RBCC Red Blood Cell Collection

HSPB1 (HSP27, HSP28) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Heat shock protein beta-1; HspB1 (28 kDa heat shock protein; Estrogen-regulated 24 kDa protein; Heat shock 27 kDa protein; HSP 27; Stress-responsive protein 27; SRP27)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P04792
ID HSPB1_HUMAN Reviewed; 205 AA.
AC P04792; B2R4N8; Q6FI47; Q96C20; Q96EI7; Q9UC31; Q9UC34; Q9UC35;
read moreAC Q9UC36;
DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot.
DT 26-SEP-2001, sequence version 2.
DT 22-JAN-2014, entry version 173.
DE RecName: Full=Heat shock protein beta-1;
DE Short=HspB1;
DE AltName: Full=28 kDa heat shock protein;
DE AltName: Full=Estrogen-regulated 24 kDa protein;
DE AltName: Full=Heat shock 27 kDa protein;
DE Short=HSP 27;
DE AltName: Full=Stress-responsive protein 27;
DE Short=SRP27;
GN Name=HSPB1; Synonyms=HSP27, HSP28;
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 [GENOMIC DNA].
RX PubMed=3714473; DOI=10.1093/nar/14.10.4127;
RA Hickey E., Brandon S.E., Potter R., Stein G., Stein J., Weber L.A.;
RT "Sequence and organization of genes encoding the human 27 kDa heat
RT shock protein.";
RL Nucleic Acids Res. 14:4127-4145(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Lung;
RX PubMed=2243808; DOI=10.1093/nar/18.21.6457;
RA Carper S.W., Rocheleau T.A., Storm F.K.;
RT "cDNA sequence of a human heat shock protein HSP27.";
RL Nucleic Acids Res. 18:6457-6457(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND SUBUNIT.
RC TISSUE=Cervix carcinoma;
RX PubMed=10777697; DOI=10.1006/bbrc.2000.2553;
RA Hino M., Kurogi K., Okubo M.-A., Murata-Hori M., Hosoya H.;
RT "Small heat shock protein 27 (HSP27) associates with
RT tubulin/microtubules in HeLa cells.";
RL Biochem. Biophys. Res. Commun. 271:164-169(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary carcinoma;
RA Briolay J., Chareyron P., Mehlen P., Arrigo A.;
RT "Identification of a new cDNA sequence from human breast carcinoma
RT cells encoding the 28kDa heat shock protein.";
RL Submitted (JUN-1993) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=9110174;
RA Yu W., Andersson B., Worley K.C., Muzny D.M., Ding Y., Liu W.,
RA Ricafrente J.Y., Wentland M.A., Lennon G., Gibbs R.A.;
RT "Large-scale concatenation cDNA sequencing.";
RL Genome Res. 7:353-358(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skeletal muscle;
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 [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [10]
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 [11]
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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung, Ovary, Pancreas, Skin, and Uterus;
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 [13]
RP PROTEIN SEQUENCE OF 5-12; 97-112; 141-154 AND 172-188.
RX PubMed=2295696; DOI=10.1172/JCI114413;
RA Strahler J.R., Kuick R., Eckerskorn C., Lottspeich F.,
RA Richardson B.C., Fox D.A., Stoolman L.M., Hanson C.A., Nichols D.,
RA Tueche H.J., Hanash S.M.;
RT "Identification of two related markers for common acute lymphoblastic
RT leukemia as heat shock proteins.";
RL J. Clin. Invest. 85:200-207(1990).
RN [14]
RP PROTEIN SEQUENCE OF 6-37; 57-75; 80-89; 97-127 AND 141-188,
RP PHOSPHORYLATION AT SER-82, AND MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [15]
RP PROTEIN SEQUENCE OF 13-20; 38-46; 97-110; 141-154 AND 172-186, AND
RP PHOSPHORYLATION.
RC TISSUE=Mammary carcinoma;
RX PubMed=8325890;
RA Faucher C., Capdevielle J., Canal I., Ferrara P., Mazarguil H.,
RA McGuire W.L., Darbon J.-M.;
RT "The 28-kDa protein whose phosphorylation is induced by protein kinase
RT C activators in MCF-7 cells belongs to the family of low molecular
RT mass heat shock proteins and is the estrogen-regulated 24-kDa
RT protein.";
RL J. Biol. Chem. 268:15168-15173(1993).
RN [16]
RP PROTEIN SEQUENCE OF 21-59; 93-98; 129-134 AND 178-193, ASSOCIATION
RP WITH CRYAB, AND TISSUE SPECIFICITY.
RC TISSUE=Pectoralis muscle;
RX PubMed=1560006;
RA Kato K., Shinohara H., Goto S., Inaguma Y., Morishita R., Asano T.;
RT "Copurification of small heat shock protein with alpha B crystallin
RT from human skeletal muscle.";
RL J. Biol. Chem. 267:7718-7725(1992).
RN [17]
RP PROTEIN SEQUENCE OF 76-89, AND PHOSPHORYLATION AT SER-78 AND SER-82.
RX PubMed=1730670;
RA Landry J., Lambert H., Zhou M., Lavoie J.N., Hickey E., Weber L.A.,
RA Anderson C.W.;
RT "Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and
RT mitogen-activated kinases that recognize the same amino acid motif as
RT S6 kinase II.";
RL J. Biol. Chem. 267:794-803(1992).
RN [18]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 109-205.
RC TISSUE=Mammary carcinoma;
RX PubMed=2743305;
RA Fuqua S.A.W., Blum-Salingaros M., McGuire W.L.;
RT "Induction of the estrogen-regulated '24K' protein by heat shock.";
RL Cancer Res. 49:4126-4129(1989).
RN [19]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 122-205.
RX PubMed=1763035; DOI=10.1073/pnas.88.24.11212;
RA Mendelsohn M.E., Zhu Y., O'Neill S.;
RT "The 29-kDa proteins phosphorylated in thrombin-activated human
RT platelets are forms of the estrogen receptor-related 27-kDa heat shock
RT protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:11212-11216(1991).
RN [20]
RP PHOSPHORYLATION AT SER-15; SER-78 AND SER-82 BY MAPKAPK2.
RX PubMed=1332886; DOI=10.1016/0014-5793(92)81216-9;
RA Stokoe D., Engel K., Campbell D.G., Cohen P., Gaestel M.;
RT "Identification of MAPKAP kinase 2 as a major enzyme responsible for
RT the phosphorylation of the small mammalian heat shock proteins.";
RL FEBS Lett. 313:307-313(1992).
RN [21]
RP PHOSPHORYLATION BY MAPKAPK2.
RX PubMed=8093612;
RA Jakob U., Gaestel M., Engel K., Buchner J.;
RT "Small heat shock proteins are molecular chaperones.";
RL J. Biol. Chem. 268:1517-1520(1993).
RN [22]
RP PHOSPHORYLATION AT SER-15; SER-78 AND SER-82.
RX PubMed=8774846; DOI=10.1016/0014-5793(96)00816-2;
RA Clifton A.D., Young P.R., Cohen P.;
RT "A comparison of the substrate specificity of MAPKAP kinase-2 and
RT MAPKAP kinase-3 and their activation by cytokines and cellular
RT stress.";
RL FEBS Lett. 392:209-214(1996).
RN [23]
RP PHOSPHORYLATION AT SER-15; SER-78 AND SER-82, AND MUTAGENESIS OF
RP SER-15; SER-78 AND SER-82.
RX PubMed=10383393; DOI=10.1074/jbc.274.27.18947;
RA Rogalla T., Ehrnsperger M., Preville X., Kotlyarov A., Lutsch G.,
RA Ducasse C., Paul C., Wieske M., Arrigo A.P., Buchner J., Gaestel M.;
RT "Regulation of Hsp27 oligomerization, chaperone function, and
RT protective activity against oxidative stress/tumor necrosis factor
RT alpha by phosphorylation.";
RL J. Biol. Chem. 274:18947-18956(1999).
RN [24]
RP INTERACTION WITH HSPBAP1.
RX PubMed=10751411; DOI=10.1074/jbc.M001981200;
RA Liu C., Gilmont R.R., Benndorf R., Welsh M.J.;
RT "Identification and characterization of a novel protein from Sertoli
RT cells, PASS1, that associates with mammalian small stress protein
RT hsp27.";
RL J. Biol. Chem. 275:18724-18731(2000).
RN [25]
RP PHOSPHORYLATION AT SER-78 AND SER-82, AND MASS SPECTROMETRY.
RX PubMed=15976317; DOI=10.1161/01.RES.0000174815.10996.08;
RA De Souza A.I., Wait R., Mitchell A.G., Banner N.R., Dunn M.J.,
RA Rose M.L.;
RT "Heat shock protein 27 is associated with freedom from graft
RT vasculopathy after human cardiac transplantation.";
RL Circ. Res. 97:192-198(2005).
RN [26]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15 AND SER-65, 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 [27]
RP INDUCTION, AND MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells
RT reveal differential cellular gene expression in response to
RT enterovirus 71 infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [28]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-82 AND SER-83, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [29]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [30]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [31]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15 AND SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [32]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-82 AND SER-199, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [33]
RP SUBCELLULAR LOCATION.
RX PubMed=19464326; DOI=10.1016/j.bbamcr.2009.05.005;
RA Vos M.J., Kanon B., Kampinga H.H.;
RT "HSPB7 is a SC35 speckle resident small heat shock protein.";
RL Biochim. Biophys. Acta 1793:1343-1353(2009).
RN [34]
RP PHOSPHORYLATION AT SER-78 AND SER-82.
RX PubMed=19166925; DOI=10.1016/j.cellsig.2009.01.009;
RA Kostenko S., Johannessen M., Moens U.;
RT "PKA-induced F-actin rearrangement requires phosphorylation of Hsp27
RT by the MAPKAP kinase MK5.";
RL Cell. Signal. 21:712-718(2009).
RN [35]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [36]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-123, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [37]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15; SER-65; SER-78;
RP SER-82 AND SER-199, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [38]
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 [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-82, 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 [40]
RP VARIANTS CMT2F PHE-135 AND TRP-136, AND VARIANTS HMN2B TRP-127;
RP PHE-135; ILE-151 AND LEU-182.
RX PubMed=15122254; DOI=10.1038/ng1354;
RA Evgrafov O.V., Mersiyanova I., Irobi J., Van Den Bosch L., Dierick I.,
RA Leung C.L., Schagina O., Verpoorten N., Van Impe K., Fedotov V.,
RA Dadali E., Auer-Grumbach M., Windpassinger C., Wagner K., Mitrovic Z.,
RA Hilton-Jones D., Talbot K., Martin J.-J., Vasserman N., Tverskaya S.,
RA Polyakov A., Liem R.K.H., Gettemans J., Robberecht W., De Jonghe P.,
RA Timmerman V.;
RT "Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth
RT disease and distal hereditary motor neuropathy.";
RL Nat. Genet. 36:602-606(2004).
RN [41]
RP VARIANT CMT2F ALA-164.
RX PubMed=22206013; DOI=10.1371/journal.pone.0029393;
RA Lin K.P., Soong B.W., Yang C.C., Huang L.W., Chang M.H., Lee I.H.,
RA Antonellis A., Lee Y.C.;
RT "The mutational spectrum in a cohort of Charcot-Marie-Tooth disease
RT type 2 among the Han Chinese in Taiwan.";
RL PLoS ONE 6:E29393-E29393(2011).
CC -!- FUNCTION: Involved in stress resistance and actin organization.
CC -!- SUBUNIT: Interacts with TGFB1I1 (By similarity). Associates with
CC alpha- and beta-tubulin, microtubules and CRYAB. Interacts with
CC HSPB8 and HSPBAP1.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-352682, EBI-352682;
CC P02511:CRYAB; NbExp=2; IntAct=EBI-352682, EBI-739060;
CC Q9UER7:DAXX; NbExp=3; IntAct=EBI-352682, EBI-77321;
CC Q15029:EFTUD2; NbExp=2; IntAct=EBI-352682, EBI-357897;
CC P00533:EGFR; NbExp=3; IntAct=EBI-352682, EBI-297353;
CC P11413:G6PD; NbExp=2; IntAct=EBI-352682, EBI-4289891;
CC Q9UJY1:HSPB8; NbExp=3; IntAct=EBI-352682, EBI-739074;
CC P49137:MAPKAPK2; NbExp=2; IntAct=EBI-352682, EBI-993299;
CC Q16644:MAPKAPK3; NbExp=2; IntAct=EBI-352682, EBI-1384657;
CC Q8IW41:MAPKAPK5; NbExp=2; IntAct=EBI-352682, EBI-1201460;
CC P08473:MME; NbExp=4; IntAct=EBI-352682, EBI-353759;
CC P04637:TP53; NbExp=2; IntAct=EBI-352682, EBI-366083;
CC P63104:YWHAZ; NbExp=2; IntAct=EBI-352682, EBI-347088;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Cytoplasm, cytoskeleton,
CC spindle. Note=Cytoplasmic in interphase cells. Colocalizes with
CC mitotic spindles in mitotic cells. Translocates to the nucleus
CC during heat shock and resides in sub-nuclear structures known as
CC SC35 speckles or nuclear splicing speckles.
CC -!- TISSUE SPECIFICITY: Detected in all tissues tested: skeletal
CC muscle, heart, aorta, large intestine, small intestine, stomach,
CC esophagus, bladder, adrenal gland, thyroid, pancreas, testis,
CC adipose tissue, kidney, liver, spleen, cerebral cortex, blood
CC serum and cerebrospinal fluid. Highest levels are found in the
CC heart and in tissues composed of striated and smooth muscle.
CC -!- INDUCTION: Expressed in response to environmental stresses such as
CC heat shock, or estrogen stimulation in MCF-7 cells. Up-regulated
CC in response to enterovirus 71 (EV71) infection (at protein level).
CC -!- PTM: Phosphorylated in MCF-7 cells on exposure to protein kinase C
CC activators and heat shock.
CC -!- PTM: Phosphorylation by MAPKAPK2 and MAPKAPK3 in response to
CC stress leads to dissociate HSP27/HSPB1 from large small heat-shock
CC protein (sHsps) oligomers and impair its chaperone activity and
CC ability to protect against oxidative stress effectively.
CC Phosphorylation by MAPKAPK5 in response to PKA stimulation induces
CC F-actin rearrangement.
CC -!- DISEASE: Charcot-Marie-Tooth disease 2F (CMT2F) [MIM:606595]: A
CC dominant axonal form of Charcot-Marie-Tooth disease, a disorder of
CC the peripheral nervous system, characterized by progressive
CC weakness and atrophy, initially of the peroneal muscles and later
CC of the distal muscles of the arms. Charcot-Marie-Tooth disease is
CC classified in two main groups on the basis of electrophysiologic
CC properties and histopathology: primary peripheral demyelinating
CC neuropathies (designated CMT1 when they are dominantly inherited)
CC and primary peripheral axonal neuropathies (CMT2). Neuropathies of
CC the CMT2 group are characterized by signs of axonal degeneration
CC in the absence of obvious myelin alterations, normal or slightly
CC reduced nerve conduction velocities, and progressive distal muscle
CC weakness and atrophy. Nerve conduction velocities are normal or
CC slightly reduced. Onset of Charcot-Marie-Tooth disease type 2F is
CC between 15 and 25 years with muscle weakness and atrophy usually
CC beginning in feet and legs (peroneal distribution). Upper limb
CC involvement occurs later. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- DISEASE: Neuronopathy, distal hereditary motor, 2B (HMN2B)
CC [MIM:608634]: A neuromuscular disorder. Distal hereditary motor
CC neuronopathies constitute a heterogeneous group of neuromuscular
CC disorders caused by selective degeneration of motor neurons in the
CC anterior horn of the spinal cord, without sensory deficit in the
CC posterior horn. The overall clinical picture consists of a
CC classical distal muscular atrophy syndrome in the legs without
CC clinical sensory loss. The disease starts with weakness and
CC wasting of distal muscles of the anterior tibial and peroneal
CC compartments of the legs. Later on, weakness and atrophy may
CC expand to the proximal muscles of the lower limbs and/or to the
CC distal upper limbs. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the small heat shock protein (HSP20)
CC family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA62175.1; Type=Frameshift; Positions=194;
CC Sequence=AAB20722.1; Type=Frameshift; Positions=194;
CC Sequence=CAA34498.1; Type=Frameshift; Positions=194;
CC -!- WEB RESOURCE: Name=Inherited peripheral neuropathies mutation db;
CC URL="http://www.molgen.ua.ac.be/CMTMutations/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/HSPB1";
CC -!- WEB RESOURCE: Name=NIEHS SNPs;
CC URL="http://egp.gs.washington.edu/data/hspb1/";
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/HSPB1ID40880ch7q11.html";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L39370; AAA62175.1; ALT_FRAME; Genomic_DNA.
DR EMBL; X54079; CAA38016.1; -; mRNA.
DR EMBL; Z23090; CAA80636.1; -; mRNA.
DR EMBL; AB020027; BAB17232.1; -; mRNA.
DR EMBL; U90906; AAB51056.1; -; mRNA.
DR EMBL; CR407614; CAG28542.1; -; mRNA.
DR EMBL; CR536489; CAG38728.1; -; mRNA.
DR EMBL; BT019888; AAV38691.1; -; mRNA.
DR EMBL; AK311894; BAG34835.1; -; mRNA.
DR EMBL; DQ379985; ABC88475.1; -; Genomic_DNA.
DR EMBL; AC006388; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471220; EAW71803.1; -; Genomic_DNA.
DR EMBL; BC000510; AAH00510.1; -; mRNA.
DR EMBL; BC012292; AAH12292.1; -; mRNA.
DR EMBL; BC012768; AAH12768.1; -; mRNA.
DR EMBL; BC014920; AAH14920.1; -; mRNA.
DR EMBL; BC073768; AAH73768.1; -; mRNA.
DR EMBL; X16477; CAA34498.1; ALT_FRAME; mRNA.
DR EMBL; S74571; AAB20722.1; ALT_FRAME; mRNA.
DR PIR; S12102; HHHU27.
DR RefSeq; NP_001531.1; NM_001540.3.
DR UniGene; Hs.520973; -.
DR PDB; 3Q9P; X-ray; 2.00 A; A=90-171.
DR PDB; 3Q9Q; X-ray; 2.20 A; A/B=90-171.
DR PDBsum; 3Q9P; -.
DR PDBsum; 3Q9Q; -.
DR ProteinModelPortal; P04792; -.
DR SMR; P04792; 18-188.
DR DIP; DIP-412N; -.
DR IntAct; P04792; 58.
DR MINT; MINT-1368692; -.
DR BindingDB; P04792; -.
DR ChEMBL; CHEMBL5976; -.
DR PhosphoSite; P04792; -.
DR DMDM; 19855073; -.
DR DOSAC-COBS-2DPAGE; P04792; -.
DR OGP; P04792; -.
DR REPRODUCTION-2DPAGE; IPI00025512; -.
DR REPRODUCTION-2DPAGE; P04792; -.
DR SWISS-2DPAGE; P04792; -.
DR UCD-2DPAGE; P04792; -.
DR PaxDb; P04792; -.
DR PeptideAtlas; P04792; -.
DR PRIDE; P04792; -.
DR DNASU; 3315; -.
DR Ensembl; ENST00000248553; ENSP00000248553; ENSG00000106211.
DR GeneID; 3315; -.
DR KEGG; hsa:3315; -.
DR UCSC; uc003uew.3; human.
DR CTD; 3315; -.
DR GeneCards; GC07P075931; -.
DR HGNC; HGNC:5246; HSPB1.
DR HPA; CAB004439; -.
DR HPA; CAB047331; -.
DR HPA; HPA000497; -.
DR MIM; 602195; gene.
DR MIM; 606595; phenotype.
DR MIM; 608634; phenotype.
DR neXtProt; NX_P04792; -.
DR Orphanet; 99940; Autosomal dominant Charcot-Marie-Tooth disease type 2F.
DR Orphanet; 139525; Distal hereditary motor neuropathy type 2.
DR PharmGKB; PA29511; -.
DR eggNOG; NOG307785; -.
DR HOVERGEN; HBG054766; -.
DR InParanoid; P04792; -.
DR KO; K04455; -.
DR OMA; RTPSWDP; -.
DR OrthoDB; EOG7WHHBK; -.
DR PhylomeDB; P04792; -.
DR Reactome; REACT_21257; Metabolism of RNA.
DR Reactome; REACT_71; Gene Expression.
DR ChiTaRS; HSPB1; human.
DR GeneWiki; Hsp27; -.
DR GenomeRNAi; 3315; -.
DR NextBio; 13148; -.
DR PRO; PR:P04792; -.
DR ArrayExpress; P04792; -.
DR Bgee; P04792; -.
DR CleanEx; HS_HSPB1; -.
DR Genevestigator; P04792; -.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005856; C:cytoskeleton; TAS:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR GO; GO:0000502; C:proteasome complex; ISS:BHF-UCL.
DR GO; GO:0005819; C:spindle; IEA:UniProtKB-SubCell.
DR GO; GO:0030018; C:Z disc; IEA:Ensembl.
DR GO; GO:0005080; F:protein kinase C binding; ISS:BHF-UCL.
DR GO; GO:0008426; F:protein kinase C inhibitor activity; ISS:BHF-UCL.
DR GO; GO:0043130; F:ubiquitin binding; ISS:BHF-UCL.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0006928; P:cellular component movement; TAS:UniProtKB.
DR GO; GO:0010467; P:gene expression; TAS:Reactome.
DR GO; GO:0007243; P:intracellular protein kinase cascade; IMP:BHF-UCL.
DR GO; GO:0016071; P:mRNA metabolic process; TAS:Reactome.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:1902176; P:negative regulation of intrinsic apoptotic signaling pathway in response to oxidative stress; ISS:BHF-UCL.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:0043536; P:positive regulation of blood vessel endothelial cell migration; IMP:BHF-UCL.
DR GO; GO:0038033; P:positive regulation of endothelial cell chemotaxis by VEGF-activated vascular endothelial growth factor receptor signaling pathway; IMP:BHF-UCL.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; ISS:BHF-UCL.
DR GO; GO:0042535; P:positive regulation of tumor necrosis factor biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB cascade; ISS:BHF-UCL.
DR GO; GO:0006446; P:regulation of translational initiation; TAS:ProtInc.
DR GO; GO:0006986; P:response to unfolded protein; NAS:UniProtKB.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR InterPro; IPR002068; a-crystallin/Hsp20_dom.
DR InterPro; IPR001436; Alpha-crystallin/HSP.
DR InterPro; IPR008978; HSP20-like_chaperone.
DR Pfam; PF00011; HSP20; 1.
DR PIRSF; PIRSF036514; Sm_HSP_B1; 1.
DR PRINTS; PR00299; ACRYSTALLIN.
DR SUPFAM; SSF49764; SSF49764; 1.
DR PROSITE; PS01031; HSP20; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Chaperone; Charcot-Marie-Tooth disease;
KW Complete proteome; Cytoplasm; Cytoskeleton; Direct protein sequencing;
KW Disease mutation; Neurodegeneration; Neuropathy; Nucleus;
KW Phosphoprotein; Reference proteome; Stress response.
FT CHAIN 1 205 Heat shock protein beta-1.
FT /FTId=PRO_0000125927.
FT REGION 70 205 Interaction with TGFB1I1 (By similarity).
FT MOD_RES 15 15 Phosphoserine; by MAPKAPK2 and MAPKAPK3.
FT MOD_RES 26 26 Phosphoserine (By similarity).
FT MOD_RES 65 65 Phosphoserine.
FT MOD_RES 78 78 Phosphoserine; by MAPKAPK2, MAPKAPK3 and
FT MAPKAPK5.
FT MOD_RES 82 82 Phosphoserine; by MAPKAPK2, MAPKAPK3 and
FT MAPKAPK5.
FT MOD_RES 83 83 Phosphoserine.
FT MOD_RES 86 86 Phosphoserine (By similarity).
FT MOD_RES 123 123 N6-acetyllysine.
FT MOD_RES 199 199 Phosphoserine.
FT VARIANT 127 127 R -> W (in HMN2B).
FT /FTId=VAR_018506.
FT VARIANT 135 135 S -> F (in CMT2F and HMN2B).
FT /FTId=VAR_018507.
FT VARIANT 136 136 R -> W (in CMT2F).
FT /FTId=VAR_018508.
FT VARIANT 151 151 T -> I (in HMN2B).
FT /FTId=VAR_018509.
FT VARIANT 164 164 T -> A (in CMT2F).
FT /FTId=VAR_067085.
FT VARIANT 182 182 P -> L (in HMN2B).
FT /FTId=VAR_018510.
FT MUTAGEN 15 15 S->D: Mimicks phosphorylation state,
FT leading to dreased ability to act as
FT molecular chaperones; when associated
FT with D-78 and D-82.
FT MUTAGEN 78 78 S->D: Mimicks phosphorylation state,
FT leading to dreased ability to act as
FT molecular chaperones; when associated
FT with D-15 and D-82.
FT MUTAGEN 82 82 S->D: Mimicks phosphorylation state,
FT leading to dreased ability to act as
FT molecular chaperones; when associated
FT with D-15 and D-78.
FT CONFLICT 10 10 L -> I (in Ref. 13; AA sequence).
FT CONFLICT 109 109 L -> R (in Ref. 12; AAH12292).
FT CONFLICT 121 121 T -> S (in Ref. 12; AAH12292).
FT CONFLICT 127 127 R -> L (in Ref. 12; AAH12292).
FT STRAND 94 100
FT TURN 102 104
FT STRAND 107 114
FT STRAND 117 124
FT STRAND 136 143
FT HELIX 150 152
FT STRAND 154 157
FT STRAND 161 168
SQ SEQUENCE 205 AA; 22783 MW; 1B4DC44A6F6606D5 CRC64;
MTERRVPFSL LRGPSWDPFR DWYPHSRLFD QAFGLPRLPE EWSQWLGGSS WPGYVRPLPP
AAIESPAVAA PAYSRALSRQ LSSGVSEIRH TADRWRVSLD VNHFAPDELT VKTKDGVVEI
TGKHEERQDE HGYISRCFTR KYTLPPGVDP TQVSSSLSPE GTLTVEAPMP KLATQSNEIT
IPVTFESRAQ LGGPEAAKSD ETAAK
//

MIM 602195
*RECORD*
*FIELD* NO
602195
*FIELD* TI
*602195 HEAT-SHOCK 27-KD PROTEIN 1; HSPB1
;;HEAT-SHOCK PROTEIN 27; HSP27
*FIELD* TX
read more
CLONING

The heat-shock proteins (HSPs) belong to a larger group of polypeptides,
the stress proteins, that are induced in various combinations in
response to environmental challenges and developmental transitions.
Synthesis of the small (27-kD) HSP has been shown to be correlated with
the acquisition of thermotolerance. Hickey et al. (1986) cloned a HeLa
cell cDNA encoding HSP27. By screening a human genomic library with this
HSP27 cDNA, Hickey et al. (1986) isolated the HSP27 genomic sequence.
The deduced 199-amino acid HSP27 protein shows sequence similarity to
mammalian alpha-crystallins (e.g., 123580). Approximately 20% of its
residues are susceptible to phosphorylation. The HSP27 gene produced a
2.2-kb transcript in an in vitro transcription assay.

Carper et al. (1990) cloned an HSP27 cDNA derived from heat-shocked
human A549 lung carcinoma cells. The cDNA encodes a deduced 205-amino
acid protein whose first 193 amino acids are identical to those of the
predicted HSP27 protein reported by Hickey et al. (1986). Carper et al.
(1990) suggested that the C-terminal differences of these deduced HSP27
proteins may be a result of a DNA sequencing artifact.

- PSEUDOGENES

Hickey et al. (1986) identified a processed HSP27 pseudogene.

GENE STRUCTURE

Hickey et al. (1986) determined that the HSP27 gene has 3 exons.

MAPPING

Hunt et al. (1997) mapped the mouse Hsp25 gene to chromosome 5 in a
region homologous to 7q in the human. They also mapped the mouse Hsp105
gene to chromosome 5 but suggested that the human homolog is probably on
13q, not chromosome 7.

Stock et al. (2003) used FISH to map the HSP27 gene to 7q11.23. This
band also contains the site of the deletion associated with Williams
syndrome (194050). Stock et al. (2003) used 2-color FISH on previously
G-banded and photographed metaphase chromosomes from Williams syndrome
cell lines and peripheral blood. In 6 Williams syndrome patients with
longer deletions that extended telomeric to the classic Williams
syndrome deletion region, they found that HSP27 was telomeric to several
markers and was deleted in 3. They discussed the possible role of HSP27
in the cognitive features of Williams syndrome.

GENE FUNCTION

New et al. (1998) demonstrated that MAPKAPK5 (606723) is a major
stress-activated kinase that can phosphorylate HSP27 in vitro.

Using a cellular model of Huntington disease (143100), Wyttenbach et al.
(2002) identified HSP27 as a suppressor of polyglutamine
(polyQ)-mediated cell death. In contrast to HSP40 (see 604572) and HSP70
(see 140550) chaperones, HSP27 suppressed polyQ death without
suppressing polyQ aggregation. While polyQ-induced cell death was
reduced by inhibiting cytochrome c release from mitochondria, protection
by HSP27 was regulated by its phosphorylation status and was independent
of its ability to bind to cytochrome c. However, mutant huntingtin (HTT;
613004) caused increased levels of reactive oxygen species (ROS) in
neuronal and nonneuronal cells. ROS contributed to cell death because
both N-acetyl-L-cysteine and glutathione in its reduced form suppressed
polyQ-mediated cell death. HSP27 decreased ROS in cells expressing
mutant huntingtin, suggesting that this chaperone may protect cells
against oxidative stress. The authors proposed that a polyQ mutation may
induce ROS that directly contribute to cell death, and that HSP27 may be
an antagonist of this process.

The alpha-crystallin subunits alpha-A (123580) and alpha-B (123590) each
can form an oligomer by itself or with the other. Fu and Liang (2002)
used a 2-hybrid system to study heterogeneous interactions among lens
crystallins of different classes. They found interactions between
alpha-A- (or alpha-B-) and beta-B2- (123620) or gamma-C-(123680)
crystallins, but the intensity of interaction was one-third that of
alpha-A-alpha-B interactions. HSP27 showed similar interaction
properties with alpha-B-crystallin. Experiments with N- and C-terminal
domain-truncated mutants demonstrated that both N- and C-terminal
domains were important in alpha-A-crystallin self-interaction, but that
only the C-terminal domain was important in alpha-B-crystallin
self-interaction.

When fed a diet supplemented with cholesterol, Apoe (107741) -/- mice
develop inflammatory atherosclerosis. Rayner et al. (2008) found that
overexpression of human HSP27 reduced atherosclerotic lesions in aortic
arches excised from Apoe -/- female mice by 35% compared with Apoe -/-
controls. HSP27 overexpression had no effect on atherosclerotic lesions
in Apoe -/- male mice. However, there was an inverse correlation between
serum HSP27 level and atherosclerotic lesion area in both male and
female Apoe -/- mice. HSP27 was secreted from cultured human macrophages
in response to estrogen and acetylated low density lipoprotein (acLDL).
Extracellular HSP27 bound the scavenger receptor SRA (MSR1; 153622) on
murine macrophages and prevented acLDL uptake. Extracellular HSP27 also
decreased acLDL-induced release of the proinflammatory cytokine Il1b
(147720) and increased the release of the antiinflammatory cytokine Il10
(124092) by mouse macrophages. Overexpression of HSP27 in Apoe -/- mouse
macrophages reduced their adherence and migration in vitro. Rayner et
al. (2008) concluded that HSP27 is atheroprotective, possibly by
competing for uptake of atherogenic lipids by macrophages or by
attenuating inflammation.

De Thonel et al. (2010) stated that HSP27 is a ubiquitin-binding protein
involved in proteasomal degradation of certain proteins under stress
conditions. They found that HSP27 was involved in proteasome-mediated
degradation of GATA1 (305371), a transcription factor that directs
erythroblast proliferation, but not differentiation. Knockdown of HSP27
or overexpression of GATA1 inhibited differentiation of primary cultured
human erythroid cells and the K562 erythroleukemia cell line.
HSP27-mediated GATA1 degradation was reduced by proteasome inhibitors
and required prior acetylation of GATA1 and serine phosphorylation of
HSP27 via the p38 MAP kinase (MAPK14; 600289) pathway.

MOLECULAR GENETICS

In affected members of 2 families with axonal Charcot-Marie-Tooth
disease type 2F (CMT2F; 606595) and in affected members of 4 families
with distal hereditary motor neuropathy (HMN2B; 608634), Evgrafov et al.
(2004) identified mutations in the HSPB1 gene (602195.0001-602195.0004).

Benndorf and Welsh (2004) reviewed the role of heat-shock proteins in
neuromuscular function, as indicated by the association of mutations in
2 of these genes, HSP22 (608014) and HSP27, with human neuromuscular
disorders.

Houlden et al. (2008) identified 4 different heterozygous mutations in
the HSPB1 gene (see, e.g., 602195.0001; 602195.0007) in affected members
of 4 of 25 families with autosomal dominant distal HMN. An additional
patient with autosomal recessive inheritance was found to have a
homozygous mutation (602195.0008). All patients had a predominant motor
neuropathy without clinical sensory abnormalities. No HSPB1 mutations
were found in 90 families with CMT2.

ANIMAL MODEL

D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing
the S135F (602195.0001) or P182L (602195.0004) Hspb1 mutations developed
clinical and pathologic features of axonal CMT or distal HMN. Mutant
mice developed progressive motor impairment, decreased muscle strength,
and clawed hindpaws, features that were more apparent in P182L mice, as
P182L is associated with the dHMN phenotype. S135F mutants showed
sensory abnormalities, whereas P182L mutant mice did not. Sensory loss
in the S135F mutants was associated with decreased sensory amplitudes on
electrophysiologic studies and impaired mitochondrial axonal transport
in dorsal root ganglion cells. Both mouse mutants showed distal axonal
loss on nerve biopsy, and both had a decrease in acetylated
alpha-tubulin (TUBA1A; 602529) in peripheral nerves. Treatment of S135F
mutant mice with an HDAC6 (300272) inhibitor resulted in restoration of
axonal transport and partial reversal of the CMT phenotype.

*FIELD* AV
.0001
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
HSPB1, SER135PHE

In affected members of a Russian family with Charcot-Marie-Tooth disease
type 2F (606595) previously reported by Ismailov et al. (2001), Evgrafov
et al. (2004) identified a 404C-T transition in exon 2 of the HSPB1
gene, resulting in a ser135-to-phe (S135F) substitution. In affected
members of an unrelated family from the United Kingdom with distal
hereditary motor neuropathy IIB (608634), the authors identified the
same mutation. The S135F mutation occurs in a highly conserved
alpha-crystallin domain of the protein. In vitro expression of the
mutant protein resulted in reduced viability of neuronal cells and
impaired neurofilament assembly. Evgrafov et al. (2004) suggested that
these deficits may be responsible for premature axonal degeneration,
which underlies both CMT and dHMN.

Houlden et al. (2008) identified a heterozygous S135F mutation in
affected members of a large family with dHMN2B. The mean age at onset
was 21 years, and sensory abnormalities were not present.

In cultured mouse motor neurons, Zhai et al. (2007) showed that
expression of S135F-mutant HSPB1 led to progressive degeneration of
motor neurons with disruption of the neurofilament network and
aggregation of NEFL (162280) protein. The 2 proteins were found to
associate together, and the S135F mutant had a dominant effect.
Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to
disruption of the neurofilament network and aggregation of NEFL, and
wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007)
suggested that disruption of the neurofilament network with aggregation
of NEFL is a common triggering event of motor neuron degeneration in
CMT2E (607684) and CMT2F.

.0002
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F, INCLUDED
HSPB1, ARG127TRP

In affected members of a Belgian family with distal hereditary motor
neuropathy IIB (608634), Evgrafov et al. (2004) identified a 379C-T
transition in exon 2 of the HSPB1 gene, resulting in an arg127-to-trp
(R127W) substitution. The mutation occurs in a highly conserved
alpha-crystallin domain of the protein.

In affected members of 4 Chinese Han families with late-onset
Charcot-Marie-Tooth disease type 2F (606595), Tang et al. (2005)
identified the R127W substitution. Haplotype analysis indicated a
founder effect. Three mutation carriers from different families, ranging
in age from 23 to 37 years, were asymptomatic, possibly reflecting
age-dependent penetrance.

.0003
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
HSPB1, THR151ILE

In affected members of a Croatian family with distal hereditary motor
neuropathy IIB (608634), Evgrafov et al. (2004) identified a 452C-T
transition in exon 2 of the HSPB1 gene, resulting in a thr151-to-ile
(T151I) substitution. The mutation occurs in a highly conserved
alpha-crystallin domain of the protein.

.0004
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
HSPB1, PRO182LEU

In affected members of an Austrian family with distal hereditary motor
neuropathy IIB (608634), Evgrafov et al. (2004) identified a 545C-T
transition in exon 3 of the HSPB1 gene, resulting in a pro182-to-leu
(P182L) substitution. The mutation occurs in the variable C-terminal
tail of the protein.

By in vitro functional expression studies, Ackerley et al. (2006) showed
that in mouse primary cortical cells the P182L-mutant protein formed
aggregates and failed to be transported down neuronal processes unlike
the wildtype protein. Coexpression of the mutant and wildtype protein
resulted in sequestration of the wildtype protein into mutant
aggregates. Mutant HSPB1 also disrupted the formation of intracellular
neurofilaments and disrupted the transport of specific cellular cargoes,
such as the p150 dynactin (DCTN1; 601143), but not mitochondria.

.0005
CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F
HSPB1, ARG136TRP

In affected members of a Belgian family with Charcot-Marie-Tooth disease
type 2F (606595), Evgrafov et al. (2004) identified a 406C-T transition
in exon 2 of the HSPB1 gene, resulting in an arg136-to-trp (R136W)
substitution. The mutation occurs in a highly conserved alpha-crystallin
domain of the protein.

.0006
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
HSPB1, PRO182SER

In a Japanese patient with HMN2B (608634), Kijima et al. (2005)
identified heterozygosity for a 544C-T transition in exon 3 of the HSBP1
gene, resulting in a pro182-to-ser (P182S) substitution. The mutation
was not detected in his parents or older brother or in 100 control
chromosomes.

.0007
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB
HSPB1, ARG140GLY

In affected individuals from an Indian family with HMN2B (608634),
Houlden et al. (2008) identified a heterozygous 418C-G transversion in
exon 2 of the HSPB1 gene, resulting in an arg140-to-gly (R140G)
substitution in the alpha-crystallin domain. The mean age of onset in
this family was 29 years, and both father and son had distal motor
neuropathy without sensory abnormalities. Two additional Indian patients
with sporadic HMN2B were also found to carry the R140G mutation.

.0008
NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB, AUTOSOMAL RECESSIVE
HSPB1, LEU99MET

In a Pakistani patient, born of consanguineous parents, with distal
HMN2B (608634), Houlden et al. (2008) identified a homozygous 295C-A
transversion in exon 1 of the HSPB1 gene, resulting in a leu99-to-met
(L99M) substitution in the alpha-crystallin domain. He had onset at age
37 years of difficulty walking, and had distal muscle weakness and
atrophy without sensory involvement. The patient's unaffected mother and
sister were heterozygous for the mutation, suggesting that it may act in
a dose-dependent fashion. This was the first report of autosomal
recessive inheritance of HSPB1 mutations. The mutation occurred in a
conserved residue and was not found in 220 controls.

*FIELD* RF
1. Ackerley, S.; James, P. A.; Kalli, A.; French, S.; Davies, K. E.;
Talbot, K.: A mutation in the small heat-shock protein HSPB1 leading
to distal hereditary motor neuronopathy disrupts neurofilament assembly
and the axonal transport of specific cellular cargoes. Hum. Molec.
Genet. 15: 347-354, 2006.

2. Benndorf, R.; Welsh, M. J.: Shocking degeneration. Nature Genet. 36:
547-548, 2004.

3. Carper, S. W.; Rocheleau, T. A.; Storm, F. K.: cDNA sequence of
a human heat shock protein HSP27. Nucleic Acids Res. 18: 6457 only,
1990.

4. d'Ydewalle, C.; Krishnan, J.; Chiheb, D. M.; Van Damme, P.; Irobi,
J.; Kozikowski, A. P.; Vanden Berghe, P.; Timmerman, V.; Robberecht,
W.; Van Den Bosch, L.: HDAC6 inhibitors reverse axonal loss in a
mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nature
Med. 17: 968-974, 2011.

5. de Thonel, A.; Vandekerckhove, J.; Lanneau, D.; Selvakumar, S.;
Courtois, G.; Hazoume, A.; Brunet, M.; Maurel, S.; Hammann, A.; Ribeil,
J. A.; Zermati, Y.; Gabet, A. S.; Boyes, J.; Solary, E.; Hermine,
O.; Garrido, C.: HSP27 controls GATA-1 protein level during erythroid
cell differentiation. Blood 116: 85-96, 2010.

6. Evgrafov, O. V.; Mersiyanova, I.; Irobi, J.; Van Den Bosch, L.;
Dierick, I.; Leung, C. L.; Schagina, O.; Verpoorten, N.; Van Impe,
K.; Fedotov, V.; Dadali, E.; Auer-Grumbach, M.; and 14 others:
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth
disease and distal hereditary motor neuropathy. Nature Genet. 36:
602-606, 2004.

7. Fu, L.; Liang, J. J.-N.: Detection of protein-protein interactions
among lens crystallins in a mammalian two-hybrid system assay. J.
Biol. Chem. 277: 4255-4260, 2002.

8. Hickey, E.; Brandon, S. E.; Potter, R.; Stein, G.; Stein, J.; Weber,
L. A.: Sequence and organization of genes encoding the human 27 kDa
heat shock protein. Nucleic Acids Res. 14: 4127-4145, 1986. Note:
Erratum: Nucleic Acids Res. 14: 8230 only, 1986.

9. Hickey, E.; Brandon, S. E.; Sadis, S.; Smale, G.; Weber, L. A.
: Molecular cloning of sequences encoding the human heat-shock proteins
and their expression during hyperthermia. Gene 43: 147-154, 1986.

10. Houlden, H.; Laura, M.; Wavrant-De Vrieze, F.; Blake, J.; Wood,
N.; Reilly, M. M.: Mutations in the HSP27 (HSPB1) gene cause dominant,
recessive, and sporadic distal HMN/CMT type 2. Neurology 71: 1660-1668,
2008.

11. Hunt, C. R.; Goswami, P. C.; Kozak, C. A.: Assignment of the
mouse Hsp25 and Hsp105 genes to the distal region of chromosome 5
by linkage analysis. Genomics 45: 462-463, 1997.

12. Ismailov, S. M.; Fedotov, V. P.; Dadali, E. L.; Polyakov, A. V.;
Van Broeckhoven, C.; Ivanov, V. I.; De Jonghe, P.; Timmerman, V.;
Evgrafov, O. V.: A new locus for autosomal dominant Charcot-Marie-Tooth
disease type 2 (CMT2F) maps to chromosome 7q11-q21. Europ. J. Hum.
Genet. 9: 646-650, 2001.

13. Kijima, K.; Numakura, C.; Goto, T.; Takahashi, T.; Otagiri, T.;
Umetsu, K.; Hayasaka, K.: Small heat shock protein 27 mutation in
a Japanese patient with distal hereditary motor neuropathy. J. Hum.
Genet. 50: 473-476, 2005.

14. New, L.; Jiang, Y.; Zhao, M.; Liu, K.; Zhu, W.; Flood, L. J.;
Kato, Y.; Parry, G. C. N.; Han, J.: PRAK, a novel protein kinase
regulated by the p38 MAP kinase. EMBO J. 17: 3372-3384, 1998.

15. Rayner, K.; Chen, Y.-X.; McNulty, M.; Simard, T.; Zhao, X.; Wells,
D. J.; de Belleroche, J.; O'Brien, E. R.: Extracellular release of
the atheroprotective heat shock protein 27 is mediated by estrogen
and competitively inhibits acLDL binding to scavenger receptor-A. Circ.
Res. 103: 133-141, 2008.

16. Stock, A. D.; Spallone, P. A.; Dennis, T. R.; Netski, D.; Morris,
C. A.; Mervis, C. B.; Hobart, H. H.: Heat shock protein 27 gene:
chromosomal and molecular location and relationship to Williams syndrome. Am.
J. Med. Genet. 120A: 320-325, 2003.

17. Tang, B.; Liu, X.; Zhao, G.; Luo, W.; Xia, K.; Pan, Q.; Cai, F.;
Hu, Z.; Zhang, C.; Chen, B.; Zhang, F.; Shen, L.; Zhang, R.; Jiang,
H.: Mutation analysis of the small heat shock protein 27 gene in
Chinese patients with Charcot-Marie-Tooth disease. Arch. Neurol. 62:
1201-1207, 2005.

18. Wyttenbach, A.; Sauvageot, O.; Carmichael, J.; Diaz-Latoud, C.;
Arrigo, A.-P.; Rubinsztein, D. C.: Heat shock protein 27 prevents
cellular polyglutamine toxicity and suppresses the increase of reactive
oxygen species caused by huntingtin. Hum. Molec. Genet. 11: 1137-1151,
2002.

19. Zhai, J.; Lin, H.; Julien, J.-P.; Schlaepfer, W. W.: Disruption
of neurofilament network with aggregation of light neurofilament protein:
a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth
disease-linked mutations in NFL and HSPB1. Hum. Molec. Genet. 16:
3103-3116, 2007.

*FIELD* CN
Cassandra L. Kniffin - updated: 12/15/2011
Patricia A. Hartz - updated: 6/15/2011
Cassandra L. Kniffin - updated: 10/30/2009
Cassandra L. Kniffin - updated: 9/2/2009
Patricia A. Hartz - updated: 4/15/2009
Cassandra L. Kniffin - updated: 4/6/2009
Victor A. McKusick - updated: 12/16/2005
Cassandra L. Kniffin - updated: 11/4/2005
Victor A. McKusick - updated: 6/14/2004
Jane Kelly - updated: 3/5/2004
Victor A. McKusick - updated: 8/5/2003
George E. Tiller - updated: 12/17/2002
Dawn Watkins-Chow - updated: 2/26/2002
Patti M. Sherman - updated: 5/11/1999
Barbara J. Biery - updated: 4/21/1999

*FIELD* CD
Victor A. McKusick: 12/16/1997

*FIELD* ED
carol: 12/16/2011
ckniffin: 12/15/2011
mgross: 8/30/2011
terry: 6/15/2011
wwang: 11/5/2009
ckniffin: 10/30/2009
wwang: 9/15/2009
wwang: 9/10/2009
ckniffin: 9/2/2009
mgross: 4/15/2009
wwang: 4/15/2009
ckniffin: 4/6/2009
ckniffin: 3/16/2007
carol: 12/29/2005
wwang: 12/28/2005
terry: 12/16/2005
wwang: 11/15/2005
wwang: 11/14/2005
ckniffin: 11/4/2005
ckniffin: 4/4/2005
tkritzer: 6/29/2004
terry: 6/14/2004
alopez: 5/28/2004
tkritzer: 5/4/2004
ckniffin: 5/3/2004
alopez: 3/5/2004
tkritzer: 8/6/2003
tkritzer: 8/5/2003
cwells: 12/17/2002
mgross: 2/26/2002
alopez: 4/14/2000
mgross: 5/27/1999
psherman: 5/11/1999
psherman: 4/21/1999
terry: 7/24/1998
mark: 12/16/1997

MIM 606595
*RECORD*
*FIELD* NO
606595
*FIELD* TI
#606595 CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F; CMT2F
;;CHARCOT-MARIE-TOOTH DISEASE, NEURONAL, TYPE 2F;;
read moreCHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2F
*FIELD* TX
A number sign (#) is used with this entry because Charcot-Marie-Tooth
disease type 2F is caused by mutation in the gene encoding heat-shock
27-kD protein-1 (HSPB1; 602195).

CLINICAL FEATURES

Ismailov et al. (2001) reported a 6-generation family with autosomal
dominant Charcot-Marie-Tooth disease of the axonal type (CMT2; see
118200) from the Voronezh province of Russia. Fourteen individuals were
diagnosed with CMT2 with a similar clinical phenotype. Disease onset
occurred between the age of 15 and 25 years. Patients had symmetrical
progressive weakness and atrophy of the lower limb muscles, resulting in
foot drop and steppage gait. Wasting of upper limb muscles caused
clawing of the hands several years later. Depressed or absent deep
tendon reflexes were observed at an early stage. Mild to moderate
sensory impairments occurred in the feet and hands in all the patients.
The course of the disease was slowly progressive with disability after
15 to 20 years, but reproductive fitness was conserved and life span not
restricted. Electrophysiologic findings were characteristic for axonal
neuropathy. Initial linkage analysis excluded linkage to previously
mapped forms of CMT.

Tang et al. (2005) reported 4 Chinese families with CMT2F confirmed by
genetic analysis (602195.0002). Age at onset ranged from 35 to 60 years,
with difficulty in walking, followed by weakness and atrophy of the
distal parts of the limbs. Tendon reflexes were depressed or absent,
with mild stocking sensory loss to pricking pain or vibration in the
feet. Most patients had talipes cavus or claw hand deformity. Variable
symptoms included cramps, fasciculations, numbness, and tingling in the
lower limbs. Sural nerve biopsy of 1 patient showed chronic axonal
neuropathy. Tang et al. (2005) noted that the phenotype in these
families differed slightly from that reported by Ismailov et al. (2001).

MAPPING

Ismailov et al. (2001) performed a genomewide scan and found linkage of
the disorder in 1 family to STR markers on chromosome 7q11-q21. A
maximum 2-point lod score of 5.87 (theta = 0.00) was obtained for
D7S2204; multipoint linkage analysis gave a maximum lod score of 6.43 at
the same marker. Haplotype analysis indicated that the disease locus is
located in a 14.5-cM interval between markers D7S2435 and D7S806. Based
on a recombinant in a 76-year-old unaffected individual, the presence of
the CMT2F gene in the telomeric part of the linked region was unlikely.

MOLECULAR GENETICS

In affected members of a Russian family with CMT2F, previously reported
by Ismailov et al. (2001), Evgrafov et al. (2004) identified a mutation
in the HSPB1 gene (S135F; 602195.0001). In affected members of a Belgian
family with CMT2F, the authors identified a second mutation in the HSPB1
gene (602195.0005).

In affected members of 4 Han Chinese families with CMT2F, Tang et al.
(2005) identified the same mutation in the HSPB1 gene (602195.0002).
Haplotype analysis indicated a founder effect.

PATHOGENESIS

In cultured mouse motor neurons, Zhai et al. (2007) showed that
expression of S135F-mutant HSPB1 led to progressive degeneration of
motor neurons with disruption of the neurofilament network and
aggregation of NEFL (162280) protein. The 2 proteins were found to
associate together, and the S135F mutant had a dominant effect.
Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to
disruption of the neurofilament network and aggregation of NEFL, and
wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007)
suggested that disruption of the neurofilament network with aggregation
of NEFL is a common triggering event of motor neuron degeneration in
CMT2E (607684) and CMT2F.

ANIMAL MODEL

D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing
the S135F (602195.0001) Hspb1 mutation developed clinical and pathologic
features of axonal CMT. Mutant mice developed progressive motor
impairment, decreased muscle strength, clawed hindpaws, and sensory
abnormalities. Sensory loss in the S135F mutants was associated with
decreased sensory amplitudes on electrophysiologic studies and impaired
mitochondrial axonal transport in dorsal root ganglion cells. There was
distal axonal loss on nerve biopsy, as well as a decrease in acetylated
alpha-tubulin (TUBA1A; 602529) in peripheral nerves. Treatment of S135F
mutant mice with an HDAC6 (300272) inhibitor resulted in restoration of
axonal transport and partial reversal of the CMT phenotype.

*FIELD* RF
1. d'Ydewalle, C.; Krishnan, J.; Chiheb, D. M.; Van Damme, P.; Irobi,
J.; Kozikowski, A. P.; Vanden Berghe, P.; Timmerman, V.; Robberecht,
W.; Van Den Bosch, L.: HDAC6 inhibitors reverse axonal loss in a
mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nature
Med. 17: 968-974, 2011.

2. Evgrafov, O. V.; Mersiyanova, I.; Irobi, J.; Van Den Bosch, L.;
Dierick, I.; Leung, C. L.; Schagina, O.; Verpoorten, N.; Van Impe,
K.; Fedotov, V.; Dadali, E.; Auer-Grumbach, M.; and 14 others:
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth
disease and distal hereditary motor neuropathy. Nature Genet. 36:
602-606, 2004.

3. Ismailov, S. M.; Fedotov, V. P.; Dadali, E. L.; Polyakov, A. V.;
Van Broeckhoven, C.; Ivanov, V. I.; De Jonghe, P.; Timmerman, V.;
Evgrafov, O. V.: A new locus for autosomal dominant Charcot-Marie-Tooth
disease type 2 (CMT2F) maps to chromosome 7q11-q21. Europ. J. Hum.
Genet. 9: 646-650, 2001.

4. Tang, B.; Liu, X.; Zhao, G.; Luo, W.; Xia, K.; Pan, Q.; Cai, F.;
Hu, Z.; Zhang, C.; Chen, B.; Zhang, F.; Shen, L.; Zhang, R.; Jiang,
H.: Mutation analysis of the small heat shock protein 27 gene in
Chinese patients with Charcot-Marie-Tooth disease. Arch. Neurol. 62:
1201-1207, 2005.

5. Zhai, J.; Lin, H.; Julien, J.-P.; Schlaepfer, W. W.: Disruption
of neurofilament network with aggregation of light neurofilament protein:
a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth
disease-linked mutations in NFL and HSPB1. Hum. Molec. Genet. 16:
3103-3116, 2007.

*FIELD* CS
INHERITANCE:
Autosomal dominant

SKELETAL:
[Hands];
Claw hand deformities (in severe cases);
[Feet];
Pes cavus

NEUROLOGIC:
[Peripheral nervous system];
Distal limb muscle weakness due to peripheral neuropathy;
Distal limb muscle atrophy due to peripheral neuropathy;
Upper limb involvement occurs later;
'Steppage' gait;
Foot drop;
Distal sensory impairment;
Hyporeflexia;
Areflexia;
Fasciculations;
Muscle cramps;
Normal or mildly decreased motor nerve conduction velocity (NCV) (greater
than 38 m/s);
Sural nerve biopsy shows chronic axonal neuropathy

MISCELLANEOUS:
Variable age at onset (range 15 to 60 years);
Usually begins in feet and legs (peroneal distribution);
Genetic heterogeneity (see CMT2A, 118210)

MOLECULAR BASIS:
Caused by mutation in the heat-shock 27-kD protein (HSPB1, 602195.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 11/04/2005

*FIELD* CD
Cassandra L. Kniffin: 4/22/2003

*FIELD* ED
ckniffin: 11/04/2005
ckniffin: 5/3/2004
ckniffin: 5/2/2003

*FIELD* CN
Cassandra L. Kniffin - updated: 12/15/2011
Cassandra L. Kniffin - updated: 9/2/2009
Cassandra L. Kniffin - updated: 11/4/2005

*FIELD* CD
Michael B. Petersen: 1/7/2002

*FIELD* ED
carol: 12/16/2011
ckniffin: 12/15/2011
terry: 3/3/2010
wwang: 9/10/2009
ckniffin: 9/2/2009
wwang: 11/14/2005
ckniffin: 11/4/2005
alopez: 5/28/2004
tkritzer: 5/4/2004
ckniffin: 5/3/2004
alopez: 3/17/2004
carol: 4/29/2003
ckniffin: 4/24/2003
ckniffin: 4/14/2003
carol: 1/7/2002

MIM 608634
*RECORD*
*FIELD* NO
608634
*FIELD* TI
#608634 NEURONOPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB; HMN2B
;;HMN IIB;;
NEUROPATHY, DISTAL HEREDITARY MOTOR, TYPE IIB; DHMN2B
read more*FIELD* TX
A number sign (#) is used with this entry because distal hereditary
motor neuronopathy type 2B (dHMN2B or HMN2B) is caused by heterozygous
mutation in the gene encoding heat-shock 27-kD protein-1 (HSPB1; 602195)
on chromosome 7q11. Axonal Charcot-Marie-Tooth disease type 2F (CMT2F;
606595) is an allelic disorder with a similar phenotype.

For a general phenotypic description and a discussion of genetic
heterogeneity of distal HMN (dHMN), see HMN type I (HMN1; 182960).

CLINICAL FEATURES

Houlden et al. (2008) reported 5 families with HMN2B. All patients had a
remarkably similar slowly progressive disease course with a mean age at
onset ranging from 21 to 54 years. Muscle weakness and atrophy started
and predominated in the distal lower limb muscles. Muscle weakness and
wasting progressed to the upper limbs approximately 5 to 10 years later
along with proximal lower limb problems. Sensory disturbances were
absent in all patients except 1 proband with a long history of diabetes
mellitus. Tendon reflexes were depressed or absent in all cases. One of
the families was consanguineous, consistent with autosomal recessive
inheritance.

MOLECULAR GENETICS

In affected members of 4 different families with dHMN, Evgrafov et al.
(2004) identified 4 different mutations in the HSPB1 gene
(602195.0001-602195.0004).

Houlden et al. (2008) identified 4 different heterozygous mutations in
the HSPB1 gene (see, e.g., 602195.0001; 602195.0007) in affected members
of 4 of 25 families with HMN2B. Two of 30 patients with sporadic dHMN
also had mutations. An additional patient with autosomal recessive
inheritance was found to have a homozygous mutation (602195.0008). All
patients had a predominant motor neuropathy without clinical sensory
abnormalities. No HSPB1 mutations were found in 90 families with CMT2.

ANIMAL MODEL

D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing
the P182L (602195.0004) Hspb1 mutation developed clinical and pathologic
features of distal HMN. Mutant mice developed progressive motor
impairment, decreased muscle strength, and clawed hindpaws, but no
sensory abnormalities. There was distal axonal loss on nerve biopsy, as
well as a decrease in acetylated alpha-tubulin (TUBA1A; 602529) in
peripheral nerves.

*FIELD* RF
1. d'Ydewalle, C.; Krishnan, J.; Chiheb, D. M.; Van Damme, P.; Irobi,
J.; Kozikowski, A. P.; Vanden Berghe, P.; Timmerman, V.; Robberecht,
W.; Van Den Bosch, L.: HDAC6 inhibitors reverse axonal loss in a
mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nature
Med. 17: 968-974, 2011.

2. Evgrafov, O. V.; Mersiyanova, I.; Irobi, J.; Van Den Bosch, L.;
Dierick, I.; Leung, C. L.; Schagina, O.; Verpoorten, N.; Van Impe,
K.; Fedotov, V.; Dadali, E.; Auer-Grumbach, M.; and 14 others:
Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth
disease and distal hereditary motor neuropathy. Nature Genet. 36:
602-606, 2004.

3. Houlden, H.; Laura, M.; Wavrant-De Vrieze, F.; Blake, J.; Wood,
N.; Reilly, M. M.: Mutations in the HSP27 (HSPB1) gene cause dominant,
recessive, and sporadic distal HMN/CMT type 2. Neurology 71: 1660-1668,
2008.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Peripheral nervous system];
Paresis of extensor muscles of the big toe is often the presenting
symptom;
Muscle weakness, distal (lower limbs more affected than upper limbs),
due to motor neuronopathy;
Paralysis and atrophy of distal lower limb muscles over time;
Difficulty walking;
EMG shows neurogenic abnormalities;
Neurophysiologic studies show a predominantly motor neuropathy;
Hyporeflexia of lower limbs;
Areflexia of lower limbs;
No sensory deficit

MISCELLANEOUS:
Onset usually in adulthood although childhood onset has been reported;
Slowly progressive;
Autosomal recessive inheritance has been reported in 1 family;
Allelic disorder to Charcot-Marie-Tooth disease 2F (CMT2F, 606595);
See also distal HMN2A (158590)

MOLECULAR BASIS:
Caused by mutation in the heat-shock 27-kD protein 1 gene (HSPB1,
602195.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 4/6/2009

*FIELD* CD
Cassandra L. Kniffin: 3/14/2007

*FIELD* ED
joanna: 01/05/2010
ckniffin: 4/6/2009
joanna: 5/23/2007
ckniffin: 3/16/2007

*FIELD* CN
Cassandra L. Kniffin - updated: 12/15/2011
Cassandra L. Kniffin - updated: 4/6/2009

*FIELD* CD
Cassandra L. Kniffin: 5/3/2004

*FIELD* ED
carol: 12/20/2013
carol: 12/16/2011
ckniffin: 12/15/2011
wwang: 4/29/2010
ckniffin: 4/23/2010
wwang: 4/15/2009
ckniffin: 4/6/2009
joanna: 2/2/2009
carol: 3/16/2007
ckniffin: 3/16/2007
ckniffin: 4/4/2005
alopez: 5/28/2004
tkritzer: 5/4/2004
ckniffin: 5/3/2004