RBCC Red Blood Cell Collection

TPM1 (C15orf13, TMSA) [Confidence: high (present in two of the MS resources)]
Tropomyosin alpha-1 chain (Alpha-tropomyosin; Tropomyosin-1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00014581
IPI00014581 Splice isoform 1 of P09493 Tropomyosin 1 alpha chain Splice isoform 1 of P09493 Tropomyosin 1 alpha chain membrane n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 4 3 cytoskeleton AISEELDHALNDMTSI, SLEAQAEK found at its expected molecular weight found at molecular weight

UniProt P09493
ID TPM1_HUMAN Reviewed; 284 AA.
AC P09493; B7Z5T7; D9YZV2; D9YZV3; D9YZV8; P09494; P10469; Q6DV89;
read moreAC Q6DV90; Q7Z6L8; Q86W64; Q96IK2; Q9UCI1; Q9UCI2; Q9UCY9; Q9Y427;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1990, sequence version 2.
DT 22-JAN-2014, entry version 153.
DE RecName: Full=Tropomyosin alpha-1 chain;
DE AltName: Full=Alpha-tropomyosin;
DE AltName: Full=Tropomyosin-1;
GN Name=TPM1; Synonyms=C15orf13, TMSA;
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 PROTEIN SEQUENCE (ISOFORM 1).
RX PubMed=3548719; DOI=10.1016/0006-291X(87)91486-0;
RA Mische S.M., Manjula B.N., Fischetti V.A.;
RT "Relation of streptococcal M protein with human and rabbit
RT tropomyosin: the complete amino acid sequence of human cardiac alpha
RT tropomyosin, a highly conserved contractile protein.";
RL Biochem. Biophys. Res. Commun. 142:813-818(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3).
RC TISSUE=Fibroblast;
RX PubMed=3336357;
RA Lin C.-S., Leavitt J.;
RT "Cloning and characterization of a cDNA encoding transformation-
RT sensitive tropomyosin isoform 3 from tumorigenic human fibroblasts.";
RL Mol. Cell. Biol. 8:160-168(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 3).
RX PubMed=3336363;
RA McLeod A.R., Gooding C.;
RT "Human hTM alpha gene: expression in muscle and nonmuscle tissue.";
RL Mol. Cell. Biol. 8:433-440(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 6), AND TISSUE SPECIFICITY.
RC TISSUE=Heart;
RX PubMed=15249230; DOI=10.1016/j.bbrc.2004.06.084;
RA Denz C.R., Narshi A., Zajdel R.W., Dube D.K.;
RT "Expression of a novel cardiac-specific tropomyosin isoform in
RT humans.";
RL Biochem. Biophys. Res. Commun. 320:1291-1297(2004).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Tongue;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC TISSUE=Uterus;
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 [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NHLBI resequencing and genotyping service (RS&G;);
RL Submitted (DEC-2009) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16572171; DOI=10.1038/nature04601;
RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K.,
RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K.,
RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N.,
RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S.,
RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K.,
RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R.,
RA Fahey J., Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G.,
RA Johnson E., Jones C., Kamat A., Kaur A., Locke D.P., Madan A.,
RA Munson G., Jaffe D.B., Lui A., Macdonald P., Mauceli E., Naylor J.W.,
RA Nesbitt R., Nicol R., O'Leary S.B., Ratcliffe A., Rounsley S., She X.,
RA Sneddon K.M.B., Stewart S., Sougnez C., Stone S.M., Topham K.,
RA Vincent D., Wang S., Zimmer A.R., Birren B.W., Hood L., Lander E.S.,
RA Nusbaum C.;
RT "Analysis of the DNA sequence and duplication history of human
RT chromosome 15.";
RL Nature 440:671-675(2006).
RN [9]
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 [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 4 AND 5).
RC TISSUE=Brain, Hippocampus, and Placenta;
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 [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 58-284 (ISOFORM 2).
RC TISSUE=Liver;
RX PubMed=3138425; DOI=10.1007/BF02100079;
RA Colote S., Widada J.S., Ferraz C., Bonhomme F., Marti J.,
RA Liautard J.-P.;
RT "Evolution of tropomyosin functional domains: differential splicing
RT and genomic constraints.";
RL J. Mol. Evol. 27:228-235(1988).
RN [12]
RP PROTEIN SEQUENCE OF 134-149 AND 153-167.
RC TISSUE=Colon;
RX PubMed=8450225;
RA Das K.M., Dasgupta A., Mandal A., Geng X.;
RT "Autoimmunity to cytoskeletal protein tropomyosin. A clue to the
RT pathogenetic mechanism for ulcerative colitis.";
RL J. Immunol. 150:2487-2493(1993).
RN [13]
RP MASS SPECTROMETRY.
RC TISSUE=Mammary cancer;
RX PubMed=11840567;
RX DOI=10.1002/1615-9861(200202)2:2<212::AID-PROT212>3.0.CO;2-H;
RA Harris R.A., Yang A., Stein R.C., Lucy K., Brusten L., Herath A.,
RA Parekh R., Waterfield M.D., O'Hare M.J., Neville M.A., Page M.J.,
RA Zvelebil M.J.;
RT "Cluster analysis of an extensive human breast cancer cell line
RT protein expression map database.";
RL Proteomics 2:212-223(2002).
RN [14]
RP PHOSPHORYLATION AT SER-283, AND MUTAGENESIS OF SER-283.
RX PubMed=17895359; DOI=10.1242/jcs.003251;
RA Houle F., Poirier A., Dumaresq J., Huot J.;
RT "DAP kinase mediates the phosphorylation of tropomyosin-1 downstream
RT of the ERK pathway, which regulates the formation of stress fibers in
RT response to oxidative stress.";
RL J. Cell Sci. 120:3666-3677(2007).
RN [15]
RP TISSUE SPECIFICITY, AND MASS SPECTROMETRY.
RA Ahamed M.E.;
RL Submitted (APR-2007) to UniProtKB.
RN [16]
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 [17]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-213 (ISOFORMS 10; 3; 4 AND
RP 8), 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 [18]
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 [19]
RP VARIANTS CMH3 ASN-175 AND GLY-180.
RX PubMed=8205619; DOI=10.1016/0092-8674(94)90054-X;
RA Thierfelder L., Watkins H., Macrae C., Lamas R., McKenna W.J.,
RA Vosberg H.-P., Seidman J.G., Seidman C.E.;
RT "Alpha-tropomyosin and cardiac troponin T mutations cause familial
RT hypertrophic cardiomyopathy: a disease of the sarcomere.";
RL Cell 77:701-712(1994).
RN [20]
RP VARIANTS CMH3 VAL-63 AND ASN-175.
RX PubMed=8523464; DOI=10.1016/0022-2828(95)90026-8;
RA Nakajima-Taniguchi C., Matsui H., Nagata S., Kishimoto T.,
RA Yamauchi-Takihara K.;
RT "Novel missense mutation in alpha-tropomyosin gene found in Japanese
RT patients with hypertrophic cardiomyopathy.";
RL J. Mol. Cell. Cardiol. 27:2053-2058(1995).
RN [21]
RP VARIANT CMH3 ASN-175.
RX PubMed=7898523; DOI=10.1056/NEJM199504203321603;
RA Watkins H., McKenna W.J., Thierfelder L., Suk H.J., Anan R.,
RA O'Donoghue A., Spirito P., Matsumori A., Moravec C.S., Seidman J.G.,
RA Seidman C.E.;
RT "Mutations in the genes for cardiac troponin T and alpha-tropomyosin
RT in hypertrophic cardiomyopathy.";
RL N. Engl. J. Med. 332:1058-1064(1995).
RN [22]
RP VARIANT CMH3 ASN-175.
RX PubMed=9822100; DOI=10.1016/S0735-1097(98)00448-3;
RA Jaeaeskelaeinen P., Soranta M., Miettinen R., Saarinen L.,
RA Pihlajamaeki J., Silvennoinen K., Tikanoja T., Laakso M., Kuusisto J.;
RT "The cardiac beta-myosin heavy chain gene is not the predominant gene
RT for hypertrophic cardiomyopathy in the Finnish population.";
RL J. Am. Coll. Cardiol. 32:1709-1716(1998).
RN [23]
RP VARIANTS CMD1Y LYS-40 AND LYS-54.
RX PubMed=11273725; DOI=10.1006/jmcc.2000.1339;
RA Olson T.M., Kishimoto N.Y., Whitby F.G., Michels V.V.;
RT "Mutations that alter the surface charge of alpha-tropomyosin are
RT associated with dilated cardiomyopathy.";
RL J. Mol. Cell. Cardiol. 33:723-732(2001).
RN [24]
RP VARIANT CMH3 VAL-180.
RX PubMed=12974739; DOI=10.1034/j.1399-0004.2003.00151.x;
RA Erdmann J., Daehmlow S., Wischke S., Senyuva M., Werner U., Raible J.,
RA Tanis N., Dyachenko S., Hummel M., Hetzer R., Regitz-Zagrosek V.;
RT "Mutation spectrum in a large cohort of unrelated consecutive patients
RT with hypertrophic cardiomyopathy.";
RL Clin. Genet. 64:339-349(2003).
RN [25]
RP VARIANTS LVNC9 LYS-192 AND GLU-248.
RX PubMed=21551322; DOI=10.1161/CIRCGENETICS.110.959270;
RA Probst S., Oechslin E., Schuler P., Greutmann M., Boye P., Knirsch W.,
RA Berger F., Thierfelder L., Jenni R., Klaassen S.;
RT "Sarcomere gene mutations in isolated left ventricular noncompaction
RT cardiomyopathy do not predict clinical phenotype.";
RL Circ. Cardiovasc. Genet. 4:367-374(2011).
CC -!- FUNCTION: Binds to actin filaments in muscle and non-muscle cells.
CC Plays a central role, in association with the troponin complex, in
CC the calcium dependent regulation of vertebrate striated muscle
CC contraction. Smooth muscle contraction is regulated by interaction
CC with caldesmon. In non-muscle cells is implicated in stabilizing
CC cytoskeleton actin filaments.
CC -!- SUBUNIT: Heterodimer of an alpha and a beta chain (By similarity).
CC Interacts with HRG (via the HRR domain); the interaction
CC contributes to the antiangiogenic properties of the
CC histidine/proline-rich region (HRR) of HRG (By similarity).
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=10;
CC Comment=Additional isoforms seem to exist;
CC Name=1; Synonyms=Skeletal muscle, TPM1alpha;
CC IsoId=P09493-1; Sequence=Displayed;
CC Name=2; Synonyms=Smooth muscle;
CC IsoId=P09493-2; Sequence=VSP_006576, VSP_006578, VSP_006579;
CC Note=Incomplete sequence;
CC Name=3; Synonyms=Fibroblast, TM3;
CC IsoId=P09493-3; Sequence=VSP_006577, VSP_006579;
CC Note=Contains a N6-acetyllysine at position 213;
CC Name=4;
CC IsoId=P09493-4; Sequence=VSP_006577;
CC Note=Contains a N6-acetyllysine at position 213;
CC Name=5;
CC IsoId=P09493-5; Sequence=VSP_017498, VSP_017499;
CC Name=6; Synonyms=10, TPM1kappa;
CC IsoId=P09493-6; Sequence=VSP_036064;
CC Name=7;
CC IsoId=P09493-7; Sequence=VSP_036064, VSP_006579;
CC Note=No experimental confirmation available;
CC Name=8;
CC IsoId=P09493-8; Sequence=VSP_047297, VSP_047298, VSP_047299,
CC VSP_047300, VSP_006579;
CC Note=Gene prediction based on EST data. Contains a
CC N6-acetyllysine at position 213;
CC Name=9;
CC IsoId=P09493-9; Sequence=VSP_006579;
CC Note=Gene prediction based on EST data;
CC Name=10;
CC IsoId=P09493-10; Sequence=VSP_047299, VSP_047300, VSP_047301;
CC Note=No experimental confirmation available. Contains a
CC N6-acetyllysine at position 213;
CC -!- TISSUE SPECIFICITY: Detected in primary breast cancer tissues but
CC undetectable in normal breast tissues in Sudanese patients.
CC Isoform 1 is expressed in adult and fetal skeletal muscle and
CC cardiac tissues, with higher expression levels in the cardiac
CC tissues. Isoform 10 is expressed in adult and fetal cardiac
CC tissues, but not in skeletal muscle.
CC -!- DOMAIN: The molecule is in a coiled coil structure that is formed
CC by 2 polypeptide chains. The sequence exhibits a prominent seven-
CC residues periodicity.
CC -!- PTM: Phosphorylated at Ser-283 by DAPK1 in response to oxidative
CC stress and this phosphorylation enhances stress fiber formation in
CC endothelial cells.
CC -!- MASS SPECTROMETRY: Mass=32875.93; Method=MALDI; Range=1-284
CC (P09493-3); Source=PubMed:11840567;
CC -!- DISEASE: Cardiomyopathy, familial hypertrophic 3 (CMH3)
CC [MIM:115196]: A hereditary heart disorder characterized by
CC ventricular hypertrophy, which is usually asymmetric and often
CC involves the interventricular septum. The symptoms include
CC dyspnea, syncope, collapse, palpitations, and chest pain. They can
CC be readily provoked by exercise. The disorder has inter- and
CC intrafamilial variability ranging from benign to malignant forms
CC with high risk of cardiac failure and sudden cardiac death.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1Y (CMD1Y) [MIM:611878]: A
CC disorder characterized by ventricular dilation and impaired
CC systolic function, resulting in congestive heart failure and
CC arrhythmia. Patients are at risk of premature death. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Left ventricular non-compaction 9 (LVNC9) [MIM:611878]: A
CC disease due to an arrest of myocardial morphogenesis. It is
CC characterized by a hypertrophic left ventricle with deep
CC trabeculations and with poor systolic function, with or without
CC associated left ventricular dilation. In some cases, it is
CC associated with other congenital heart anomalies. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the tropomyosin family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TPM1";
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DR EMBL; M19267; AAA36771.1; -; mRNA.
DR EMBL; M19713; AAA61225.1; -; mRNA.
DR EMBL; M19714; AAA61226.1; -; mRNA.
DR EMBL; M19715; AAA61227.1; -; mRNA.
DR EMBL; AY640414; AAT68294.1; -; mRNA.
DR EMBL; AY640415; AAT68295.1; -; mRNA.
DR EMBL; AK299387; BAH13023.1; -; mRNA.
DR EMBL; AL050179; CAB43309.2; -; mRNA.
DR EMBL; GU324929; ADL14500.1; -; Genomic_DNA.
DR EMBL; GU324930; ADL14501.1; -; Genomic_DNA.
DR EMBL; GU324933; ADL14504.1; -; Genomic_DNA.
DR EMBL; GU324935; ADL14506.1; -; Genomic_DNA.
DR EMBL; AC079328; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471082; EAW77619.1; -; Genomic_DNA.
DR EMBL; CH471082; EAW77622.1; -; Genomic_DNA.
DR EMBL; CH471082; EAW77623.1; -; Genomic_DNA.
DR EMBL; CH471082; EAW77627.1; -; Genomic_DNA.
DR EMBL; CH471082; EAW77628.1; -; Genomic_DNA.
DR EMBL; BC007433; AAH07433.1; -; mRNA.
DR EMBL; BC050473; AAH50473.1; -; mRNA.
DR EMBL; BC053545; AAH53545.1; -; mRNA.
DR EMBL; X12369; CAA30930.1; -; mRNA.
DR PIR; A27674; A27674.
DR PIR; A27678; A25825.
DR PIR; S05585; S05585.
DR RefSeq; NP_000357.3; NM_000366.5.
DR RefSeq; NP_001018004.1; NM_001018004.1.
DR RefSeq; NP_001018005.1; NM_001018005.1.
DR RefSeq; NP_001018006.1; NM_001018006.1.
DR RefSeq; NP_001018007.1; NM_001018007.1.
DR RefSeq; NP_001018008.1; NM_001018008.1.
DR RefSeq; NP_001018020.1; NM_001018020.1.
DR RefSeq; XP_005254700.1; XM_005254643.1.
DR UniGene; Hs.133892; -.
DR UniGene; Hs.602995; -.
DR ProteinModelPortal; P09493; -.
DR SMR; P09493; 1-284.
DR IntAct; P09493; 14.
DR MINT; MINT-1458755; -.
DR PhosphoSite; P09493; -.
DR DMDM; 136092; -.
DR UCD-2DPAGE; P09493; -.
DR PaxDb; P09493; -.
DR PRIDE; P09493; -.
DR DNASU; 7168; -.
DR Ensembl; ENST00000267996; ENSP00000267996; ENSG00000140416.
DR Ensembl; ENST00000288398; ENSP00000288398; ENSG00000140416.
DR Ensembl; ENST00000334895; ENSP00000334624; ENSG00000140416.
DR Ensembl; ENST00000358278; ENSP00000351022; ENSG00000140416.
DR Ensembl; ENST00000403994; ENSP00000385107; ENSG00000140416.
DR Ensembl; ENST00000559397; ENSP00000452879; ENSG00000140416.
DR Ensembl; ENST00000559556; ENSP00000453941; ENSG00000140416.
DR GeneID; 7168; -.
DR KEGG; hsa:7168; -.
DR UCSC; uc002alh.3; human.
DR CTD; 7168; -.
DR GeneCards; GC15P063334; -.
DR HGNC; HGNC:12010; TPM1.
DR HPA; CAB017698; -.
DR HPA; HPA000261; -.
DR MIM; 115196; phenotype.
DR MIM; 191010; gene.
DR MIM; 611878; phenotype.
DR neXtProt; NX_P09493; -.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 155; Familial isolated hypertrophic cardiomyopathy.
DR Orphanet; 54260; Left ventricular noncompaction.
DR PharmGKB; PA36690; -.
DR eggNOG; NOG304012; -.
DR HOGENOM; HOG000231521; -.
DR HOVERGEN; HBG107404; -.
DR KO; K10373; -.
DR OrthoDB; EOG7673C8; -.
DR Reactome; REACT_17044; Muscle contraction.
DR ChiTaRS; TPM1; human.
DR GeneWiki; TPM1; -.
DR GenomeRNAi; 7168; -.
DR NextBio; 28070; -.
DR PRO; PR:P09493; -.
DR ArrayExpress; P09493; -.
DR Bgee; P09493; -.
DR Genevestigator; P09493; -.
DR GO; GO:0032059; C:bleb; IMP:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031941; C:filamentous actin; IEA:Ensembl.
DR GO; GO:0005862; C:muscle thin filament tropomyosin; TAS:ProtInc.
DR GO; GO:0032587; C:ruffle membrane; IDA:BHF-UCL.
DR GO; GO:0001725; C:stress fiber; IDA:BHF-UCL.
DR GO; GO:0003779; F:actin binding; TAS:BHF-UCL.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:BHF-UCL.
DR GO; GO:0008307; F:structural constituent of muscle; TAS:ProtInc.
DR GO; GO:0060048; P:cardiac muscle contraction; IMP:BHF-UCL.
DR GO; GO:0034614; P:cellular response to reactive oxygen species; IEP:BHF-UCL.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0030049; P:muscle filament sliding; ISS:BHF-UCL.
DR GO; GO:0030336; P:negative regulation of cell migration; ISS:BHF-UCL.
DR GO; GO:0032781; P:positive regulation of ATPase activity; ISS:BHF-UCL.
DR GO; GO:0045785; P:positive regulation of cell adhesion; ISS:BHF-UCL.
DR GO; GO:0003065; P:positive regulation of heart rate by epinephrine; ISS:BHF-UCL.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; ISS:BHF-UCL.
DR GO; GO:0006937; P:regulation of muscle contraction; TAS:ProtInc.
DR GO; GO:0031529; P:ruffle organization; ISS:BHF-UCL.
DR GO; GO:0045214; P:sarcomere organization; IMP:BHF-UCL.
DR GO; GO:0055010; P:ventricular cardiac muscle tissue morphogenesis; IMP:BHF-UCL.
DR GO; GO:0042060; P:wound healing; ISS:BHF-UCL.
DR InterPro; IPR000533; Tropomyosin.
DR Pfam; PF00261; Tropomyosin; 1.
DR PRINTS; PR00194; TROPOMYOSIN.
DR PROSITE; PS00326; TROPOMYOSIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Actin-binding; Alternative splicing; Cardiomyopathy;
KW Coiled coil; Complete proteome; Cytoplasm; Cytoskeleton;
KW Direct protein sequencing; Disease mutation; Isopeptide bond;
KW Muscle protein; Phosphoprotein; Reference proteome; Ubl conjugation.
FT CHAIN 1 284 Tropomyosin alpha-1 chain.
FT /FTId=PRO_0000205620.
FT COILED 1 284 By similarity.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 283 283 Phosphoserine; by DAPK1.
FT CROSSLNK 77 77 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin) (By
FT similarity).
FT VAR_SEQ 1 80 MDAIKKKMQMLKLDKENALDRAEQAEADKKAAEDRSKQLED
FT ELVSLQKKLKGTEDELDKYSEALKDAQEKLELAEKKATD
FT -> MCRLRIFLRTASSEHLHERKLRET (in isoform
FT 2).
FT /FTId=VSP_006576.
FT VAR_SEQ 1 80 MDAIKKKMQMLKLDKENALDRAEQAEADKKAAEDRSKQLED
FT ELVSLQKKLKGTEDELDKYSEALKDAQEKLELAEKKATD
FT -> MAGSSSLEAVRRKIRSLQEQADAAEERAGTLQRELDHE
FT RKLRET (in isoform 5).
FT /FTId=VSP_017498.
FT VAR_SEQ 41 80 DELVSLQKKLKGTEDELDKYSEALKDAQEKLELAEKKATD
FT -> EDIAAKEKLLRVSEDERDRVLEELHKAEDSLLAAEEAA
FT AK (in isoform 6 and isoform 7).
FT /FTId=VSP_036064.
FT VAR_SEQ 41 53 DELVSLQKKLKGT -> EDIAAKEKLLRVS (in
FT isoform 8).
FT /FTId=VSP_047297.
FT VAR_SEQ 57 80 LDKYSEALKDAQEKLELAEKKATD -> RDRVLEELHKAED
FT SLLAAEEAAAK (in isoform 8).
FT /FTId=VSP_047298.
FT VAR_SEQ 189 212 KCAELEEELKTVTNNLKSLEAQAE -> QVRQLEEQLRIMD
FT SDLESINAAED (in isoform 2).
FT /FTId=VSP_006578.
FT VAR_SEQ 189 212 KCAELEEELKTVTNNLKSLEAQAE -> QVRQLEEQLRIMD
FT QTLKALMAAED (in isoform 3 and isoform 4).
FT /FTId=VSP_006577.
FT VAR_SEQ 189 192 KCAE -> QVRQ (in isoform 8 and isoform
FT 10).
FT /FTId=VSP_047299.
FT VAR_SEQ 196 212 ELKTVTNNLKSLEAQAE -> QLRIMDQTLKALMAAED
FT (in isoform 8 and isoform 10).
FT /FTId=VSP_047300.
FT VAR_SEQ 258 284 DELYAQKLKYKAISEELDHALNDMTSI -> EKVAHAKEEN
FT LSMHQMLDQTLLELNNM (in isoform 2, isoform
FT 3, isoform 7, isoform 8 and isoform 9).
FT /FTId=VSP_006579.
FT VAR_SEQ 259 284 ELYAQKLKYKAISEELDHALNDMTSI -> QLYQQLEQNRR
FT LTNELKLALNED (in isoform 5).
FT /FTId=VSP_017499.
FT VAR_SEQ 284 284 I -> M (in isoform 10).
FT /FTId=VSP_047301.
FT VARIANT 40 40 E -> K (in CMD1Y).
FT /FTId=VAR_043986.
FT VARIANT 54 54 E -> K (in CMD1Y).
FT /FTId=VAR_043987.
FT VARIANT 63 63 A -> V (in CMH3).
FT /FTId=VAR_013135.
FT VARIANT 175 175 D -> N (in CMH3; dbSNP:rs28934270).
FT /FTId=VAR_007601.
FT VARIANT 180 180 E -> G (in CMH3; dbSNP:rs28934269).
FT /FTId=VAR_007602.
FT VARIANT 180 180 E -> V (in CMH3).
FT /FTId=VAR_029452.
FT VARIANT 192 192 E -> K (in LVNC9).
FT /FTId=VAR_070121.
FT VARIANT 248 248 K -> E (in LVNC9).
FT /FTId=VAR_070122.
FT MUTAGEN 283 283 S->A: Loss of phosphorylation and
FT decreased formation of actin stress
FT fibers.
FT MUTAGEN 283 283 S->E: Increased formation of actin stress
FT fibers.
FT CONFLICT 109 109 A -> V (in Ref. 11; CAA30930).
FT CONFLICT 203 203 N -> D (in Ref. 4; AAT68294/AAT68295).
SQ SEQUENCE 284 AA; 32709 MW; F57139E2B0972F4D CRC64;
MDAIKKKMQM LKLDKENALD RAEQAEADKK AAEDRSKQLE DELVSLQKKL KGTEDELDKY
SEALKDAQEK LELAEKKATD AEADVASLNR RIQLVEEELD RAQERLATAL QKLEEAEKAA
DESERGMKVI ESRAQKDEEK MEIQEIQLKE AKHIAEDADR KYEEVARKLV IIESDLERAE
ERAELSEGKC AELEEELKTV TNNLKSLEAQ AEKYSQKEDR YEEEIKVLSD KLKEAETRAE
FAERSVTKLE KSIDDLEDEL YAQKLKYKAI SEELDHALND MTSI
//

MIM 115196
*RECORD*
*FIELD* NO
115196
*FIELD* TI
#115196 CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3; CMH3
*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
read moreform of familial hypertrophic cardiomyopathy linked to 15q2 is caused by
mutation in the alpha-tropomyosin gene (TPM1; 191010).

For a general phenotypic description and a discussion of genetic
heterogeneity of hypertrophic cardiomyopathy, see CMH1 (192600).

MAPPING

By linkage analysis, Thierfelder et al. (1993) identified a form of
familial hypertrophic cardiomyopathy that maps to 15q2. This was
designated CMH3, CMH1 (192600) being the locus on chromosome 14 and CMH2
(115195) being the locus on chromosome 1. At least one more form of
familial CMH is thought to exist because there are families that do not
show linkage to any of these 3 locations. Although the gene for cardiac
actin (ACTC; 102540) maps to 15q, it was excluded as a candidate gene on
the basis of recombination with the CMH3 clinical phenotype (Thierfelder
et al., 1993).

Schleef et al. (1993) mapped the murine alpha-tropomyosin (TPM1; 191010)
gene to a region that is syntenic to human chromosome 15. Because
alpha-tropomyosin is an important component of muscle thin filaments, it
became a candidate gene for CMH3.

MOLECULAR GENETICS

In affected members of 2 families with hypertrophic cardiomyopathy
mapping to the CMH3 locus on chromosome 15q2, Thierfelder et al. (1994)
screened the candidate gene TPM1 and identified heterozygosity for 2
missense mutations, E180G (191010.0001) and D175N (191010.0002),
respectively.

Watkins et al. (1995) concluded that mutations in the TPM1 gene are a
rare cause of CMH, accounting for approximately 3% of cases. These
mutations, like those in the cardiac troponin T gene (TNNT2; 191045)
that cause CMH2 (115195), are characterized by relatively mild and
sometimes subclinical hypertrophy but a high incidence of sudden death.
Genetic testing may therefore be especially important in this group.

In a large Spanish American family with multiple members affected with
hypertrophic cardiomyopathy, Karibe et al. (2001) identified a
heterozygous missense mutation in the TPM1 gene (V95A; 191010.0003) that
segregated with disease. The authors noted that this mutation was
associated with the same mild degree of left ventricular hypertrophy as
seen in some CMH1 families harboring specific mutations in MYH7
(160760.0010, 160760.0012, 160760.0001). Penetrance was estimated at 53%
on the basis of an abnormal echocardiogram; however, 2 mutation carriers
with normal echocardiograms and normal ECGs were only in their
mid-thirties at the time of the study. Penetrance could not be
accurately assessed by ECG, since 6 older mutation-negative family
members had minor T-wave changes. Cumulative survival rates in this
family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years.

In a 36-year-old woman of Italian extraction with cardiomyopathy, in
whom a transthoracic echocardiogram was consistent with a restrictive
phenotype (RCM), Caleshu et al. (2011) sequenced the exons and
exon-intron boundaries of 8 known cardiomyopathy-associated genes and
identified homozygosity for a missense mutation (N279H) in the TPM1
gene. The patient's cardiac catheterization pattern was consistent with
a restrictive phenotype, although the dip-plateau ('square-root sign')
was absent. Her first-cousin parents were each heterozygous for the
mutation. Her affected 75-year-old father had been diagnosed with
hypertrophic cardiomyopathy at 42 years of age, and had a history of
heart failure but was currently asymptomatic. His most recent
echocardiogram showed moderate asymmetric hypertrophy, mild pulmonary
hypertension, mild left ventricular systolic dysfunction, and moderate
biatrial enlargement, suggesting a chronic restrictive physiology. The
asymptomatic 67-year-old mother underwent echocardiography after her
daughter's diagnosis that revealed septal and posterior wall thicknesses
that were at the upper limit of normal, with mild biatrial enlargement
with normal systolic function and no significant evidence of restrictive
physiology.

ANIMAL MODEL

Muthuchamy et al. (1999) generated a transgenic mouse model of CMH3.
They employed site-directed mutagenesis to convert the wildtype murine
GAC sequence at codon 175 to AAC, thus introducing the missense mutation
asp175 to asn (191010.0002). S1 nuclease mapping and Western blot
analysis demonstrated an increase in mutant alpha-tropomyosin mRNA and
protein and a concomitant decrease in endogenous mRNA and protein. In
vivo studies demonstrated a significant impairment of left ventricular
systolic function, and in vitro analysis of papillary muscle fibers
showed a decrease in contractile function. Histologic examination of
transgenic cardiac tissue showed patchy ventricular myocyte disarray and
hypertrophy. This mild and patchy phenotype was in agreement with the
clinical features of patients with the asp175-to-asn mutation (Coviello
et al., 1997).

*FIELD* RF
1. Caleshu, C.; Sakhuja, R.; Nussbaum, R. L.; Schiller, N. B.; Ursell,
P. C.; Eng, C.; De Marco, T.; McGlothlin, D.; Burchard, E. G.; Rame,
J. E.: Furthering the link between the sarcomere and primary cardiomyopathies:
restrictive cardiomyopathy associated with multiple mutations in genes
previously associated with hypertrophic or dilated cardiomyopathy. Am.
J. Med. Genet. 155A: 2229-2235, 2011.

2. Coviello, D. A.; Maron, B. J.; Spirito, P.; Watkins, H.; Vosberg,
H.-P.; Thierfelder, L.; Schoen, F. J.; Seidman, J. G.; Seidman, C.
E.: Clinical features of hypertrophic cardiomyopathy caused by mutation
of a 'hot spot' in the alpha-tropomyosin gene. J. Am. Coll. Cardiol. 29:
635-640, 1997.

3. Karibe, A.; Tobacman, L. S.; Strand, J.; Butters, C.; Back, N.;
Bachinski, L. L.; Arai, A. E.; Ortiz, A.; Roberts, R.; Homsher, E.;
Fananapazir, L.: Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosi
n mutation (V95A) is associated with mild cardiac phenotype, abnormal
calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation 103:
65-71, 2001.

4. Muthuchamy, M.; Pieples, K.; Rethinasamy, P.; Hoit, B.; Grupp,
I. L.; Boivin, G. P.; Wolska, B.; Evans, C.; Solaro, R. J.; Wieczorek,
D. F.: Mouse model of a familial hypertrophic cardiomyopathy mutation
in alpha-tropomyosin manifests cardiac dysfunction. Circ. Res. 85:
47-56, 1999.

5. Schleef, M.; Werner, K.; Satzger, U.; Kaupmann, K.; Jokusch, H.
: Chromosomal location and genomic cloning of the mouse alpha-tropomyosin
gene Tpm-1. Genomics 17: 519-521, 1993.

6. Thierfelder, L.; MacRae, C.; Watkins, H.; Tomfohrde, J.; Williams,
M.; McKenna, W.; Bohm, K.; Noeske, G.; Schlepper, M.; Bowcock, A.;
Vosberg, H.-P.; Seidman, J. G.; Seidman, C.: A familial hypertrophic
cardiomyopathy locus maps to chromosome 15q2. Proc. Nat. Acad. Sci. 90:
6270-6274, 1993.

7. Thierfelder, L.; Watkins, H.; MacRae, C.; Lamas, R.; McKenna, W.;
Vosberg, H.-P.; Seidman, J. G.; Seidman, C. E.: Alpha-tropomyosin
and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy:
a disease of the sarcomere. Cell 77: 701-712, 1994.

8. Watkins, H.; McKenna, W. J.; Thierfelder, L.; Suk, H. J.; Anan,
R.; O'Donoghue, A.; Spirito, P.; Matsumori, A.; Moravec, C. S.; Seidman,
J. G.; Seidman, C. E.: Mutations in the genes for cardiac troponin
T and alpha-tropomyosin in hypertrophic cardiomyopathy. New Eng.
J. Med. 332: 1058-1064, 1995.

*FIELD* CS

Cardiac:
Hypertrophic cardiomyopathy

Inheritance:
Autosomal dominant (15);
other forms at loci on chromosomes 1, 11, 14, and at least one other
locus

*FIELD* CN
Marla J. F. O'Neill - updated: 9/30/2011
Paul Brennan - updated: 4/3/2000

*FIELD* CD
Victor A. McKusick: 3/10/1993

*FIELD* ED
carol: 09/30/2011
terry: 9/30/2011
alopez: 1/18/2011
mcapotos: 8/30/2000
alopez: 4/3/2000
pfoster: 11/10/1995
mimadm: 9/24/1994
jason: 7/29/1994
carol: 7/9/1993
carol: 5/21/1993
carol: 3/10/1993

MIM 191010
*RECORD*
*FIELD* NO
191010
*FIELD* TI
*191010 TROPOMYOSIN 1; TPM1
;;TROPOMYOSIN, SKELETAL MUSCLE ALPHA; TMSA
*FIELD* TX

read moreDESCRIPTION

Tropomyosins are ubiquitous proteins of 35 to 45 kD associated with the
actin filaments of myofibrils and stress fibers. In vertebrates, 4 known
tropomyosin genes code for diverse isoforms that are expressed in a
tissue-specific manner and regulated by an alternative splicing
mechanism (Lees-Miller and Helfman, 1991). The vertebrate
alpha-tropomyosin gene consists of 15 exons; 5 exons are found in all
transcripts, while 10 exons are alternatively used in different
alpha-tropomyosin RNAs (Lees-Miller and Helfman, 1991). The striated
muscle isoform is expressed in both cardiac and skeletal muscle tissues.

CLONING

MacLeod and Gooding (1988) isolated a cDNA clone from a human skeletal
muscle library which contains the complete protein-coding sequence of a
skeletal muscle alpha-tropomyosin. In cultured human fibroblasts, the
TMSA gene was found to encode both skeletal muscle and smooth muscle
type of alpha-tropomyosins by using an alternative mRNA-splicing
mechanism.

MAPPING

Eyre et al. (1995) developed a sequence tagged site (STS) for the TPM1
gene and used it to isolate a genomic clone containing part of the gene.
Using this clone, they localized TPM1 to 15q22 by fluorescence in situ
hybridization. By PCR of radiation hybrids, Tiso et al. (1997) mapped
the TPM1 gene more precisely to 15q22.1. Schleef et al. (1993) mapped
the mouse homolog, Tpm-1, to the d-se region of chromosome 9, using
interspecies backcrosses.

BIOCHEMICAL FEATURES

- Crystal Structure

Brown et al. (2001) described the crystal structure of the tropomyosin
molecule. Their results revealed the effects of clusters of core
alanines on the axial register, symmetry, and conformational variability
of 2-stranded coiled coils that appear to be important for tropomyosin's
role in the regulation of muscle contraction.

GENE FUNCTION

Using 2-dimensional differentiation in-gel electrophoresis to examine
tumors derived from MCF-7 breast cancer cells that were either treated
or untreated with anti-microRNA-21 (MIRN21; 611020), Zhu et al. (2007)
identified the tumor suppressor TPM1 as an MIRN21 target. They
identified a putative MIRN21-binding site in the 3-prime UTRs of 2 TPM1
splice variants, V1 and V5. Zhu et al. (2007) cloned the 3-prime UTR of
TPM1 into a luciferase reporter construct and found that MIRN21
downregulated reporter activity, whereas anti-MIRN21 upregulated it.
Deletion of the MIRN21-binding site abolished the effect of MIRN21 on
luciferase activity. Western blot and RT-PCR analyses showed that TPM1
mRNA level was unchanged in the presence of MIRN21, but TPM1 protein
level was reduced, implying that MIRN21 blocked TPM1 translation.
Overexpression of TPM1 in MCF-7 cells suppressed anchorage-independent
growth, whereas overexpression of MIRN21 increased tumor growth. Zhu et
al. (2007) concluded that MIRN21 acts as an oncogene by suppressing
TPM1.

MOLECULAR GENETICS

- Hypertrophic Cardiomyopathy 3

To assess linkage between the human TPM1 gene and type 3 familial
hypertrophic cardiomyopathy (CMH3; 115196), which had previously been
mapped to 15q2, Thierfelder et al. (1994) identified a short tandem
repeat polymorphism (STR). A combined maximum 2-point lod score of 6.94
at theta = 0.0 was obtained for linkage of the TPM1 marker to CMH3 in 2
families. A point mutation was identified in each of the 2 families used
in the linkage study: asp175-to-asn (191010.0002) in one, and
glu180-to-gly (191010.0001) in the other. Watkins et al. (1995)
concluded that mutations in the TPM1 gene are a rare cause of CMH,
accounting for approximately 3% of cases. These mutations, like those in
the cardiac troponin T gene (TNNT2; 191045), are characterized by
relatively mild and sometimes subclinical hypertrophy but a high
incidence of sudden death. Genetic testing may therefore be especially
important in this group.

- Dilated Cardiomyopathy 1Y

Using a candidate gene approach, Olson et al. (2001) analyzed the TPM1
gene in 350 unrelated patients with sporadic and familial dilated
cardiomyopathy (see CMD1Y, 611878) and identified heterozygous missense
mutations in 2 familial cases: E54K (191010.0004) and E40K
(191010.0005), respectively. Each substitution was predicted to create a
strong local increase in positive charge in an otherwise relatively
negatively charged and highly conserved region of the molecule.

- Left Ventricular Noncompaction 9

In a cohort of 63 unrelated white patients of western European descent
with left ventricular noncompaction (LVNC9; see 611878), Probst et al.
(2011) analyzed 8 sarcomere genes and identified 2 probands with
heterozygous missense mutations in the TPM1 gene (191010.0006 and
191010.0007).

GENOTYPE/PHENOTYPE CORRELATIONS

Using depletion and reconstitution of TPM1 and troponin in porcine
cardiac myofibrils, Chang et al. (2005) studied 3 CMH-associated TPM1
mutations (E62Q; E180G, 190010.0001; and L185R) and 2 CMD-associated
mutations (E54K and E40K) and found that all CMH-associated mutations
increased the Ca(2+) sensitivity of ATPase activity and had decreased
abilities to inhibit ATPase activity, whereas the CMD-associated
mutations decreased the Ca(2+) sensitivity of ATPase activity and had no
effect on the inhibition of ATPase activity. Chang et al. (2005)
concluded that mutations that cause CMH and CMD disrupt discrete
mechanisms, and suggested that this may explain the manifestation of
distinct cardiomyopathic phenotypes.

Mirza et al. (2005) studied all 8 published mutations causing dilated
cardiomyopathy (CMD), including 5 in the TNNT2 gene (lys210del, R141W,
R131W, R205L, and D270N; 191045.0006-191045.0010, respectively), 2 in
the TPM1 gene (E54K and E40K), and 1 in the TNNC1 gene (G159D,
191040.0001). Thin filaments, reconstituted with a 1:1 ratio of
mutant:wildtype proteins, all showed reduced Ca(2+) sensitivity of
activation in ATPase and motility assays, and, except for the E54K
alpha-tropomyosin mutant which showed no effect, all showed lower
maximum Ca(2+) activation. Incorporation of the TNNT2 mutations R141W
and R205L into skinned guinea pig cardiac trabeculae also decreased
Ca(2+) sensitivity of force generation. Thus, diverse thin filament CMD
mutations appeared to affect different aspects of regulatory function
yet change contractility in a consistent manner. Mirza et al. (2005)
stated that the CMD mutations depressed myofibrillar function, an effect
opposite to that of CMH-causing thin filament mutations, and suggested
that decreased contractility might trigger pathways that ultimately lead
to the clinical phenotype.

Robinson et al. (2007) used a fluorescent probe to assess Ca(2+) binding
of CMH-causing mutations in the TNNT2 (R92Q; 191045.0002) and TNNI3
(R145G; 191044.0001) genes, and CMD-causing mutations in the TNNT2
(e.g., lys210del and R141W), TNNC1 (G159D), and TPM1 (E45K and E40K)
genes. Both CMH mutations increased Ca(2+) affinity, whereas the CMD
mutations decreased affinity, except for 1 in TNNT2, which caused a
significant decrease in cooperativity. Robinson et al. (2007) suggested
that Ca(2+) affinity changes caused by cardiomyopathy mutant proteins
may directly affect the Ca(2+) transient and hence Ca(2+)-sensitive
disease state remodeling pathways in vivo, representing a novel
mechanism for this class of mutation.

ANIMAL MODEL

Blanchard et al. (1997) used gene targeting in embryonic stem cells and
blastocyst-mediated transgenesis to create functional mouse
alpha-tropomyosin knockouts. Homozygous mice died in utero between
embryonic days 9.5 and 13.5 and lacked alpha-tropomyosin mRNA.
Heterozygotes had an approximately 50% reduction in alpha-tropomyosin
mRNA levels but no reduction in alpha-tropomyosin protein. No
differences in myofibrillar ultrastructure or contractile function were
found. The authors postulated that mice have a regulatory mechanism that
maintains the level of myofibrillar tropomyosin despite a reduction in
mRNA. Furthermore, they concluded that, assuming human and mouse cardiac
muscle are similar, simple haploinsufficiency for alpha-tropomyosin
would not cause the pathologic changes seen in human type 3 hypertrophic
cardiomyopathy (115196) and that alterations in protein stoichiometry
may produce a poison polypeptide that disrupts myofibrillar organization
on incorporation into the sarcomere.

Muthuchamy et al. (1999) constructed a transgenic mouse model of CMH3 by
introducing the missense mutation asp175 to asn (191010.0002) by
site-directed mutagenesis. This mutation occurs in a cardiac troponin
T-binding region. The transgenic CMH3 mice exhibited significant in vivo
and in vitro evidence of myocardial functional impairment. Histologic
analysis of transgenic myocardium showed variable myocyte disarray and
hypertrophy, as reported in the human form of the disease.

Rajan et al. (2007) generated transgenic mice expressing E54K Tpm1 in
the adult heart and observed the development of dilated cardiomyopathy
with progression to heart failure and frequently death by 6 months.
Echocardiographic analyses confirmed the dilated cardiac phenotype with
a significant decrease in left ventricular fractional shortening;
work-performing heart analyses showed significantly impaired systolic
and diastolic function, and force measurements revealed that cardiac
myofilaments had significantly decreased Ca(2+) sensitivity and tension
generation. Real-time RT-PCR quantification demonstrated increased
expression of beta-myosin heavy chain (MYH7; 160760), brain natriuretic
peptide (see NPPA, 108780), and skeletal actin (see ACTA1, 102610), and
decreased expression of sarcoplasmic reticulum Ca(2+) ATPase (ATP2A2;
108740) and ryanodine receptor (RYR2; 180902). The thermal denaturation
curve of the mutant protein shifted to the right compared to wildtype,
implying a decrease in flexibility. Rajan et al. (2007) stated that
these findings are consistent with those seen in human CMD and heart
failure.

*FIELD* AV
.0001
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3
TPM1, GLU180GLY

In members of family MZ afflicted with a form of familial hypertrophic
cardiomyopathy linked to 15q (115196), Thierfelder et al. (1994)
identified an A-to-G transition at nucleotide 595 in exon 5 of the TPM1
gene in heterozygous state. The substitution changed codon 180 from GAG
to GGG and predicted that a negatively charged glutamic acid residue is
replaced by a neutral glycine residue.

.0002
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3
TPM1, ASP175ASN

In members of family MI afflicted with a form of familial hypertrophic
cardiomyopathy linked to 15q (115196), Thierfelder et al. (1994) found
heterozygosity for a G-to-A transition at nucleotide 579 that altered
codon 175 from GAC to AAC. The substitution predicted that the mutated
allele present in affected individuals would encode a neutral asparagine
residue instead of the negatively charged aspartic acid residue found in
unaffected individuals.

Watkins et al. (1995) investigated whether the D175N mutation was really
responsible for hypertrophic cardiomyopathy or was only a polymorphism,
because some features of the 2 identified mutations in the
alpha-tropomyosin gene contrasted with those of mutations in other
disease genes for CMH. Unlike the beta-cardiac myosin heavy chain gene
(MYH7; 160760) and the cardiac troponin-T gene, the alpha-tropomyosin
gene is expressed ubiquitously, yet the disease phenotype is limited to
cardiac muscle. Watkins et al. (1995) found that the D175N mutation was
present in the proband and 2 affected offspring, but in none of the
proband's 3 sibs. Although both parents were deceased, the haplotypes of
the 4 parental chromosomes could be reconstructed. (The haplotypes made
use of an intragenic polymorphism in 10 flanking polymorphisms spanning
a region of 35 cM.) One parental chromosome was transmitted to 2
offspring: 1 bearing the D175N mutation (the affected proband) and 1
clinically unaffected sib who lacked the mutation. Thus the D175N
mutation must have arisen de novo.

.0003
CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 3
TPM1, VAL95ALA

Karibe et al. (2001) described a large Spanish American family with
multiple members affected with hypertrophic cardiomyopathy (115196).
They found a novel val95-to-ala (V95A) mutation in TPM1 to segregate
with the disease phenotype. This mutation was associated with the same
mild degree of left ventricular hypertrophy as seen in some CMH1
families harboring specific mutations in MYH7 (160760.0010, 160760.0012,
160760.0001). Penetrance was estimated at 53% on the basis of an
abnormal echocardiogram; however, 2 mutation carriers with normal
echocardiograms and normal ECGs were only in their mid-thirties at the
time of the study. Penetrance could not be accurately assessed by ECG,
since 6 older mutation-negative family members had minor T-wave changes.
Cumulative survival rates in this family were 73% +/- 10% at 40 years
and 32% +/- 13% at 60 years. Expression of mutant and control
tropomyosin in a bacterial system allowed a functional assessment of
this mutation. An increase in calcium binding and abnormal myosin
cycling were observed; both were felt to be important contributors to
disease pathogenesis.

.0004
CARDIOMYOPATHY, DILATED, 1Y
TPM1, GLU54LYS

In a 27-year-old man with dilated cardiomyopathy (611878) who died while
awaiting cardiac transplantation, Olson et al. (2001) identified
heterozygosity for a G-A transition in exon 2 of the TPM1 gene,
resulting in a glu54-to-lys (E54K) substitution at a highly conserved
residue. The mutation was not found in 348 unrelated CMD patients or 160
unrelated controls.

.0005
CARDIOMYOPATHY, DILATED, 1Y
TPM1, GLU40LYS

In a girl with dilated cardiomyopathy (611878) who underwent cardiac
transplantation at 10 years of age, Olson et al. (2001) identified
heterozygosity for a G-A transition in exon 2 of the TPM1 gene,
resulting in a glu40-to-lys (E40K) substitution at a highly conserved
residue. Her affected mother also carried the mutation, which was not
found in 3 unaffected family members, 348 unrelated CMD patients, or 160
unrelated controls.

.0006
LEFT VENTRICULAR NONCOMPACTION 9
TPM1, LYS248GLU

In 4 affected individuals over 3 generations of a white family of
western European descent with left ventricular noncompaction (LVNC9; see
611878), Probst et al. (2011) identified heterozygosity for a c.933A-G
transition in exon 8 of the TPM1 gene, resulting in a lys248-to-glu
(K248E) substitution at an evolutionarily conserved residue. The male
proband presented at age 63 years with congestive heart failure. He had
2 affected but asymptomatic children. The father had noncompacted
segments at the apex and midventricular wall by echocardiography,
whereas his son and daughter were affected only at the apex. A
granddaughter who carried the mutation had severe congestive heart
failure requiring cardiac transplantation at 5 years of age; she was
diagnosed with dilated cardiomyopathy and did not show signs of LVNC.

.0007
LEFT VENTRICULAR NONCOMPACTION 9
TPM1, GLU192LYS

In a 55-year-old white man of western European descent with left
ventricular noncompaction (LVNC9; see 611878), Probst et al. (2011)
identified heterozygosity for a c.765G-A transition in exon 6 of the
TPM1 gene, resulting in a glu192-to-lys (E192K) substitution at a highly
conserved residue. Echocardiography revealed pronounced noncompaction of
the apex and left midventricular wall, as well as increased right
ventricular trabeculations. His son, who did not carry the mutation,
showed normal left ventricular morphology and function on
echocardiogram.

*FIELD* RF
1. Blanchard, E. M.; Iizuka, K.; Christe, M.; Conner, D. A.; Geisterfer-Lowrance,
A.; Schoen, F. J.; Maughan, D. W.; Seidman, C. E.; Seidman, J. G.
: Targeted ablation of the murine alpha-tropomyosin gene. Circulation
Res. 81: 1005-1010, 1997.

2. Brown, J. H.; Kim, K.-H.; Jun, G.; Greenfield, N. J.; Dominguez,
R.; Volkmann, N.; Hitchcock-DeGregori, S. E.; Cohen, C.: Deciphering
the design of the tropomyosin molecule. Proc. Nat. Acad. Sci. 98:
8496-8501, 2001.

3. Chang, A. N.; Harada, K.; Ackerman, M. J.; Potter, J. D.: Functional
consequences of hypertrophic and dilated cardiomyopathy-causing mutations
in alpha-tropomyosin. J. Biol. Chem. 280: 34343-34349, 2005.

4. Eyre, H.; Akkari, P. A.; Wilton, S. D.; Callen, D. C.; Baker, E.;
Laing, N. G.: Assignment of the human skeletal muscle alpha-tropomyosin
gene (TPM1) to band 15q22 by fluorescence in situ hybridization. Cytogenet.
Cell Genet. 69: 15-17, 1995.

5. Karibe, A.; Tobacman, L. S.; Strand, J.; Butters, C.; Back, N.;
Bachinski, L. L.; Arai, A. E.; Ortiz, A.; Roberts, R.; Homsher, E.;
Fananapazir, L.: Hypertrophic cardiomyopathy caused by a novel alpha-tropomyosin
mutation (V95A) is associated with mild cardiac phenotype, abnormal
calcium binding to troponin, abnormal myosin cycling, and poor prognosis. Circulation 103:
65-71, 2001.

6. Lees-Miller, J. P.; Helfman, D. M.: The molecular basis for tropomyosin
isoform diversity. BioEssays 13: 429-437, 1991.

7. MacLeod, A. R.; Gooding, C.: Human hTM-alpha gene: expression
in muscle and nonmuscle tissue. Molec. Cell. Biol. 8: 433-440, 1988.

8. Mirza, M.; Marston, S.; Willott, R.; Ashley, C.; Mogensen, J.;
McKenna, W.; Robinson, P.; Redwood, C.; Watkins, H.: Dilated cardiomyopathy
mutations in three thin filament regulatory proteins result in a common
functional phenotype. J. Biol. Chem. 280: 28498-28506, 2005.

9. Muthuchamy, M.; Pieples, K.; Rethinasamy, P.; Hoit, B.; Grupp,
I. L.; Boivin, G. P.; Wolska, B.; Evans, C.; Solaro, R. J.; Wieczorek,
D. F.: Mouse model of a familial hypertrophic cardiomyopathy mutation
in alpha-tropomyosin manifests cardiac dysfunction. Circ. Res. 85:
47-56, 1999.

10. Olson, T. M.; Kishimoto, N. Y.; Whitby, F. G.; Michels, V. V.
: Mutations that alter the surface charge of alpha-tropomyosin are
associated with dilated cardiomyopathy. J. Molec. Cell Cardiol. 33:
723-732, 2001.

11. Probst, S.; Oechslin, E.; Schuler, P.; Greutmann, M.; Boye, P.;
Knirsch, W.; Berger, F.; Thierfelder, L.; Jenni, R.; Klaassen, S.
: Sarcomere gene mutations in isolated left ventricular noncompaction
cardiomyopathy do not predict clinical phenotype. Circ. Cardiovasc.
Genet. 4: 367-374, 2011.

12. Rajan, S.; Ahmed, R. P. H.; Jagatheesan, G.; Petrashevskaya, N.;
Boivin, G. P.; Urboniene, D.; Arteaga, G. M.; Wolska, B. M.; Solaro,
R. J.; Liggett, S. B.; Wieczorek, D. F.: Dilated cardiomyopathy mutant
tropomyosin mice develop cardiac dysfunction with significantly decreased
fractional shortening and myofilament calcium sensitivity. Circ.
Res. 101: 205-214, 2007. Note: Erratum: Circ. Res. 101: e80, 2007.

13. Robinson, P.; Griffiths, P. J.; Watkins, H.; Redwood, C. S.:
Dilated and hypertrophic cardiomyopathy mutations in troponin and
alpha-tropomyosin have opposing effects on the calcium affinity of
cardiac thin filaments. Circ. Res. 101: 1266-1273, 2007.

14. Schleef, M.; Werner, K.; Satzger, U.; Kaupmann, K.; Jockusch,
H.: Chromosomal localization and genomic cloning of the mouse alpha-tropomyosin
gene Tpm-1. Genomics 17: 519-521, 1993.

15. Thierfelder, L.; Watkins, H.; MacRae, C.; Lamas, R.; McKenna,
W.; Vosberg, H.-P.; Seidman, J. G.; Seidman, C. E.: Alpha-tropomyosin
and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy:
a disease of the sarcomere. Cell 77: 701-712, 1994.

16. Tiso, N.; Rampoldi, L.; Pallavicini, A.; Zimbello, R.; Pandolfo,
D.; Valle, G.; Lanfranchi, G.; Danieli, G. A.: Fine mapping of five
human skeletal muscle genes: alpha-tropomyosin, beta-tropomyosin,
troponin-I slow-twitch, troponin-I fast-twitch, and troponin-C fast. Biochem.
Biophys. Res. Commun. 230: 347-350, 1997.

17. Watkins, H.; Anan, R.; Coviello, D. A.; Spirito, P.; Seidman,
J. G.; Seidman, C. E.: A de novo mutation in alpha-tropomyosin that
causes hypertrophic cardiomyopathy. Circulation 91: 2302-2305, 1995.

18. Watkins, H.; McKenna, W. J.; Thierfelder, L.; Suk, H. J.; Anan,
R.; O'Donoghue, A.; Spirito, P.; Matsumori, A.; Moravec, C. S.; Seidman,
J. G.; Seidman, C. E.: Mutations in the genes for cardiac troponin
T and alpha-tropomyosin in hypertrophic cardiomyopathy. New Eng.
J. Med. 332: 1058-1064, 1995.

19. Zhu, S.; Si, M.-L.; Wu, H.; Mo, Y.-Y.: MicroRNA-21 targets the
tumor suppressor gene tropomyosin 1 (TPM1). J. Biol. Chem. 282:
14328-14336, 2007.

*FIELD* CN
Marla J. F. O'Neill - updated: 9/3/2013
Marla J. F. O'Neill - updated: 12/2/2008
Marla J. F. O'Neill - updated: 3/6/2008
Marla J. F. O'Neill - updated: 3/5/2008
Alan F. Scott - updated: 5/11/2007
Paul Brennan - updated: 4/18/2002
Victor A. McKusick - updated: 9/26/2001
Paul Brennan - updated: 4/3/2000
Paul Brennan - updated: 5/2/1998
Rebekah S. Rasooly - updated: 3/4/1998

*FIELD* CD
Victor A. McKusick: 2/25/1988

*FIELD* ED
carol: 09/03/2013
carol: 9/3/2013
terry: 7/9/2012
terry: 7/6/2012
wwang: 6/10/2011
wwang: 12/4/2008
terry: 12/2/2008
carol: 3/6/2008
carol: 3/5/2008
mgross: 5/11/2007
alopez: 7/9/2003
terry: 7/7/2003
alopez: 4/18/2002
mcapotos: 10/9/2001
mcapotos: 9/26/2001
alopez: 4/3/2000
carol: 10/20/1999
mgross: 4/8/1999
carol: 6/25/1998
carol: 5/2/1998
alopez: 3/4/1998
terry: 6/13/1996
mark: 7/3/1995
pfoster: 4/3/1995
jason: 6/17/1994
carol: 8/25/1993
carol: 8/28/1992
supermim: 3/16/1992

MIM 611878
*RECORD*
*FIELD* NO
611878
*FIELD* TI
#611878 CARDIOMYOPATHY, DILATED, 1Y; CMD1Y
LEFT VENTRICULAR NONCOMPACTION 9, INCLUDED; LVNC9, INCLUDED
read more*FIELD* TX
A number sign (#) is used with this entry because dilated
cardiomyopathy-1Y (CMD1Y) and left ventricular noncompaction-9 (LVNC9)
are caused by heterozygous mutation in the TPM1 gene (191010) on
chromosome 15q22.1.

For a general phenotypic description and a discussion of genetic
heterogeneity of dilated cardiomyopathy, see CMD1A (115200).

CLINICAL FEATURES

Olson et al. (2001) described 2 probands with familial dilated
cardiomyopathy. One was a 27-year-old man whose father and paternal
uncle died from heart failure at age 27 and 49 years, respectively.
Because of suspected familial CMD, screening echocardiogram was
performed when the proband was 17 years old but was reportedly normal.
At 26 years of age, the proband developed shortness of breath, edema,
and nonsustained ventricular tachycardia. He had no echocardiographic
features of hypertrophic cardiomyopathy, coronary arteries were normal
by angiography, and cardiac biopsy findings were nonspecific and
consistent with idiopathic CMD. Despite aggressive medical therapy and
implantation of an automatic cardioverter defibrillator, he died at age
27 while on a cardiac transplant waiting list. The second proband
presented at 3 months of age with congestive heart failure and was
diagnosed with idiopathic CMD based on echocardiographic findings; her
heart failure progressed while on medical therapy and she underwent
cardiac transplantation at 10 years of age. Electron microscopy of her
explanted heart tissue revealed an abnormal sarcomere structure in which
the thin filaments of many sarcomeres appeared irregular and fragmented;
the sarcomeres were also contracted with decreased distance between Z
bands and the sarcolemma had a scalloped appearance. The girl's mother,
who had developed heart palpitations during pregnancy that recurred 6
months after delivery, was diagnosed with idiopathic CMD at 33 years of
age based on echocardiographic and cardiac biopsy findings and the
absence of coronary artery disease on angiography. She remained stable
on minimal medical therapy. Family history included a maternal
grandfather who had died at 59 years of age from presumed myocardial
infarction, and his father and several sibs reportedly died in their 50s
from heart disease.

- Left Ventricular Noncompaction 9

Probst et al. (2011) described 2 white families of western European
descent with left ventricular noncompaction (LVNC) due to mutations in
the TPM1 gene (see MOLECULAR GENETICS). In the first family, the proband
was a man who presented at 63 years of age with congestive heart failure
and was found to have noncompacted segments of the apex and
midventricular wall, with a left ventricular ejection fraction (LVEF) of
19% and left ventricular fractional shortening (LVFS) of 18%. He had 2
affected asymptomatic children, a 32-year-old daughter and a 34-year-old
son, who were identified only by family screening and were found to have
noncompacted apical segments by echocardiography, with an LVEF of 37%
and 53% and an LVFS of 20% and 32%, respectively. In addition, a
granddaughter had congestive heart failure and atrial fibrillation that
was believed to be due to myocarditis, for which she underwent cardiac
transplantation at age 5 years. She was diagnosed with dilated
cardiomyopathy without signs of LVNC. A myocardial tissue sample from
the explanted left ventricular apex revealed pronounced endomyocardial
fibroelastosis and minimal interstitial fibrosis. In the second family,
the 55-year-old male proband presented with chest pain and dyspnea, and
echocardiography revealed pronounced LVNC of the apex and midventricular
wall, with increased right ventricular trabeculations. Cardiac MRI
showed normal left ventricular (LV) mass and extensive diffuse fibrosis
of the LV, predominantly located on the epicardium and extending
transmurally into the anterior and inferior LV wall. The hypertrophic
interventricular septum was spared and showed no recesses or prominent
trabeculations. Family history revealed that the proband's father had
died from heart disease at age 60 and an uncle had a sudden cardiac
death at age 40.

MOLECULAR GENETICS

In affected individuals from 2 unrelated families with idiopathic
dilated cardiomyopathy, Olson et al. (2001) identified heterozygosity
for missense mutations in the TPM1 gene: E54K (191010.0004) and E40K
(191010.0005).

- Left Ventricular Noncompaction 9

In a cohort of 63 unrelated white patients of western European descent
with left ventricular noncompaction, Probst et al. (2011) analyzed 8
sarcomere genes and identified 2 probands with heterozygous missense
mutations in the TPM1 gene (191010.0006 and 191010.0007).

*FIELD* RF
1. Olson, T. M.; Kishimoto, N. Y.; Whitby, F. G.; Michels, V. V.:
Mutations that alter the surface charge of alpha-tropomyosin are associated
with dilated cardiomyopathy. J. Molec. Cell Cardiol. 33: 723-732,
2001.

2. Probst, S.; Oechslin, E.; Schuler, P.; Greutmann, M.; Boye, P.;
Knirsch, W.; Berger, F.; Thierfelder, L.; Jenni, R.; Klaassen, S.
: Sarcomere gene mutations in isolated left ventricular noncompaction
cardiomyopathy do not predict clinical phenotype. Circ. Cardiovasc.
Genet. 4: 367-374, 2011.

*FIELD* CN
Marla J. F. O'Neill - updated: 9/3/2013

*FIELD* CD
Marla J. F. O'Neill: 3/5/2008

*FIELD* ED
carol: 09/05/2013
carol: 9/4/2013
carol: 9/3/2013
carol: 7/3/2008
carol: 3/6/2008
carol: 3/5/2008