAA32209.1; -; mRNA.
DR EMBL; AF075601; AAD43194.1; -; mRNA.
DR EMBL; CR533498; CAG38529.1; -; mRNA.
DR EMBL; AB209859; BAD93096.1; ALT_INIT; mRNA.
DR EMBL; AK223601; BAD97321.1; -; mRNA.
DR EMBL; AK291953; BAF84642.1; -; mRNA.
DR EMBL; AL136707; CAB66642.1; -; mRNA.
DR EMBL; AC079306; AAS07392.1; -; Genomic_DNA.
DR EMBL; AC079306; AAS07393.1; -; Genomic_DNA.
DR EMBL; CH236954; EAL23923.1; -; Genomic_DNA.
DR EMBL; CH236954; EAL23924.1; -; Genomic_DNA.
DR EMBL; CH471149; EAX04570.1; -; Genomic_DNA.
DR EMBL; BC000177; AAH00177.1; -; mRNA.
DR EMBL; BC002446; AAH02446.1; -; mRNA.
DR RefSeq; NP_005485.1; NM_005494.2.
DR RefSeq; NP_490647.1; NM_058246.3.
DR UniGene; Hs.188591; -.
DR UniGene; Hs.490745; -.
DR ProteinModelPortal; O75190; -.
DR SMR; O75190; 1-102.
DR IntAct; O75190; 26.
DR MINT; MINT-4713234; -.
DR PhosphoSite; O75190; -.
DR PaxDb; O75190; -.
DR PRIDE; O75190; -.
DR DNASU; 10049; -.
DR Ensembl; ENST00000262177; ENSP00000262177; ENSG00000105993.
DR Ensembl; ENST00000429029; ENSP00000397556; ENSG00000105993.
DR GeneID; 10049; -.
DR KEGG; hsa:10049; -.
DR UCSC; uc003wnk.3; human.
DR CTD; 10049; -.
DR GeneCards; GC07P157128; -.
DR HGNC; HGNC:14888; DNAJB6.
DR HPA; CAB004670; -.
DR HPA; HPA024258; -.
DR MIM; 603511; phenotype.
DR MIM; 611332; gene.
DR neXtProt; NX_O75190; -.
DR Orphanet; 34516; Autosomal dominant limb-girdle muscular dystrophy type 1D.
DR PharmGKB; PA27418; -.
DR eggNOG; COG0484; -.
DR HOVERGEN; HBG066998; -.
DR InParanoid; O75190; -.
DR KO; K09512; -.
DR OMA; NPFEFGF; -.
DR PhylomeDB; O75190; -.
DR ChiTaRS; DNAJB6; human.
DR GeneWiki; DNAJB6; -.
DR GenomeRNAi; 10049; -.
DR NextBio; 37959; -.
DR PRO; PR:O75190; -.
DR ArrayExpress; O75190; -.
DR Bgee; O75190; -.
DR CleanEx; HS_DNAJB6; -.
DR Genevestigator; O75190; -.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0030018; C:Z disc; IDA:UniProtKB.
DR GO; GO:0001671; F:ATPase activator activity; IDA:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:Ensembl.
DR GO; GO:0031072; F:heat shock protein binding; IDA:UniProtKB.
DR GO; GO:0060710; P:chorio-allantoic fusion; IEA:Ensembl.
DR GO; GO:0045109; P:intermediate filament organization; IDA:UniProtKB.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0006457; P:protein folding; IDA:UniProtKB.
DR GO; GO:0034504; P:protein localization to nucleus; IEA:Ensembl.
DR GO; GO:0006986; P:response to unfolded protein; NAS:UniProtKB.
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 Alternative splicing; Chaperone; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation;
KW Limb-girdle muscular dystrophy; Nucleus; Phosphoprotein;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 326 DnaJ homolog subfamily B member 6.
FT /FTId=PRO_0000071025.
FT DOMAIN 2 69 J.
FT REGION 2 146 Interaction with HSP70.
FT REGION 119 242 Interaction with KRT18.
FT COMPBIAS 83 172 Gly/Phe-rich.
FT COMPBIAS 155 194 Ser-rich.
FT MOD_RES 277 277 Phosphoserine.
FT VAR_SEQ 232 241 VADDDALAEE -> KEQLLRLDNK (in isoform B).
FT /FTId=VSP_001289.
FT VAR_SEQ 242 326 Missing (in isoform B).
FT /FTId=VSP_001290.
FT VAR_SEQ 301 326 LKEGGKRKKQKQREESKKKKSTKGNH -> VQREAAVEQAQ
FT SETSLGARGQRGHK (in isoform C).
FT /FTId=VSP_026180.
FT VARIANT 89 89 F -> I (in LGMD1E; the mutation results
FT in inefficient inhibition of protein
FT aggregation by isoform B).
FT /FTId=VAR_067833.
FT VARIANT 93 93 F -> L (in LGMD1E; the mutation results
FT in inefficient inhibition of protein
FT aggregation by isoform B).
FT /FTId=VAR_067834.
FT VARIANT 96 96 P -> R (in LGMD1E).
FT /FTId=VAR_067835.
FT CONFLICT 128 128 G -> S (in Ref. 9; BAD97321).
SQ SEQUENCE 326 AA; 36087 MW; ECF1628BF7A524F3 CRC64;
MVDYYEVLGV QRHASPEDIK KAYRKLALKW HPDKNPENKE EAERKFKQVA EAYEVLSDAK
KRDIYDKYGK EGLNGGGGGG SHFDSPFEFG FTFRNPDDVF REFFGGRDPF SFDFFEDPFE
DFFGNRRGPR GSRSRGTGSF FSAFSGFPSF GSGFSSFDTG FTSFGSLGHG GLTSFSSTSF
GGSGMGNFKS ISTSTKMVNG RKITTKRIVE NGQERVEVEE DGQLKSLTIN GVADDDALAE
ERMRRGQNAL PAQPAGLRPP KPPRPASLLR HAPHCLSEEE GEQDRPRAPG PWDPLASAAG
LKEGGKRKKQ KQREESKKKK STKGNH
//
ID DNJB6_HUMAN Reviewed; 326 AA.
AC O75190; A4D232; A8K7D8; O95806; Q53EN8; Q59EF2; Q6FIC8; Q75MA2;
read moreAC Q9UIK6;
DT 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT 18-OCT-2001, sequence version 2.
DT 22-JAN-2014, entry version 134.
DE RecName: Full=DnaJ homolog subfamily B member 6;
DE AltName: Full=HHDJ1;
DE AltName: Full=Heat shock protein J2;
DE Short=HSJ-2;
DE AltName: Full=MRJ;
DE AltName: Full=MSJ-1;
GN Name=DNAJB6; Synonyms=HSJ2, MRJ, MSJ1;
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] (ISOFORM B), INTERACTION WITH PTTG, AND
RP TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=9915854; DOI=10.1074/jbc.274.5.3151;
RA Pei L.;
RT "Pituitary tumor-transforming gene protein associates with ribosomal
RT protein S10 and a novel human homologue of DnaJ in testicular cells.";
RL J. Biol. Chem. 274:3151-3158(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), FUNCTION, AND TISSUE
RP SPECIFICITY.
RX PubMed=11896048; DOI=10.1074/jbc.M109613200;
RA Chuang J.-Z., Zhou H., Zhu M., Li S.-H., Li X.-J., Sung C.-H.;
RT "Characterization of a brain-enriched chaperone, MRJ, that inhibits
RT Huntingtin aggregation and toxicity independently.";
RL J. Biol. Chem. 277:19831-19838(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
RX PubMed=12974469; DOI=10.1023/A:1024916223616;
RA Hanai R., Mashima K.;
RT "Characterization of two isoforms of a human DnaJ homologue, HSJ2.";
RL Mol. Biol. Rep. 30:149-153(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RC TISSUE=Pancreas;
RA Zhang J.S., Nelson M., Wang L., Smith D.I.;
RL Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B), AND TISSUE SPECIFICITY.
RC TISSUE=Testis;
RX PubMed=10319584; DOI=10.1007/s100380050139;
RA Seki N., Hattori A., Hayashi A., Kozuma S., Miyajima N., Saito T.;
RT "Cloning, tissue expression, and chromosomal assignment of human MRJ
RT gene for a member of the DNAJ protein family.";
RL J. Hum. Genet. 44:185-189(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RA Zhang W., Wan T., Yuan Z., Cao X.;
RT "HSJ2, a novel human homologue of the bacterial heat-shock protein
RT DnaJ.";
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND C).
RC TISSUE=Aortic endothelium, and Kidney;
RA Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S.,
RA Ohara O., Nagase T., Kikuno R.F.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM B).
RC TISSUE=Fetal kidney;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12690205; DOI=10.1126/science.1083423;
RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S.,
RA Kwasnicka D., Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z.,
RA Lu F., Zeesman S., Nowaczyk M.J., Teshima I., Chitayat D., Shuman C.,
RA Weksberg R., Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J.,
RA Rahman N., Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F.,
RA Belloni E., Shaffer L.G., Pober B., Morton C.C., Gusella J.F.,
RA Bruns G.A.P., Korf B.R., Quade B.J., Ligon A.H., Ferguson H.,
RA Higgins A.W., Leach N.T., Herrick S.R., Lemyre E., Farra C.G.,
RA Kim H.-G., Summers A.M., Gripp K.W., Roberts W., Szatmari P.,
RA Winsor E.J.T., Grzeschik K.-H., Teebi A., Minassian B.A., Kere J.,
RA Armengol L., Pujana M.A., Estivill X., Wilson M.D., Koop B.F.,
RA Tosi S., Moore G.E., Boright A.P., Zlotorynski E., Kerem B.,
RA Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W.,
RA Mural R.J., Adams M.D., Tsui L.-C.;
RT "Human chromosome 7: DNA sequence and biology.";
RL Science 300:767-772(2003).
RN [13]
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 (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS A AND B).
RC TISSUE=Placenta, and Skin;
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 [15]
RP PROTEIN SEQUENCE OF 2-12; 48-60; 71-101; 208-242 AND 271-287, CLEAVAGE
RP OF INITIATOR METHIONINE, LACK OF N-TERMINAL ACETYLATION, AND MASS
RP SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [16]
RP FUNCTION, INTERACTION WITH HSP70 AND KRT18, AND SUBCELLULAR LOCATION.
RX PubMed=10954706; DOI=10.1074/jbc.M003492200;
RA Izawa I., Nishizawa M., Ohtakara K., Ohtsuka K., Inada H., Inagaki M.;
RT "Identification of Mrj, a DnaJ/Hsp40 family protein, as a keratin 8/18
RT filament regulatory protein.";
RL J. Biol. Chem. 275:34521-34527(2000).
RN [17]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-277, AND MASS
RP SPECTROMETRY.
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 [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
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 [19]
RP FUNCTION AS SUPPRESSOR OF PROTEIN AGGREGATION.
RX PubMed=20159555; DOI=10.1016/j.molcel.2010.01.001;
RA Hageman J., Rujano M.A., van Waarde M.A., Kakkar V., Dirks R.P.,
RA Govorukhina N., Oosterveld-Hut H.M., Lubsen N.H., Kampinga H.H.;
RT "A DNAJB chaperone subfamily with HDAC-dependent activities suppresses
RT toxic protein aggregation.";
RL Mol. Cell 37:355-369(2010).
RN [20]
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 [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-277, 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 [22]
RP FUNCTION IN INHIBITION OF HUNTINGTIN AGGREGATION, SUBUNIT, INTERACTION
RP WITH BAG3; HSPB8 AND STUB1, TISSUE SPECIFICITY, SUBCELLULAR LOCATION,
RP VARIANTS LGMD1E ILE-89 AND LEU-93, AND CHARACTERIZATION OF VARIANTS
RP LGMD1E ILE-89 AND LEU-93.
RX PubMed=22366786; DOI=10.1038/ng.1103;
RA Sarparanta J., Jonson P.H., Golzio C., Sandell S., Luque H.,
RA Screen M., McDonald K., Stajich J.M., Mahjneh I., Vihola A.,
RA Raheem O., Penttila S., Lehtinen S., Huovinen S., Palmio J., Tasca G.,
RA Ricci E., Hackman P., Hauser M., Katsanis N., Udd B.;
RT "Mutations affecting the cytoplasmic functions of the co-chaperone
RT DNAJB6 cause limb-girdle muscular dystrophy.";
RL Nat. Genet. 44:450-455(2012).
RN [23]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [24]
RP VARIANTS LGMD1E LEU-93 AND ARG-96.
RX PubMed=22334415; DOI=10.1002/ana.22683;
RA Harms M.B., Sommerville R.B., Allred P., Bell S., Ma D., Cooper P.,
RA Lopate G., Pestronk A., Weihl C.C., Baloh R.H.;
RT "Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
RT myopathy.";
RL Ann. Neurol. 71:407-416(2012).
CC -!- FUNCTION: Plays an indispensable role in the organization of
CC KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone
CC for neuronal proteins including huntingtin. Suppresses aggregation
CC and toxicity of polyglutamine-containing, aggregation-prone
CC proteins. Isoform B but not isoform A inhibits huntingtin
CC aggregation. Has a stimulatory effect on the ATPase activity of
CC HSP70 in a dose-dependent and time-dependent manner and hence acts
CC as a co-chaperone of HSP70. Also reduces cellular toxicity and
CC caspase-3 activity.
CC -!- SUBUNIT: Homooligomer. Interacts with BAG3, HSPB8 and STUB1.
CC Interacts with ALKBH1 (By similarity). Interacts with HSP70, KRT18
CC and PTTG. Isoform B interacts with histone deacetylases HDAC4,
CC HDAC6, and SIRT2, HDAC activity is required for antiaggregation.
CC -!- INTERACTION:
CC Q9HCU9:BRMS1; NbExp=2; IntAct=EBI-1053164, EBI-714781;
CC O75923:DYSF; NbExp=2; IntAct=EBI-1053164, EBI-2799016;
CC P05783:KRT18; NbExp=6; IntAct=EBI-1053164, EBI-297888;
CC Q13326:SGCG; NbExp=2; IntAct=EBI-1053164, EBI-5357343;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, perinuclear region. Nucleus.
CC Cytoplasm, myofibril, sarcomere, Z line.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=A;
CC IsoId=O75190-1; Sequence=Displayed;
CC Name=B;
CC IsoId=O75190-2; Sequence=VSP_001289, VSP_001290;
CC Name=C; Synonyms=a;
CC IsoId=O75190-3; Sequence=VSP_026180;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Widely expressed. Highest levels in testis and
CC brain, and lower levels in heart, spleen, intestine, ovary,
CC placenta, lung, kidney, pancreas, thymus, prostate, skeletal
CC muscle, liver and leukocytes. In testis, expressed in germ cells
CC in the earlier stages of differentiation pathway as well as in
CC spermatids. In brain, expressed at a higher level in hippocampus
CC and thalamus and a lower level in amygdala, substantia nigra,
CC corpus callosum and caudate nucleus.
CC -!- DOMAIN: The antiaggregation activity of isoform B resides in the
CC serine-rich region and the C-terminus.
CC -!- DISEASE: Limb-girdle muscular dystrophy 1E (LGMD1E) [MIM:603511]:
CC An autosomal dominant myopathy characterized by adult onset of
CC proximal muscle weakness, beginning in the hip girdle region and
CC later progressing to the shoulder girdle region. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry. There is evidence that LGMD1E is caused by dysfunction of
CC isoform B (PubMed:22366786).
CC -!- SIMILARITY: Contains 1 J domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD16010.1; Type=Frameshift; Positions=197;
CC Sequence=BAD93096.1; Type=Erroneous initiation;
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DR EMBL; AF080569; AAD16010.1; ALT_FRAME; mRNA.
DR EMBL; AB015798; BAA88769.1; -; mRNA.
DR EMBL; AB015799; BAA88770.1; -; mRNA.
DR EMBL; AF060703; AAF21257.1; -; mRNA.
DR EMBL; AB014888; BAA32209.1; -; mRNA.
DR EMBL; AF075601; AAD43194.1; -; mRNA.
DR EMBL; CR533498; CAG38529.1; -; mRNA.
DR EMBL; AB209859; BAD93096.1; ALT_INIT; mRNA.
DR EMBL; AK223601; BAD97321.1; -; mRNA.
DR EMBL; AK291953; BAF84642.1; -; mRNA.
DR EMBL; AL136707; CAB66642.1; -; mRNA.
DR EMBL; AC079306; AAS07392.1; -; Genomic_DNA.
DR EMBL; AC079306; AAS07393.1; -; Genomic_DNA.
DR EMBL; CH236954; EAL23923.1; -; Genomic_DNA.
DR EMBL; CH236954; EAL23924.1; -; Genomic_DNA.
DR EMBL; CH471149; EAX04570.1; -; Genomic_DNA.
DR EMBL; BC000177; AAH00177.1; -; mRNA.
DR EMBL; BC002446; AAH02446.1; -; mRNA.
DR RefSeq; NP_005485.1; NM_005494.2.
DR RefSeq; NP_490647.1; NM_058246.3.
DR UniGene; Hs.188591; -.
DR UniGene; Hs.490745; -.
DR ProteinModelPortal; O75190; -.
DR SMR; O75190; 1-102.
DR IntAct; O75190; 26.
DR MINT; MINT-4713234; -.
DR PhosphoSite; O75190; -.
DR PaxDb; O75190; -.
DR PRIDE; O75190; -.
DR DNASU; 10049; -.
DR Ensembl; ENST00000262177; ENSP00000262177; ENSG00000105993.
DR Ensembl; ENST00000429029; ENSP00000397556; ENSG00000105993.
DR GeneID; 10049; -.
DR KEGG; hsa:10049; -.
DR UCSC; uc003wnk.3; human.
DR CTD; 10049; -.
DR GeneCards; GC07P157128; -.
DR HGNC; HGNC:14888; DNAJB6.
DR HPA; CAB004670; -.
DR HPA; HPA024258; -.
DR MIM; 603511; phenotype.
DR MIM; 611332; gene.
DR neXtProt; NX_O75190; -.
DR Orphanet; 34516; Autosomal dominant limb-girdle muscular dystrophy type 1D.
DR PharmGKB; PA27418; -.
DR eggNOG; COG0484; -.
DR HOVERGEN; HBG066998; -.
DR InParanoid; O75190; -.
DR KO; K09512; -.
DR OMA; NPFEFGF; -.
DR PhylomeDB; O75190; -.
DR ChiTaRS; DNAJB6; human.
DR GeneWiki; DNAJB6; -.
DR GenomeRNAi; 10049; -.
DR NextBio; 37959; -.
DR PRO; PR:O75190; -.
DR ArrayExpress; O75190; -.
DR Bgee; O75190; -.
DR CleanEx; HS_DNAJB6; -.
DR Genevestigator; O75190; -.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0030018; C:Z disc; IDA:UniProtKB.
DR GO; GO:0001671; F:ATPase activator activity; IDA:UniProtKB.
DR GO; GO:0051087; F:chaperone binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IEA:Ensembl.
DR GO; GO:0031072; F:heat shock protein binding; IDA:UniProtKB.
DR GO; GO:0060710; P:chorio-allantoic fusion; IEA:Ensembl.
DR GO; GO:0045109; P:intermediate filament organization; IDA:UniProtKB.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-dependent; IEA:Ensembl.
DR GO; GO:0006457; P:protein folding; IDA:UniProtKB.
DR GO; GO:0034504; P:protein localization to nucleus; IEA:Ensembl.
DR GO; GO:0006986; P:response to unfolded protein; NAS:UniProtKB.
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 Alternative splicing; Chaperone; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation;
KW Limb-girdle muscular dystrophy; Nucleus; Phosphoprotein;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 326 DnaJ homolog subfamily B member 6.
FT /FTId=PRO_0000071025.
FT DOMAIN 2 69 J.
FT REGION 2 146 Interaction with HSP70.
FT REGION 119 242 Interaction with KRT18.
FT COMPBIAS 83 172 Gly/Phe-rich.
FT COMPBIAS 155 194 Ser-rich.
FT MOD_RES 277 277 Phosphoserine.
FT VAR_SEQ 232 241 VADDDALAEE -> KEQLLRLDNK (in isoform B).
FT /FTId=VSP_001289.
FT VAR_SEQ 242 326 Missing (in isoform B).
FT /FTId=VSP_001290.
FT VAR_SEQ 301 326 LKEGGKRKKQKQREESKKKKSTKGNH -> VQREAAVEQAQ
FT SETSLGARGQRGHK (in isoform C).
FT /FTId=VSP_026180.
FT VARIANT 89 89 F -> I (in LGMD1E; the mutation results
FT in inefficient inhibition of protein
FT aggregation by isoform B).
FT /FTId=VAR_067833.
FT VARIANT 93 93 F -> L (in LGMD1E; the mutation results
FT in inefficient inhibition of protein
FT aggregation by isoform B).
FT /FTId=VAR_067834.
FT VARIANT 96 96 P -> R (in LGMD1E).
FT /FTId=VAR_067835.
FT CONFLICT 128 128 G -> S (in Ref. 9; BAD97321).
SQ SEQUENCE 326 AA; 36087 MW; ECF1628BF7A524F3 CRC64;
MVDYYEVLGV QRHASPEDIK KAYRKLALKW HPDKNPENKE EAERKFKQVA EAYEVLSDAK
KRDIYDKYGK EGLNGGGGGG SHFDSPFEFG FTFRNPDDVF REFFGGRDPF SFDFFEDPFE
DFFGNRRGPR GSRSRGTGSF FSAFSGFPSF GSGFSSFDTG FTSFGSLGHG GLTSFSSTSF
GGSGMGNFKS ISTSTKMVNG RKITTKRIVE NGQERVEVEE DGQLKSLTIN GVADDDALAE
ERMRRGQNAL PAQPAGLRPP KPPRPASLLR HAPHCLSEEE GEQDRPRAPG PWDPLASAAG
LKEGGKRKKQ KQREESKKKK STKGNH
//
MIM
603511
*RECORD*
*FIELD* NO
603511
*FIELD* TI
#603511 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E; LGMD1E
;;MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D, FORMERLY; LGMD1D, FORMERLY
read more*FIELD* TX
A number sign (#) is used with this entry because limb-girdle muscular
dystrophy type 1E (LGMD1E) is caused by heterozygous mutation in the
DNAJB6 gene (611332) on chromosome 7q36.2.
DESCRIPTION
LGMD1E is an autosomal dominant disorder characterized by adult onset of
proximal muscle weakness, beginning in the hip girdle region and later
progressing to the shoulder girdle region (Speer et al., 1999).
For a phenotypic description and a discussion of genetic heterogeneity
of autosomal dominant limb-girdle muscular dystrophy, see LGMD1A
(159000).
CLINICAL FEATURES
Schneiderman et al. (1969) reported a large 4-generation family with
slowly progressive autosomal dominant limb-girdle muscular dystrophy.
Symptom onset generally occurred during the third decade, with muscular
weakness affecting both the upper and lower limbs, although most
affected individuals recalled being slow and clumsy as children. Most
retained ambulation, but 2 were bedridden in their seventies and
eighties. None had facial involvement. Skeletal muscle biopsy showed
dystrophic changes, including variation in fiber size, rounded fibers,
vacuoles, and small basophilic fibers with vesicular nuclei. Electron
microscopy showed focal degeneration and destruction of myofibrils,
lamellar bodies, and dense granular lysosome-like structures. The
Pelger-Huet anomaly (PHA; 169400) also segregated within this family,
and linkage with muscular dystrophy was suggested. The recombination
fraction was about 0.25, but the lod score was only 0.35. (The
Pelger-Huet anomaly was later found to be caused by mutation in the
lamin B receptor gene (LBR; 600024) on chromosome 1q42.)
Using the diagnostic classification for LGMD outlined by Speer et al.
(1992), Speer et al. (1995) described 2 families with autosomal dominant
LGMD1. One of the families had previously been reported by Schneiderman
et al. (1969) (family 1701). Individuals were considered affected when
they had progressive proximal leg weakness with or without proximal arm
weakness, absent ankle deep-tendon reflexes, and elevated creatine
kinase values. The diagnostic evaluation of at least 1 affected member
per family documented a myopathic process. Three of 15 members of family
1701 had moderately severe dysphagia. Clinically, they differed somewhat
from other LGMD1 families linked to other chromosomes in their lack of
other associated findings, i.e., dysarthria in LGMD1A, cardiac defects
in LGMD1B (159001), and childhood onset in LGMD1C (607801). Linkage
analysis excluded these families from the locus on chromosome 5q
(LGMD1A).
Sandell et al. (2010) reported a large 4-generation Finnish family with
autosomal dominant LGMD. The age at onset ranged from 20 to 60 years,
and all except 1 presented with difficulty climbing stairs; 1 patient
presented with a slow running speed. All patients showed more severe
involvement of the pelvic girdle than the shoulder girdle, resulting in
a waddling gait, and 3 of 8 had no shoulder girdle signs at ages 69, 45,
and 43 years. All were ambulatory except an 80-year-old patient. Some
patients had mild calf hypertrophy. None had contractures, dysphagia,
dysarthria, respiratory problems, or cardiac involvement. Most patients
had increased serum creatine kinase and myopathic EMG. Muscle biopsies
showed myopathic changes, such as fiber size variation, atrophic fibers,
mild to moderate fibrosis, adipose tissue, rimmed vacuoles, and internal
nuclei. Some biopsies showed cytoplasmic protein inclusions, and
electron microscopy showed myofibrillar disintegration with filamentous
inclusions and Z disc streaming.
Hackman et al. (2011) reported 4 additional Finnish families with
adult-onset slowly progressive autosomal dominant LGMD. The phenotype
was homogeneous, with onset of muscle weakness in the pelvic girdle
between the fourth and sixth decade, later involvement of the shoulder
girdle, and marked walking difficulties by the eighth decade. Muscle
biopsies showed myopathic and/or dystrophic features as well as
myofibrillar disintegration and tubulofilamentous inclusions close to
autophagic vacuoles. Some patients had mild calf hypertrophy, and none
had cardiac or respiratory involvement. One patient had dysarthria and 2
had dysphagia.
Harms et al. (2012) reported 2 unrelated families with LGMD1E. The first
was a Caucasian family in which 5 individuals had onset of limb-girdle
weakness beginning in the fourth decade. The disorder was manifest as
difficulty in climbing stairs or getting up from the floor. In 2
patients, the quadriceps muscles were less affected than the hamstrings.
None had cardiac, pulmonary, or bulbar involvement. The disorder was
slowly progressive, but a wheelchair was required after about 20 years.
Skeletal muscle biopsy from 3 patients showed a chronic myopathy with
rimmed vacuoles, variation in fiber size, and internal nuclei.
Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulations
in multiple fibers; some inclusions were around and within the vacuoles.
Serum creatine kinase was increased, and EMG showed clear myopathic
changes. Three affected individuals from an African American family had
a distal-predominant myopathy with onset between 18 and 35 years.
Weakness began in the lower limbs, often manifest as tripping, but
progressed to include the hands and proximal legs with loss of
ambulation after about 20 to 40 years. There was no cardiac or pulmonary
involvement.
MAPPING
Speer et al. (1999) reported the identification of a new locus for
autosomal dominant limb-girdle muscular dystrophy on chromosome 7q. Two
of 5 families demonstrated evidence in favor of linkage to that region;
1 of the families had been reported by Schneiderman et al. (1969)
(family 1701) and another by Speer et al. (1995) (family 1047). The
maximum 2-point lod scores were 2.63 at D7S3058 and 3.76 at D7S427,
respectively. Flanking markers placed the novel LGMD1 locus between
D7S2423 and D7S427, with multipoint analysis slightly favoring the 9-cM
interval spanned by D7S2546 and D7S2423. Three of 5 families, including
one reported by Chutkow et al. (1986) (family 383), appeared to be
unlinked to this new locus on chromosome 7, thus establishing further
heterogeneity within the LGMD1 diagnostic classification.
By genomewide linkage analysis of a Finnish family with autosomal
dominant adult-onset LGMD, Sandell et al. (2010) found linkage to a
6.4-Mb region on chromosome 7q36 (lod score of 3.76 with D7S1823) that
overlapped with the region identified by Speer et al. (1999).
In 4 additional Finnish families with adult-onset slowly progressive
autosomal dominant LGMD, Hackman et al. (2011) refined the LGMD1E locus
to a 3.4-Mb region between D7S3037 and the telomere on 7q36.
- Genetic Heterogeneity
Chutkow et al. (1986) reported a kindred with a slowly progressive
limb-girdle muscular dystrophy inherited in an autosomal dominant
pattern. The family had immigrated to the U.S. from the Palermo region
of Sicily. Onset was anywhere from the second to sixth decade, with hip
girdle involvement preceding shoulder girdle involvement. Facial muscles
were not affected. Creatine kinase was elevated in most, and muscle
biopsy showed atrophy, fatty replacements, fiber splitting, fibrosis,
and autophagic vacuoles. In the family reported by Chutkow et al.
(1986), Speer et al. (1999) excluded linkage to chromosome 7q36.
MOLECULAR GENETICS
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy, type 1E, Harms et al. (2012) identified
a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The
mutation was identified by whole-genome exome capture followed by
next-generation sequencing. Sequencing of the DNAJB6 gene in 13
additional probands with a similar disorder revealed a second mutation
(P96R; 611332.0002) in affected members of an African American family
with an autosomal dominant myopathy. DNAJB6 is a member of the
HSP40/DNAJ family of molecular cochaperones that protects client
proteins from irreversible aggregation during protein synthesis or
during times of cellular stress.
Sarparanta et al. (2012) identified 4 different heterozygous mutations
in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected
members of 9 families with LGMD1E. Five of the families were of Finnish
origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the
same mutation (611332.0003). Two additional families had previously been
reported by Speer et al. (1995, 1999). Electron microscopy of patient
muscle showed Z-disc myofibrillar disintegration and autophagic rimmed
vacuoles. DNAJB6 was detected in protein accumulations together with its
known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared
more in the periphery of the protein accumulations, in contrast to more
pronounced colocalization seen in myotilinopathies. Three of the
mutations resulted in a phe93-to-leu (F93L) substitution in a highly
conserved residue. In vitro functional expression studies showed that
the mutations increased the half-life of DNAJB6, extended this effect to
the wildtype protein, and reduced the protective antiaggregation effect
of DNAJB6. The mutations showed a dominant toxic effect mediated
specifically by the cytoplasmic isoform of DNAJB6. The compromised
antiaggregation function may lead to impaired protein quality control
and accumulation of other proteins. DNAJB6 was found to interact with
members of the chaperone-assisted selective autophagy (CASA) complex,
including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3
(603883). The findings indicated that LGMD1E is mediated by defective
chaperone function, resulting in insufficient maintenance of sarcomeric
structures or defective clearance of misfolded sarcomeric proteins.
NOMENCLATURE
According to the report of the 105th ENMC workshop, the form of
limb-girdle muscular dystrophy mapping to chromosome 7q has been
designated 'LGMD1E' (Bushby and Beckmann, 2003). OMIM had earlier
designated the form on 7q as LGMD1D but later used the symbol for a form
of LGMD and dilated cardiomyopathy thought to map to chromosome 6q in 1
family; the disorder in that family was later found to map to 2q35 and a
causative mutation was identified in the desmin gene (DES; see
125660.0008).
*FIELD* RF
1. Bushby, K. M.; Beckmann, J. S.: The 105th ENMC sponsored workshop:
pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies,
Naarden, April 12-14, 2002. Neuromusc. Disord. 13: 80-90, 2003.
2. Chutkow, J. G.; Heffner, R. R., Jr.; Kramer, A. A.; Edwards, J.
A.: Adult-onset autosomal dominant limb-girdle muscular dystrophy. Ann.
Neurol. 20: 240-248, 1986.
3. Hackman, P.; Sandell, S.; Sarparanta, J.; Luque, H.; Huovinen,
S.; Palmio, J.; Paetau, A.; Kalimo, H.; Mahjneh, I.; Udd, B.: Four
new Finnish families with LGMD1D; refinement of the clinical phenotype
and the linked 7q36 locus. Neuromusc. Disord. 21: 338-344, 2011.
4. Harms, M. B.; Sommerville, R. B.; Allred, P.; Bell, S.; Ma, D.;
Cooper, P.; Lopate, G.; Pestronk, A.; Weihl, C. C.; Baloh, R. H.:
Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
myopathy. Ann. Neurol. 71: 407-416, 2012.
5. Sandell, S.; Huovinen, S.; Sarparanta, J.; Luque, H.; Raheem, O.;
Haapasalo, H.; Hackman, P.; Udd, B.: The enigma of 7q36 linked autosomal
dominant limb girdle muscular dystrophy. J. Neurol. Neurosurg. Psychiat. 81:
834-839, 2010.
6. Sarparanta, J.; Jonson, P. H.; Golzio, C.; Sandell, S.; Luque,
H.; Screen, M.; McDonald, K.; Stajich, J. M.; Mahjneh, I.; Vihola,
A.; Raheem, O.; Penttila, S.; and 9 others: Mutations affecting
the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle
muscular dystrophy. Nature Genet. 44: 450-455, 2012.
7. Schneiderman, L. J.; Sampson, W. I.; Schoene, W. C.; Haydon, G.
B.: Genetic studies of a family with two unusual autosomal dominant
conditions: muscular dystrophy and Pelger-Huet anomaly: clinical,
pathologic and linkage considerations. Am. J. Med. 46: 380-393,
1969.
8. Speer, M. C.; Gilchrist, J. M.; Chutkow, J. G.; McMichael, R.;
Westbrook, C. A.; Stajich, J. M.; Jorgenson, E. M.; Gaskell, P. C.;
Rosi, B. L.; Ramesar, R.; Vance, J. M.; Yamaoka, L. H.; Roses, A.
D.; Pericak-Vance, M. A.: Evidence for locus heterogeneity in autosomal
dominant limb-girdle muscular dystrophy. Am. J. Hum. Genet. 57:
1371-1376, 1995.
9. Speer, M. C.; Vance, J. M.; Grubber, J. M.; Graham, F. L.; Stajich,
J. M.; Viles, K. D.; Rogala, A.; McMichael, R.; Chutkow, J.; Goldsmith,
C.; Tim, R. W.; Pericak-Vance, M. A.: Identification of a new autosomal
dominant limb-girdle muscular dystrophy locus on chromosome 7. Am.
J. Hum. Genet. 64: 556-562, 1999.
10. Speer, M. C.; Yamaoka, L. H.; Gilchrist, J. H.; Gaskell, C. P.;
Stajich, J. M.; Vance, J. M.; Kazantsev, A.; Lastra, A. A.; Haynes,
C. S.; Beckmann, J. S.; Cohen, D.; Weber, J. L.; Roses, A. D.; Pericak-Vance,
M. A.: Confirmation of genetic heterogeneity in limb-girdle muscular
dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am.
J. Hum. Genet. 50: 1211-1217, 1992.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Dysphagia (less common)
MUSCLE, SOFT TISSUE:
Hip girdle muscle weakness (usually presenting symptom);
Difficulty climbing stairs;
Gowers sign;
Waddling gait;
Distal muscle weakness and atrophy may occur, upper and lower limbs
affected;
Shoulder girdle muscle weakness;
Myopathic changes seen on EMG;
Muscle fiber splitting and fibrosis seen on muscle biopsy;
Variation in fiber size;
Internal nuclei;
Dystrophic changes;
Rimmed vacuoles;
Myofibrillar disintegration;
Tubulofilamentous inclusions;
Inclusions are DNAJB6-immunoreactive;
Inclusions are TDP43-immunoreactive;
Z-disc streaming;
Fatty replacement
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset (second to sixth decade);
Slowly progressive;
Most patients become wheelchair-bound after 20 to 30 years
MOLECULAR BASIS:
Caused by mutation in the DNAJ/HSP40 homolog, subfamily B, member
6 gene (DNAJB6, 611332.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 6/6/2003
*FIELD* ED
joanna: 05/25/2012
joanna: 4/25/2012
ckniffin: 4/2/2012
ckniffin: 1/3/2012
ckniffin: 1/12/2005
ckniffin: 6/6/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 5/8/2012
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 11/29/2011
Cassandra L. Kniffin - reorganized: 6/11/2003
*FIELD* CD
Victor A. McKusick: 2/10/1999
*FIELD* ED
terry: 05/10/2012
carol: 5/8/2012
ckniffin: 5/8/2012
carol: 4/6/2012
carol: 4/4/2012
ckniffin: 4/2/2012
carol: 12/5/2011
ckniffin: 11/29/2011
carol: 10/19/2011
carol: 4/4/2011
ckniffin: 4/4/2011
carol: 9/4/2007
mgross: 3/18/2004
terry: 7/28/2003
carol: 6/11/2003
ckniffin: 6/6/2003
carol: 5/22/2003
carol: 3/4/1999
carol: 2/18/1999
carol: 2/10/1999
*RECORD*
*FIELD* NO
603511
*FIELD* TI
#603511 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E; LGMD1E
;;MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1D, FORMERLY; LGMD1D, FORMERLY
read more*FIELD* TX
A number sign (#) is used with this entry because limb-girdle muscular
dystrophy type 1E (LGMD1E) is caused by heterozygous mutation in the
DNAJB6 gene (611332) on chromosome 7q36.2.
DESCRIPTION
LGMD1E is an autosomal dominant disorder characterized by adult onset of
proximal muscle weakness, beginning in the hip girdle region and later
progressing to the shoulder girdle region (Speer et al., 1999).
For a phenotypic description and a discussion of genetic heterogeneity
of autosomal dominant limb-girdle muscular dystrophy, see LGMD1A
(159000).
CLINICAL FEATURES
Schneiderman et al. (1969) reported a large 4-generation family with
slowly progressive autosomal dominant limb-girdle muscular dystrophy.
Symptom onset generally occurred during the third decade, with muscular
weakness affecting both the upper and lower limbs, although most
affected individuals recalled being slow and clumsy as children. Most
retained ambulation, but 2 were bedridden in their seventies and
eighties. None had facial involvement. Skeletal muscle biopsy showed
dystrophic changes, including variation in fiber size, rounded fibers,
vacuoles, and small basophilic fibers with vesicular nuclei. Electron
microscopy showed focal degeneration and destruction of myofibrils,
lamellar bodies, and dense granular lysosome-like structures. The
Pelger-Huet anomaly (PHA; 169400) also segregated within this family,
and linkage with muscular dystrophy was suggested. The recombination
fraction was about 0.25, but the lod score was only 0.35. (The
Pelger-Huet anomaly was later found to be caused by mutation in the
lamin B receptor gene (LBR; 600024) on chromosome 1q42.)
Using the diagnostic classification for LGMD outlined by Speer et al.
(1992), Speer et al. (1995) described 2 families with autosomal dominant
LGMD1. One of the families had previously been reported by Schneiderman
et al. (1969) (family 1701). Individuals were considered affected when
they had progressive proximal leg weakness with or without proximal arm
weakness, absent ankle deep-tendon reflexes, and elevated creatine
kinase values. The diagnostic evaluation of at least 1 affected member
per family documented a myopathic process. Three of 15 members of family
1701 had moderately severe dysphagia. Clinically, they differed somewhat
from other LGMD1 families linked to other chromosomes in their lack of
other associated findings, i.e., dysarthria in LGMD1A, cardiac defects
in LGMD1B (159001), and childhood onset in LGMD1C (607801). Linkage
analysis excluded these families from the locus on chromosome 5q
(LGMD1A).
Sandell et al. (2010) reported a large 4-generation Finnish family with
autosomal dominant LGMD. The age at onset ranged from 20 to 60 years,
and all except 1 presented with difficulty climbing stairs; 1 patient
presented with a slow running speed. All patients showed more severe
involvement of the pelvic girdle than the shoulder girdle, resulting in
a waddling gait, and 3 of 8 had no shoulder girdle signs at ages 69, 45,
and 43 years. All were ambulatory except an 80-year-old patient. Some
patients had mild calf hypertrophy. None had contractures, dysphagia,
dysarthria, respiratory problems, or cardiac involvement. Most patients
had increased serum creatine kinase and myopathic EMG. Muscle biopsies
showed myopathic changes, such as fiber size variation, atrophic fibers,
mild to moderate fibrosis, adipose tissue, rimmed vacuoles, and internal
nuclei. Some biopsies showed cytoplasmic protein inclusions, and
electron microscopy showed myofibrillar disintegration with filamentous
inclusions and Z disc streaming.
Hackman et al. (2011) reported 4 additional Finnish families with
adult-onset slowly progressive autosomal dominant LGMD. The phenotype
was homogeneous, with onset of muscle weakness in the pelvic girdle
between the fourth and sixth decade, later involvement of the shoulder
girdle, and marked walking difficulties by the eighth decade. Muscle
biopsies showed myopathic and/or dystrophic features as well as
myofibrillar disintegration and tubulofilamentous inclusions close to
autophagic vacuoles. Some patients had mild calf hypertrophy, and none
had cardiac or respiratory involvement. One patient had dysarthria and 2
had dysphagia.
Harms et al. (2012) reported 2 unrelated families with LGMD1E. The first
was a Caucasian family in which 5 individuals had onset of limb-girdle
weakness beginning in the fourth decade. The disorder was manifest as
difficulty in climbing stairs or getting up from the floor. In 2
patients, the quadriceps muscles were less affected than the hamstrings.
None had cardiac, pulmonary, or bulbar involvement. The disorder was
slowly progressive, but a wheelchair was required after about 20 years.
Skeletal muscle biopsy from 3 patients showed a chronic myopathy with
rimmed vacuoles, variation in fiber size, and internal nuclei.
Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulations
in multiple fibers; some inclusions were around and within the vacuoles.
Serum creatine kinase was increased, and EMG showed clear myopathic
changes. Three affected individuals from an African American family had
a distal-predominant myopathy with onset between 18 and 35 years.
Weakness began in the lower limbs, often manifest as tripping, but
progressed to include the hands and proximal legs with loss of
ambulation after about 20 to 40 years. There was no cardiac or pulmonary
involvement.
MAPPING
Speer et al. (1999) reported the identification of a new locus for
autosomal dominant limb-girdle muscular dystrophy on chromosome 7q. Two
of 5 families demonstrated evidence in favor of linkage to that region;
1 of the families had been reported by Schneiderman et al. (1969)
(family 1701) and another by Speer et al. (1995) (family 1047). The
maximum 2-point lod scores were 2.63 at D7S3058 and 3.76 at D7S427,
respectively. Flanking markers placed the novel LGMD1 locus between
D7S2423 and D7S427, with multipoint analysis slightly favoring the 9-cM
interval spanned by D7S2546 and D7S2423. Three of 5 families, including
one reported by Chutkow et al. (1986) (family 383), appeared to be
unlinked to this new locus on chromosome 7, thus establishing further
heterogeneity within the LGMD1 diagnostic classification.
By genomewide linkage analysis of a Finnish family with autosomal
dominant adult-onset LGMD, Sandell et al. (2010) found linkage to a
6.4-Mb region on chromosome 7q36 (lod score of 3.76 with D7S1823) that
overlapped with the region identified by Speer et al. (1999).
In 4 additional Finnish families with adult-onset slowly progressive
autosomal dominant LGMD, Hackman et al. (2011) refined the LGMD1E locus
to a 3.4-Mb region between D7S3037 and the telomere on 7q36.
- Genetic Heterogeneity
Chutkow et al. (1986) reported a kindred with a slowly progressive
limb-girdle muscular dystrophy inherited in an autosomal dominant
pattern. The family had immigrated to the U.S. from the Palermo region
of Sicily. Onset was anywhere from the second to sixth decade, with hip
girdle involvement preceding shoulder girdle involvement. Facial muscles
were not affected. Creatine kinase was elevated in most, and muscle
biopsy showed atrophy, fatty replacements, fiber splitting, fibrosis,
and autophagic vacuoles. In the family reported by Chutkow et al.
(1986), Speer et al. (1999) excluded linkage to chromosome 7q36.
MOLECULAR GENETICS
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy, type 1E, Harms et al. (2012) identified
a heterozygous mutation in the DNAJB6 gene (F93L; 611332.0001). The
mutation was identified by whole-genome exome capture followed by
next-generation sequencing. Sequencing of the DNAJB6 gene in 13
additional probands with a similar disorder revealed a second mutation
(P96R; 611332.0002) in affected members of an African American family
with an autosomal dominant myopathy. DNAJB6 is a member of the
HSP40/DNAJ family of molecular cochaperones that protects client
proteins from irreversible aggregation during protein synthesis or
during times of cellular stress.
Sarparanta et al. (2012) identified 4 different heterozygous mutations
in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected
members of 9 families with LGMD1E. Five of the families were of Finnish
origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the
same mutation (611332.0003). Two additional families had previously been
reported by Speer et al. (1995, 1999). Electron microscopy of patient
muscle showed Z-disc myofibrillar disintegration and autophagic rimmed
vacuoles. DNAJB6 was detected in protein accumulations together with its
known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared
more in the periphery of the protein accumulations, in contrast to more
pronounced colocalization seen in myotilinopathies. Three of the
mutations resulted in a phe93-to-leu (F93L) substitution in a highly
conserved residue. In vitro functional expression studies showed that
the mutations increased the half-life of DNAJB6, extended this effect to
the wildtype protein, and reduced the protective antiaggregation effect
of DNAJB6. The mutations showed a dominant toxic effect mediated
specifically by the cytoplasmic isoform of DNAJB6. The compromised
antiaggregation function may lead to impaired protein quality control
and accumulation of other proteins. DNAJB6 was found to interact with
members of the chaperone-assisted selective autophagy (CASA) complex,
including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3
(603883). The findings indicated that LGMD1E is mediated by defective
chaperone function, resulting in insufficient maintenance of sarcomeric
structures or defective clearance of misfolded sarcomeric proteins.
NOMENCLATURE
According to the report of the 105th ENMC workshop, the form of
limb-girdle muscular dystrophy mapping to chromosome 7q has been
designated 'LGMD1E' (Bushby and Beckmann, 2003). OMIM had earlier
designated the form on 7q as LGMD1D but later used the symbol for a form
of LGMD and dilated cardiomyopathy thought to map to chromosome 6q in 1
family; the disorder in that family was later found to map to 2q35 and a
causative mutation was identified in the desmin gene (DES; see
125660.0008).
*FIELD* RF
1. Bushby, K. M.; Beckmann, J. S.: The 105th ENMC sponsored workshop:
pathogenesis in the non-sarcoglycan limb-girdle muscular dystrophies,
Naarden, April 12-14, 2002. Neuromusc. Disord. 13: 80-90, 2003.
2. Chutkow, J. G.; Heffner, R. R., Jr.; Kramer, A. A.; Edwards, J.
A.: Adult-onset autosomal dominant limb-girdle muscular dystrophy. Ann.
Neurol. 20: 240-248, 1986.
3. Hackman, P.; Sandell, S.; Sarparanta, J.; Luque, H.; Huovinen,
S.; Palmio, J.; Paetau, A.; Kalimo, H.; Mahjneh, I.; Udd, B.: Four
new Finnish families with LGMD1D; refinement of the clinical phenotype
and the linked 7q36 locus. Neuromusc. Disord. 21: 338-344, 2011.
4. Harms, M. B.; Sommerville, R. B.; Allred, P.; Bell, S.; Ma, D.;
Cooper, P.; Lopate, G.; Pestronk, A.; Weihl, C. C.; Baloh, R. H.:
Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
myopathy. Ann. Neurol. 71: 407-416, 2012.
5. Sandell, S.; Huovinen, S.; Sarparanta, J.; Luque, H.; Raheem, O.;
Haapasalo, H.; Hackman, P.; Udd, B.: The enigma of 7q36 linked autosomal
dominant limb girdle muscular dystrophy. J. Neurol. Neurosurg. Psychiat. 81:
834-839, 2010.
6. Sarparanta, J.; Jonson, P. H.; Golzio, C.; Sandell, S.; Luque,
H.; Screen, M.; McDonald, K.; Stajich, J. M.; Mahjneh, I.; Vihola,
A.; Raheem, O.; Penttila, S.; and 9 others: Mutations affecting
the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle
muscular dystrophy. Nature Genet. 44: 450-455, 2012.
7. Schneiderman, L. J.; Sampson, W. I.; Schoene, W. C.; Haydon, G.
B.: Genetic studies of a family with two unusual autosomal dominant
conditions: muscular dystrophy and Pelger-Huet anomaly: clinical,
pathologic and linkage considerations. Am. J. Med. 46: 380-393,
1969.
8. Speer, M. C.; Gilchrist, J. M.; Chutkow, J. G.; McMichael, R.;
Westbrook, C. A.; Stajich, J. M.; Jorgenson, E. M.; Gaskell, P. C.;
Rosi, B. L.; Ramesar, R.; Vance, J. M.; Yamaoka, L. H.; Roses, A.
D.; Pericak-Vance, M. A.: Evidence for locus heterogeneity in autosomal
dominant limb-girdle muscular dystrophy. Am. J. Hum. Genet. 57:
1371-1376, 1995.
9. Speer, M. C.; Vance, J. M.; Grubber, J. M.; Graham, F. L.; Stajich,
J. M.; Viles, K. D.; Rogala, A.; McMichael, R.; Chutkow, J.; Goldsmith,
C.; Tim, R. W.; Pericak-Vance, M. A.: Identification of a new autosomal
dominant limb-girdle muscular dystrophy locus on chromosome 7. Am.
J. Hum. Genet. 64: 556-562, 1999.
10. Speer, M. C.; Yamaoka, L. H.; Gilchrist, J. H.; Gaskell, C. P.;
Stajich, J. M.; Vance, J. M.; Kazantsev, A.; Lastra, A. A.; Haynes,
C. S.; Beckmann, J. S.; Cohen, D.; Weber, J. L.; Roses, A. D.; Pericak-Vance,
M. A.: Confirmation of genetic heterogeneity in limb-girdle muscular
dystrophy: linkage of an autosomal dominant form to chromosome 5q. Am.
J. Hum. Genet. 50: 1211-1217, 1992.
*FIELD* CS
INHERITANCE:
Autosomal dominant
ABDOMEN:
[Gastrointestinal];
Dysphagia (less common)
MUSCLE, SOFT TISSUE:
Hip girdle muscle weakness (usually presenting symptom);
Difficulty climbing stairs;
Gowers sign;
Waddling gait;
Distal muscle weakness and atrophy may occur, upper and lower limbs
affected;
Shoulder girdle muscle weakness;
Myopathic changes seen on EMG;
Muscle fiber splitting and fibrosis seen on muscle biopsy;
Variation in fiber size;
Internal nuclei;
Dystrophic changes;
Rimmed vacuoles;
Myofibrillar disintegration;
Tubulofilamentous inclusions;
Inclusions are DNAJB6-immunoreactive;
Inclusions are TDP43-immunoreactive;
Z-disc streaming;
Fatty replacement
LABORATORY ABNORMALITIES:
Increased serum creatine kinase
MISCELLANEOUS:
Adult onset (second to sixth decade);
Slowly progressive;
Most patients become wheelchair-bound after 20 to 30 years
MOLECULAR BASIS:
Caused by mutation in the DNAJ/HSP40 homolog, subfamily B, member
6 gene (DNAJB6, 611332.0001)
*FIELD* CN
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 1/3/2012
*FIELD* CD
Cassandra L. Kniffin: 6/6/2003
*FIELD* ED
joanna: 05/25/2012
joanna: 4/25/2012
ckniffin: 4/2/2012
ckniffin: 1/3/2012
ckniffin: 1/12/2005
ckniffin: 6/6/2003
*FIELD* CN
Cassandra L. Kniffin - updated: 5/8/2012
Cassandra L. Kniffin - updated: 4/2/2012
Cassandra L. Kniffin - updated: 11/29/2011
Cassandra L. Kniffin - reorganized: 6/11/2003
*FIELD* CD
Victor A. McKusick: 2/10/1999
*FIELD* ED
terry: 05/10/2012
carol: 5/8/2012
ckniffin: 5/8/2012
carol: 4/6/2012
carol: 4/4/2012
ckniffin: 4/2/2012
carol: 12/5/2011
ckniffin: 11/29/2011
carol: 10/19/2011
carol: 4/4/2011
ckniffin: 4/4/2011
carol: 9/4/2007
mgross: 3/18/2004
terry: 7/28/2003
carol: 6/11/2003
ckniffin: 6/6/2003
carol: 5/22/2003
carol: 3/4/1999
carol: 2/18/1999
carol: 2/10/1999
MIM
611332
*RECORD*
*FIELD* NO
611332
*FIELD* TI
*611332 DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6
;;MRJ;;
DJ4
*FIELD* TX
DESCRIPTION
read more
DNAJB6 belongs to the evolutionarily conserved DNAJ/HSP40 family of
proteins, which regulate molecular chaperone activity by stimulating
ATPase activity. DNAJ proteins may have up to 3 distinct domains: a
conserved 70-amino acid J domain, usually at the N terminus; a
glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain
(Ohtsuka and Hata, 2000).
CLONING
By database searching for DNAJ-like proteins, Seki et al. (1999)
identified and subsequently cloned DNAJB6, which they called MRJ, from a
human fetal brain cDNA library. The deduced 241-amino acid protein has a
calculated molecular mass of 37 kD. DNAJB6 contains an N-terminal J
domain followed by a glycine-rich region, but does not contain a
cysteine-rich region. The protein shares 94% sequence identity with the
mouse homolog. RT-PCR analysis detected ubiquitous expression of DNAJB6.
By searching EST databases for J domain-containing proteins, Ohtsuka and
Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse
DnajB6. The predicted type II transmembrane protein contains 242 amino
acids.
By Northern blot analysis, Chuang et al. (2002) found that the
expression of human DNAJB6 was highest in brain and much weaker in all
other tissues examined. Within brain, expression was highest in
hippocampus and thalamus, and lower in amygdala, substantia nigra,
corpus callosum, and caudate nucleus.
Sarparanta et al. (2012) found expression of the DNAJB6 gene at Z-discs
in human skeletal muscle.
GENE FUNCTION
Chuang et al. (2002) demonstrated that full-length DNAJB6 stimulated ATP
hydrolysis by HSP70 (see HSPA1A, 140550) in a time- and
concentration-dependent manner. Both an N-terminal fragment (amino acids
1-109) and a C-terminal fragment (amino acids 108-241) enhanced the
ATPase activity of HSP70. Human embryonic kidney 293 cells transfected
with mutant huntingtin (HTT; 613004) N terminus exhibited puncta or
aggregates of mutant huntingtin distributed throughout the cytoplasm and
nucleus. Coexpression of DNAJB6 delayed aggregate formation and
significantly reduced caspase-3 (CASP3; 600636) activation induced by
mutant huntingtin. DNAJB6 also inhibited CASP3 activity augmented by the
apoptotic reagent staurosporine.
MAPPING
By PCR analysis of a human/rodent monochromosomal hybrid cell panel and
a radiation hybrid panel, Seki et al. (1999) mapped the DNAJB6 gene to
chromosome 11q25. However, Gross (2011) mapped the DNAJB6 gene to
chromosome 7q36.3 based on alignment of the DNAJB6 sequence (GenBank
GENBANK BC002446) with the genomic sequence (GRCh37).
MOLECULAR GENETICS
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy type 1E (LGMD1E; 603511), Harms et al.
(2012) identified a heterozygous mutation in the DNAJB6 gene (F93L;
611332.0001). The mutation was identified by whole-genome exome capture
followed by next-generation sequencing. Sequencing of the DNAJB6 gene in
13 additional probands with a similar disorder revealed a second
mutation (P96R; 611332.0002) in affected members of an African American
family with an autosomal dominant myopathy. Both families had
adult-onset of slowly progressive muscle weakness resulting in loss of
ambulation after about 20 years, although 1 family had greater
involvement of the proximal muscles and the other had greater
involvement of the distal muscles. Neither family had cardiac or
pulmonary involvement.
Sarparanta et al. (2012) identified 4 different heterozygous mutations
in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected
members of 9 families with LGMD1E. Five of the families were of Finnish
origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the
same mutation (611332.0003). Two additional families had previously been
reported by Speer et al. (1995, 1999). Electron microscopy of patient
muscle showed Z-disc myofibrillar disintegration and autophagic rimmed
vacuoles. DNAJB6 was detected in protein accumulations together with its
known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared
more in the periphery of the protein accumulations, in contrast to more
pronounced colocalization seen in myotilinopathies. Three of the
mutations resulted in a phe93-to-leu (F93L) substitution at a highly
conserved residue. In vitro functional expression studies showed that
the mutations increased the half-life of DNAJB6, extended this effect to
the wildtype protein, and reduced the protective antiaggregation effect
of DNAJB6. The mutations showed a dominant toxic effect mediated
specifically by the cytoplasmic isoform of DNAJB6. The compromised
antiaggregation function may lead to impaired protein quality control
and accumulation of other proteins. DNAJB6 was found to interact with
members of the chaperone-assisted selective autophagy (CASA) complex,
including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3
(603883). The findings indicated that LGMD1E is mediated by defective
chaperone function, resulting in insufficient maintenance of sarcomeric
structures or defective clearance of misfolded sarcomeric proteins.
ANIMAL MODEL
In zebrafish, Sarparanta et al. (2012) found expression of the Dnajb6
gene as early as the embryonic 5-somite stage. Injection of 2-cell
embryos with a splice-blocking morpholino resulted in a reproducible
muscle fiber detachment phenotype. Detachment of slow fibers from their
insertion sites at the vertical myoseptum was evident as early as 2 days
after fertilization, suggesting adhesion failure with mechanical load.
These data indicated that loss of Dnajb6 leads to defects in muscle
integrity. Injection of the human mutants F93L (see, e.g., 611332.0001)
or F89I (611332.0005) also caused the muscular phenotype, and
coinjection with wildtype Dnajb6 showed enhanced severity of the
phenotype, consistent with a dominant-negative effect.
*FIELD* AV
.0001
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 277T-C
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy type 1E (LGMD1E; 603511), Harms et al.
(2012) identified a heterozygous 277T-C transition in the DNAJB6 gene,
resulting in a phe93-to-leu (F93L) substitution in a highly conserved
residue within the G/F domain. The mutation was not found in over 3,000
controls. Five affected individuals had onset of limb-girdle weakness
beginning in the fourth decade. The disorder was manifest as difficulty
in climbing stairs or getting up from the floor. In 2 patients, the
quadriceps muscles were less affected than the hamstrings. None had
cardiac, pulmonary, or bulbar involvement. The disorder was slowly
progressive, but a wheelchair was required after about 20 years.
Skeletal muscle biopsy from 3 patients showed a chronic myopathy with
rimmed vacuoles, variation in fiber size, and internal nuclei.
Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulation
in multiple fibers; some inclusions were around and within the vacuoles.
Serum creatine kinase was increased, and EMG showed clear myopathic
changes.
Sarparanta et al. (2012) identified a heterozygous 277T-C transition in
4 affected individuals from an Italian family with LGMD1E. The F93L
substitution can also be caused by a 279C-G transversion (611332.0003)
and a 279C-A transversion (611332.0004).
.0002
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PRO96ARG
In affected members of an African American family with LGMD1E (603511),
Harms et al. (2012) identified a heterozygous 287C-G transversion in the
DNAJB6 gene, resulting in a pro96-to-arg (P96R) substitution at a highly
conserved residue in the G/F domain. The mutation was not found in over
3,000 controls. Three affected individuals from an African American
family had a distal-predominant myopathy with onset between ages 18 and
35 years. Weakness began in the lower limbs, often manifest as tripping,
but progressed to include the hands and proximal legs with loss of
ambulation after about 20 to 40 years. There was no cardiac or pulmonary
involvement.
.0003
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 279C-G
In 16 affected members from 5 Finnish families with LGMD1E (603511)
(Sandell et al., 2010; Hackman et al., 2011), Sarparanta et al. (2012)
identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6
gene, resulting in a phe93-to-leu (F93L) substitution at a highly
conserved residue in the G/F domain. The mutation was not found in 202
Finnish, 104 Italian, or 215 U.S. control individuals. The F93L
substitution can also be caused by a 277T-C transition (611332.0001) and
a 279C-A transversion (611332.0004).
.0004
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 279C-A
In 8 affected individuals of an Italian family with LGMD1E (603511),
Sarparanta et al. (2012) identified a heterozygous 279C-A transversion
in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L)
substitution at a highly conserved residue in the G/F domain. The F93L
substitution can also be caused by a 277T-C transition (611332.0001) and
a 279C-G transversion (611332.0003). The mutation was not found in 202
Finnish, 104 Italian, or 215 U.S. control individuals.
.0005
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE89ILE
In affected members of 2 families from the U.S. with LGMD1E (603511)
originally reported by Speer et al. (1995, 1999), Sarparanta et al.
(2012) identified a heterozygous 267T-A transversion in the DNAJB6 gene,
resulting in a phe89-to-ile (F89I) substitution at a highly conserved
residue in the G/F domain. The mutation was not found in 202 Finnish,
104 Italian, or 215 U.S. control individuals.
*FIELD* RF
1. Chuang, J.-Z.; Zhou, H.; Zhu, M.; Li, S.-H.; Li, X.-J.; Sung, C.-H.
: Characterization of a brain-enriched chaperone, MRJ, that inhibits
huntingtin aggregation and toxicity independently. J. Biol. Chem. 277:
19831-19838, 2002.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 11/29/2011.
3. Hackman, P.; Sandell, S.; Sarparanta, J.; Luque, H.; Huovinen,
S.; Palmio, J.; Paetau, A.; Kalimo, H.; Mahjneh, I.; Udd, B.: Four
new Finnish families with LGMD1D; refinement of the clinical phenotype
and the linked 7q36 locus. Neuromusc. Disord. 21: 338-344, 2011.
4. Harms, M. B.; Sommerville, R. B.; Allred, P.; Bell, S.; Ma, D.;
Cooper, P.; Lopate, G.; Pestronk, A.; Weihl, C. C.; Baloh, R. H.:
Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
myopathy. Ann. Neurol. 71: 407-416, 2012.
5. Ohtsuka, K.; Hata, M.: Mammalian HSP40/DNAJ homologs: cloning
of novel cDNAs and a proposal for their classification and nomenclature. Cell
Stress Chaperones 5: 98-112, 2000.
6. Sandell, S.; Huovinen, S.; Sarparanta, J.; Luque, H.; Raheem, O.;
Haapasalo, H.; Hackman, P.; Udd, B.: The enigma of 7q36 linked autosomal
dominant limb girdle muscular dystrophy. J. Neurol. Neurosurg. Psychiat. 81:
834-839, 2010.
7. Sarparanta, J.; Jonson, P. H.; Golzio, C.; Sandell, S.; Luque,
H.; Screen, M.; McDonald, K.; Stajich, J. M.; Mahjneh, I.; Vihola,
A.; Raheem, O.; Penttila, S.; and 9 others: Mutations affecting
the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle
muscular dystrophy. Nature Genet. 44: 450-455, 2012.
8. Seki, N.; Hattori, A.; Hayashi, A.; Kozuma, S.; Miyajima, N.; Saito,
T.: Cloning, tissue expression, and chromosomal assignment of human
MRJ gene for a member of the DNAJ protein family. J. Hum. Genet. 44:
185-189, 1999.
9. Speer, M. C.; Gilchrist, J. M.; Chutkow, J. G.; McMichael, R.;
Westbrook, C. A.; Stajich, J. M.; Jorgenson, E. M.; Gaskell, P. C.;
Rosi, B. L.; Ramesar, R.; Vance, J. M.; Yamaoka, L. H.; Roses, A.
D.; Pericak-Vance, M. A.: Evidence for locus heterogeneity in autosomal
dominant limb-girdle muscular dystrophy. Am. J. Hum. Genet. 57:
1371-1376, 1995.
10. Speer, M. C.; Vance, J. M.; Grubber, J. M.; Graham, F. L.; Stajich,
J. M.; Viles, K. D.; Rogala, A.; McMichael, R.; Chutkow, J.; Goldsmith,
C.; Tim, R. W.; Pericak-Vance, M. A.: Identification of a new autosomal
dominant limb-girdle muscular dystrophy locus on chromosome 7. Am.
J. Hum. Genet. 64: 556-562, 1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/8/2012
Cassandra L. Kniffin - updated: 4/2/2012
Matthew B. Gross - updated: 11/29/2011
*FIELD* CD
Patricia A. Hartz: 8/16/2007
*FIELD* ED
carol: 05/08/2012
ckniffin: 5/8/2012
carol: 4/4/2012
ckniffin: 4/2/2012
mgross: 11/29/2011
wwang: 9/15/2009
carol: 8/16/2007
*RECORD*
*FIELD* NO
611332
*FIELD* TI
*611332 DNAJ/HSP40 HOMOLOG, SUBFAMILY B, MEMBER 6; DNAJB6
;;MRJ;;
DJ4
*FIELD* TX
DESCRIPTION
read more
DNAJB6 belongs to the evolutionarily conserved DNAJ/HSP40 family of
proteins, which regulate molecular chaperone activity by stimulating
ATPase activity. DNAJ proteins may have up to 3 distinct domains: a
conserved 70-amino acid J domain, usually at the N terminus; a
glycine/phenylalanine (G/F)-rich region; and a cysteine-rich domain
(Ohtsuka and Hata, 2000).
CLONING
By database searching for DNAJ-like proteins, Seki et al. (1999)
identified and subsequently cloned DNAJB6, which they called MRJ, from a
human fetal brain cDNA library. The deduced 241-amino acid protein has a
calculated molecular mass of 37 kD. DNAJB6 contains an N-terminal J
domain followed by a glycine-rich region, but does not contain a
cysteine-rich region. The protein shares 94% sequence identity with the
mouse homolog. RT-PCR analysis detected ubiquitous expression of DNAJB6.
By searching EST databases for J domain-containing proteins, Ohtsuka and
Hata (2000) identified 10 mouse and human DNAJ homologs, including mouse
DnajB6. The predicted type II transmembrane protein contains 242 amino
acids.
By Northern blot analysis, Chuang et al. (2002) found that the
expression of human DNAJB6 was highest in brain and much weaker in all
other tissues examined. Within brain, expression was highest in
hippocampus and thalamus, and lower in amygdala, substantia nigra,
corpus callosum, and caudate nucleus.
Sarparanta et al. (2012) found expression of the DNAJB6 gene at Z-discs
in human skeletal muscle.
GENE FUNCTION
Chuang et al. (2002) demonstrated that full-length DNAJB6 stimulated ATP
hydrolysis by HSP70 (see HSPA1A, 140550) in a time- and
concentration-dependent manner. Both an N-terminal fragment (amino acids
1-109) and a C-terminal fragment (amino acids 108-241) enhanced the
ATPase activity of HSP70. Human embryonic kidney 293 cells transfected
with mutant huntingtin (HTT; 613004) N terminus exhibited puncta or
aggregates of mutant huntingtin distributed throughout the cytoplasm and
nucleus. Coexpression of DNAJB6 delayed aggregate formation and
significantly reduced caspase-3 (CASP3; 600636) activation induced by
mutant huntingtin. DNAJB6 also inhibited CASP3 activity augmented by the
apoptotic reagent staurosporine.
MAPPING
By PCR analysis of a human/rodent monochromosomal hybrid cell panel and
a radiation hybrid panel, Seki et al. (1999) mapped the DNAJB6 gene to
chromosome 11q25. However, Gross (2011) mapped the DNAJB6 gene to
chromosome 7q36.3 based on alignment of the DNAJB6 sequence (GenBank
GENBANK BC002446) with the genomic sequence (GRCh37).
MOLECULAR GENETICS
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy type 1E (LGMD1E; 603511), Harms et al.
(2012) identified a heterozygous mutation in the DNAJB6 gene (F93L;
611332.0001). The mutation was identified by whole-genome exome capture
followed by next-generation sequencing. Sequencing of the DNAJB6 gene in
13 additional probands with a similar disorder revealed a second
mutation (P96R; 611332.0002) in affected members of an African American
family with an autosomal dominant myopathy. Both families had
adult-onset of slowly progressive muscle weakness resulting in loss of
ambulation after about 20 years, although 1 family had greater
involvement of the proximal muscles and the other had greater
involvement of the distal muscles. Neither family had cardiac or
pulmonary involvement.
Sarparanta et al. (2012) identified 4 different heterozygous mutations
in the DNAJB6 gene (611332.0001, 611332.0003-611332.0005) in affected
members of 9 families with LGMD1E. Five of the families were of Finnish
origin (Sandell et al., 2010 and Hackman et al., 2011) and carried the
same mutation (611332.0003). Two additional families had previously been
reported by Speer et al. (1995, 1999). Electron microscopy of patient
muscle showed Z-disc myofibrillar disintegration and autophagic rimmed
vacuoles. DNAJB6 was detected in protein accumulations together with its
known ligands MLF1 (601402) and HSPA8 (600816). However, DNAJB6 appeared
more in the periphery of the protein accumulations, in contrast to more
pronounced colocalization seen in myotilinopathies. Three of the
mutations resulted in a phe93-to-leu (F93L) substitution at a highly
conserved residue. In vitro functional expression studies showed that
the mutations increased the half-life of DNAJB6, extended this effect to
the wildtype protein, and reduced the protective antiaggregation effect
of DNAJB6. The mutations showed a dominant toxic effect mediated
specifically by the cytoplasmic isoform of DNAJB6. The compromised
antiaggregation function may lead to impaired protein quality control
and accumulation of other proteins. DNAJB6 was found to interact with
members of the chaperone-assisted selective autophagy (CASA) complex,
including a myofibrillar myopathy (MFM6; 612954)-related protein BAG3
(603883). The findings indicated that LGMD1E is mediated by defective
chaperone function, resulting in insufficient maintenance of sarcomeric
structures or defective clearance of misfolded sarcomeric proteins.
ANIMAL MODEL
In zebrafish, Sarparanta et al. (2012) found expression of the Dnajb6
gene as early as the embryonic 5-somite stage. Injection of 2-cell
embryos with a splice-blocking morpholino resulted in a reproducible
muscle fiber detachment phenotype. Detachment of slow fibers from their
insertion sites at the vertical myoseptum was evident as early as 2 days
after fertilization, suggesting adhesion failure with mechanical load.
These data indicated that loss of Dnajb6 leads to defects in muscle
integrity. Injection of the human mutants F93L (see, e.g., 611332.0001)
or F89I (611332.0005) also caused the muscular phenotype, and
coinjection with wildtype Dnajb6 showed enhanced severity of the
phenotype, consistent with a dominant-negative effect.
*FIELD* AV
.0001
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 277T-C
In affected members of a Caucasian family with autosomal dominant
limb-girdle muscular dystrophy type 1E (LGMD1E; 603511), Harms et al.
(2012) identified a heterozygous 277T-C transition in the DNAJB6 gene,
resulting in a phe93-to-leu (F93L) substitution in a highly conserved
residue within the G/F domain. The mutation was not found in over 3,000
controls. Five affected individuals had onset of limb-girdle weakness
beginning in the fourth decade. The disorder was manifest as difficulty
in climbing stairs or getting up from the floor. In 2 patients, the
quadriceps muscles were less affected than the hamstrings. None had
cardiac, pulmonary, or bulbar involvement. The disorder was slowly
progressive, but a wheelchair was required after about 20 years.
Skeletal muscle biopsy from 3 patients showed a chronic myopathy with
rimmed vacuoles, variation in fiber size, and internal nuclei.
Immunostaining showed TDP43 (605078)- and DNAJB6-positive accumulation
in multiple fibers; some inclusions were around and within the vacuoles.
Serum creatine kinase was increased, and EMG showed clear myopathic
changes.
Sarparanta et al. (2012) identified a heterozygous 277T-C transition in
4 affected individuals from an Italian family with LGMD1E. The F93L
substitution can also be caused by a 279C-G transversion (611332.0003)
and a 279C-A transversion (611332.0004).
.0002
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PRO96ARG
In affected members of an African American family with LGMD1E (603511),
Harms et al. (2012) identified a heterozygous 287C-G transversion in the
DNAJB6 gene, resulting in a pro96-to-arg (P96R) substitution at a highly
conserved residue in the G/F domain. The mutation was not found in over
3,000 controls. Three affected individuals from an African American
family had a distal-predominant myopathy with onset between ages 18 and
35 years. Weakness began in the lower limbs, often manifest as tripping,
but progressed to include the hands and proximal legs with loss of
ambulation after about 20 to 40 years. There was no cardiac or pulmonary
involvement.
.0003
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 279C-G
In 16 affected members from 5 Finnish families with LGMD1E (603511)
(Sandell et al., 2010; Hackman et al., 2011), Sarparanta et al. (2012)
identified a heterozygous 279C-G transversion in exon 5 of the DNAJB6
gene, resulting in a phe93-to-leu (F93L) substitution at a highly
conserved residue in the G/F domain. The mutation was not found in 202
Finnish, 104 Italian, or 215 U.S. control individuals. The F93L
substitution can also be caused by a 277T-C transition (611332.0001) and
a 279C-A transversion (611332.0004).
.0004
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE93LEU, 279C-A
In 8 affected individuals of an Italian family with LGMD1E (603511),
Sarparanta et al. (2012) identified a heterozygous 279C-A transversion
in exon 5 of the DNAJB6 gene, resulting in a phe93-to-leu (F93L)
substitution at a highly conserved residue in the G/F domain. The F93L
substitution can also be caused by a 277T-C transition (611332.0001) and
a 279C-G transversion (611332.0003). The mutation was not found in 202
Finnish, 104 Italian, or 215 U.S. control individuals.
.0005
MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1E
DNAJB6, PHE89ILE
In affected members of 2 families from the U.S. with LGMD1E (603511)
originally reported by Speer et al. (1995, 1999), Sarparanta et al.
(2012) identified a heterozygous 267T-A transversion in the DNAJB6 gene,
resulting in a phe89-to-ile (F89I) substitution at a highly conserved
residue in the G/F domain. The mutation was not found in 202 Finnish,
104 Italian, or 215 U.S. control individuals.
*FIELD* RF
1. Chuang, J.-Z.; Zhou, H.; Zhu, M.; Li, S.-H.; Li, X.-J.; Sung, C.-H.
: Characterization of a brain-enriched chaperone, MRJ, that inhibits
huntingtin aggregation and toxicity independently. J. Biol. Chem. 277:
19831-19838, 2002.
2. Gross, M. B.: Personal Communication. Baltimore, Md. 11/29/2011.
3. Hackman, P.; Sandell, S.; Sarparanta, J.; Luque, H.; Huovinen,
S.; Palmio, J.; Paetau, A.; Kalimo, H.; Mahjneh, I.; Udd, B.: Four
new Finnish families with LGMD1D; refinement of the clinical phenotype
and the linked 7q36 locus. Neuromusc. Disord. 21: 338-344, 2011.
4. Harms, M. B.; Sommerville, R. B.; Allred, P.; Bell, S.; Ma, D.;
Cooper, P.; Lopate, G.; Pestronk, A.; Weihl, C. C.; Baloh, R. H.:
Exome sequencing reveals DNAJB6 mutations in dominantly-inherited
myopathy. Ann. Neurol. 71: 407-416, 2012.
5. Ohtsuka, K.; Hata, M.: Mammalian HSP40/DNAJ homologs: cloning
of novel cDNAs and a proposal for their classification and nomenclature. Cell
Stress Chaperones 5: 98-112, 2000.
6. Sandell, S.; Huovinen, S.; Sarparanta, J.; Luque, H.; Raheem, O.;
Haapasalo, H.; Hackman, P.; Udd, B.: The enigma of 7q36 linked autosomal
dominant limb girdle muscular dystrophy. J. Neurol. Neurosurg. Psychiat. 81:
834-839, 2010.
7. Sarparanta, J.; Jonson, P. H.; Golzio, C.; Sandell, S.; Luque,
H.; Screen, M.; McDonald, K.; Stajich, J. M.; Mahjneh, I.; Vihola,
A.; Raheem, O.; Penttila, S.; and 9 others: Mutations affecting
the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle
muscular dystrophy. Nature Genet. 44: 450-455, 2012.
8. Seki, N.; Hattori, A.; Hayashi, A.; Kozuma, S.; Miyajima, N.; Saito,
T.: Cloning, tissue expression, and chromosomal assignment of human
MRJ gene for a member of the DNAJ protein family. J. Hum. Genet. 44:
185-189, 1999.
9. Speer, M. C.; Gilchrist, J. M.; Chutkow, J. G.; McMichael, R.;
Westbrook, C. A.; Stajich, J. M.; Jorgenson, E. M.; Gaskell, P. C.;
Rosi, B. L.; Ramesar, R.; Vance, J. M.; Yamaoka, L. H.; Roses, A.
D.; Pericak-Vance, M. A.: Evidence for locus heterogeneity in autosomal
dominant limb-girdle muscular dystrophy. Am. J. Hum. Genet. 57:
1371-1376, 1995.
10. Speer, M. C.; Vance, J. M.; Grubber, J. M.; Graham, F. L.; Stajich,
J. M.; Viles, K. D.; Rogala, A.; McMichael, R.; Chutkow, J.; Goldsmith,
C.; Tim, R. W.; Pericak-Vance, M. A.: Identification of a new autosomal
dominant limb-girdle muscular dystrophy locus on chromosome 7. Am.
J. Hum. Genet. 64: 556-562, 1999.
*FIELD* CN
Cassandra L. Kniffin - updated: 5/8/2012
Cassandra L. Kniffin - updated: 4/2/2012
Matthew B. Gross - updated: 11/29/2011
*FIELD* CD
Patricia A. Hartz: 8/16/2007
*FIELD* ED
carol: 05/08/2012
ckniffin: 5/8/2012
carol: 4/4/2012
ckniffin: 4/2/2012
mgross: 11/29/2011
wwang: 9/15/2009
carol: 8/16/2007