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{{Infobox_gene}}
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'''Slow skeletal muscle troponin T''' (sTnT) is a [[protein]] that in humans is encoded by the ''TNNT1'' [[gene]].<ref name="Samson_1992"/><ref name="entrez">{{cite web | title = Entrez Gene: TNNT1 troponin T type 1 (skeletal, slow) | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7138 }}</ref>
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The TNNT1 gene is located at 19q13.4 in the human chromosomal genome, encoding the slow twitch [[skeletal muscle]] isoform of [[troponin T]] (ssTnT). ssTnT is an ~32-kDa protein consisting of 262 amino acids (including the first [[methionine]]) with an [[isoelectric point]] (pI) of 5.95. It is the [[tropomyosin]] binding and thin filament anchoring subunit of the troponin complex in the [[sarcomere]]s of slow twitch skeletal muscle fibers.<ref name = "Perry_1998"/><ref name = "Jin_2008"/><ref name = "Wei_2011"/> TNNT1 gene is specifically expressed in slow skeletal muscle of vertebrates, with one exception that dry land toad (Bufo) cardiac muscle expresses ssTnT other than  cardiac TnT.<ref name = "Feng_2012"/>
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== Evolution ==
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[[File:TnT TnI gene pairs.jpg|thumb]]
 
Three [[homologous gene]]s have evolved in vertebrates, encoding three muscle type specific [[protein isoform|isoforms]] of TnT.<ref name = "Wei_2011"/> Each of the TnT isoform genes is linked to one of the three troponin I<ref name = "Dweck_2014"/> isoform genes encoding the inhibitory subunit of the troponin complex, in chromosomal DNA to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, ssTnI-cardiac (cTnT) and cTnI-ssTnT gene pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type specific TnT and TnI isoforms may have evolved from duplications of a fsTnI-like-fsTnT-like gene pair.<ref name = "Chong_2009"/> Evolutionary lineage of the three TnI-TnT gene pairs shows that cTnI-ssTnT is the newest<ref name = "Chong_2009"/> and most closely linked.<ref name = "Huang_1999b"/>
 
Protein sequence alignment demonstrated that TNNT1 genes are highly conserved among vertebrate species (Fig. 2), especially in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged among vertebrate species.<ref name = "Jin_2008"/><ref name = "Wei_2011"/>
 
[[File:TNNT1 gene phylogenic tree.jpg|thumb]]
 
== Alternative splicing ==
 
In mammalian and avian species, TNNT1 gene has a total of 14 exons, among which exon 5 encoding an 11-amino acid in the N-terminal region is alternatively spliced, generating a high molecular weight and a low molecular weight slow TnT splice forms (Jin, Chen et al. 1998).<ref name = "Gahlmann_1987"/><ref name = "Huang_1999a"/> Biochemical studies showed that TnT splice forms have detectable different molecular conformation in the middle and C-terminal regions, producing different binding affinities for TnI and tropomyosin.<ref name = "Jin_2008"/><ref name = "Wei_2011"/> The alternative splice forms of ssTnT play a role in skeletal muscle adaptation in physiologic and pathological conditions.<ref name = "Larsson_2008"/> Alternative splicing at alternative acceptor sites of intron 5 generates a single amino acid difference in the N-terminal region of ssTnT,<ref name = "Huang_1999a"/> of which functional significance has not been established.
 
== Clinical significance ==
 
A nonsense mutation E180X in the exon 11 of TNNT1 gene causes Amish Nemaline Myopathy (ANM), which is a severe form of recessive nemaline myopathy originally found in the Old Order Amish population in Pennsylvania, USA.<ref name = "Johnston_2000"/><ref name = "Jin_2003"/> Truncation of the ssTnT polypeptide chain by the E180X mutation deletes the tropomyosin-binding site 2<ref name = "Jin_2010"/> as well as the binding sites for TnI and troponin C (TnC) in the C-terminal region (Fig. 3). Consistent with the recessive phenotype, the truncated ssTnT is incapable of incorporation into the myofilaments and completely degraded in muscle cells.<ref name = "Martin_1981"/>
 
[[File:Skeletal troponin complex structure.tif|thumb]]Tnnt1 gene targeted mouse studies reproduced the myopathic phenotypes of ANM.<ref name = "Feng_2009"/><ref name = "Wei_2014"/> ssTnT null mice showed significantly decreased type I slow fibers in diaphragm and soleus muscles with hypertrophy of type II fast fibers, increased fatigability, and active regeneration of slow fibers (Wei, Lu et al. 2014).<ref name = "Feng_2009"/>
 
Recent case reports identified three more mutations in TNNT1 gene to cause nemaline myopathies outside the Amish population. A nonsense mutation S108X in exon 9 was identified in a Hispanic male patient with severe recessive nemaline myopathy phenotype.<ref name = "Marra_2015"/> A Dutch patient with compound heterozygous TNNT1 gene mutations that cause exon 8 and exon 14 deletions also presents nemaline myopathy phenotypes.<ref name = "van_der_Pol_2014"/> A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) leading to aberrant splicing that causes C-terminal truncation of the protein (L203 truncation) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline Myopathy.<ref name="Abdulhaq_2015"/>
 
Illustrated in Fig. 3, the S108X mutation truncates ssTnT protein to cause a loss of functional structures equivalent to that of E180X. The exon 8 deletion destructs the middle region tropomyosin-binding site 1.<ref name = "Jin_2010"/><ref name = "Amarasinghe_2015"/> The L203 truncation deletes the binding sites for TnI and TnC but preserves both tropomyosin-binding sites 1 and 2.<ref name = "Jin_2010"/> It remains to be invistigated whether this novel mutation is able to bind the actin-tropomyosin thin filament in vivo and how it causes recessive nemaline myopathy.
 
Alternative splicing of exon 5 produces high and low molecular weight splice forms of ssTnT. The low molecular ssTnT was significantly upregulated in type 1 (demyelination) but not type 2 (axon loss) Charcot-Marie-Tooth disease,<ref name = "Larsson_2008"/> suggesting that structural modification of TnT in the myofilaments may contribute to adaptation to abnormalities in neuronal activation.
 
== Interactions ==
 
TNNT1 has been shown to [[Protein-protein interaction|interact]] with [[PRKG1]].<ref name=pmid10601315>{{cite journal | vauthors = Yuasa K, Michibata H, Omori K, Yanaka N | title = A novel interaction of cGMP-dependent protein kinase I with troponin T | journal = The Journal of Biological Chemistry | volume = 274 | issue = 52 | pages = 37429–34 | date = Dec 1999 | pmid = 10601315 | doi = 10.1074/jbc.274.52.37429 }}</ref>


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<ref name = "Jin_1998"/>
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<ref name = "Palm_2001"/>
| image =
<ref name = "Vinogradova_2005"/>
| image_source = 
| PDB =
| Name = Troponin T type 1 (skeletal, slow)
| HGNCid = 11948
| Symbol = TNNT1
| AltSymbols =; ANM; MGC104241
| OMIM = 191041
| ECnumber = 
| Homologene = 20704
| MGIid = 1333868
| GeneAtlas_image1 = PBB_GE_TNNT1_213201_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005515 |text = protein binding}} {{GNF_GO|id=GO:0005523 |text = tropomyosin binding}}
| Component =
| Process = {{GNF_GO|id=GO:0006937 |text = regulation of muscle contraction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 7138
    | Hs_Ensembl = ENSG00000105048
    | Hs_RefseqProtein = NP_003274
    | Hs_RefseqmRNA = NM_003283
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 19
    | Hs_GenLoc_start = 60336009
    | Hs_GenLoc_end = 60352386
    | Hs_Uniprot = P13805
    | Mm_EntrezGene = 21955
    | Mm_Ensembl = ENSMUSG00000064179
    | Mm_RefseqmRNA = XM_976504
    | Mm_RefseqProtein = XP_981598
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 4107750
    | Mm_GenLoc_end = 4119062
    | Mm_Uniprot = Q3TVB8
  }}
}}
'''Troponin T type 1 (skeletal, slow)''', also known as '''TNNT1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: TNNT1 troponin T type 1 (skeletal, slow)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7138| accessdate = }}</ref>


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==Notes==
{{PBB_Summary
{{Academic-written review
| section_title =  
| wikidate = 2015
| summary_text =  
| journal = [[Gene (journal)|Gene]]
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| authors = {{#property:P2093|from=Q37666010}}
| date    = {{#property:P577|from=Q37666010}}
| volume = {{#property:P478|from=Q37666010}}
| issue  = {{#property:P433|from=Q37666010}}
| pages  = {{#property:P304|from=Q37666010}}
| doi    = {{#property:P356|from=Q37666010}}
| pmid    = {{#property:P698|from=Q37666010}}
| pmc    = {{#property:P932|from=Q37666010}}
}}
}}


==References==
==References==
{{reflist|2}}
{{Reflist|33em|refs =
==Further reading==
 
{{refbegin | 2}}
<ref name="Abdulhaq_2015">{{cite journal | vauthors = Abdulhaq UN, Daana M, Dor T, Fellig Y, Eylon S, Schuelke M, Shaag A, Elpeleg O, Edvardson S | title = Nemaline body myopathy caused by a novel mutation in Troponin T1 (TNNT1) | journal = Muscle Nerve | volume = 53| issue = | pages = 564–9| year = 2015 | pmid = 26296490 | doi = 10.1002/mus.24885  }}</ref>
{{PBB_Further_reading
 
| citations =  
<ref name = "Amarasinghe_2015">{{cite journal | vauthors = Amarasinghe C, Jin JP | title = N-Terminal Hypervariable Region of Muscle Type Isoforms of Troponin T Differentially Modulates the Affinity of Tropomyosin-Binding Site 1 | journal = Biochemistry | volume = 54 | issue = 24 | pages = 3822–30 | date = Jun 2015 | pmid = 26024675 | doi = 10.1021/acs.biochem.5b00348 }}</ref>
*{{cite journal | author=Nadal-Ginard B, Mahdavi V |title=Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. |journal=J. Clin. Invest. |volume=84 |issue= 6 |pages= 1693-700 |year= 1990 |pmid= 2687327 |doi= }}
 
*{{cite journal | author=Wu AH, Ford L |title=Release of cardiac troponin in acute coronary syndromes: ischemia or necrosis? |journal=Clin. Chim. Acta |volume=284 |issue= 2 |pages= 161-74 |year= 1999 |pmid= 10451243 |doi= }}
<ref name = "Chong_2009">{{cite journal | vauthors = Chong SM, Jin JP | title = To investigate protein evolution by detecting suppressed epitope structures | journal = Journal of Molecular Evolution | volume = 68 | issue = 5 | pages = 448–60 | date = May 2009 | pmid = 19365646 | pmc = 2752406 | doi = 10.1007/s00239-009-9202-0 | bibcode = 2009JMolE..68..448C }}</ref>
*{{cite journal | author=Novelli G, Gennarelli M, Zelano G, ''et al.'' |title=Polymerase chain reaction in the detection of mRNA transcripts from the slow skeletal troponin T (TNNT1) gene in myotonic dystrophy and normal muscle. |journal=Cell Biochem. Funct. |volume=10 |issue= 4 |pages= 251-6 |year= 1993 |pmid= 1473264 |doi= 10.1002/cbf.290100407 }}
 
*{{cite journal | author=Samson F, de Jong PJ, Trask BJ, ''et al.'' |title=Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis. |journal=Genomics |volume=13 |issue= 4 |pages= 1374-5 |year= 1992 |pmid= 1505979 |doi= }}
<ref name = "Dweck_2014">{{cite journal | vauthors = Dweck D, Sanchez-Gonzalez MA, Chang AN, Dulce RA, Badger CD, Koutnik AP, Ruiz EL, Griffin B, Liang J, Kabbaj M, Fincham FD, Hare JM, Overton JM, Pinto JR | title = Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy | journal = The Journal of Biological Chemistry | volume = 289 | issue = 33 | pages = 23097–111 | date = Aug 2014 | pmid = 24973218 | pmc = 4132808 | doi = 10.1074/jbc.M114.561472 }}</ref>
*{{cite journal | author=Gahlmann R, Troutt AB, Wade RP, ''et al.'' |title=Alternative splicing generates variants in important functional domains of human slow skeletal troponin T. |journal=J. Biol. Chem. |volume=262 |issue= 33 |pages= 16122-6 |year= 1987 |pmid= 2824479 |doi=  }}
 
*{{cite journal | author=Heeley DH, Golosinska K, Smillie LB |title=The effects of troponin T fragments T1 and T2 on the binding of nonpolymerizable tropomyosin to F-actin in the presence and absence of troponin I and troponin C. |journal=J. Biol. Chem. |volume=262 |issue= 21 |pages= 9971-8 |year= 1987 |pmid= 3611073 |doi= }}
<ref name = "Feng_2012">{{cite journal | vauthors = Feng HZ, Chen X, Hossain MM, Jin JP | title = Toad heart utilizes exclusively slow skeletal muscle troponin T: an evolutionary adaptation with potential functional benefits | journal = The Journal of Biological Chemistry | volume = 287 | issue = 35 | pages = 29753–64 | date = Aug 2012 | pmid = 22778265 | pmc = 3436204 | doi = 10.1074/jbc.M112.373191 }}</ref>
*{{cite journal | author=Pearlstone JR, Smillie LB |title=Effects of troponin-I plus-C on the binding of troponin-T and its fragments to alpha-tropomyosin. Ca2+ sensitivity and cooperativity. |journal=J. Biol. Chem. |volume=258 |issue= 4 |pages= 2534-42 |year= 1983 |pmid= 6822572 |doi= }}
 
*{{cite journal | author=Samson F, Mesnard L, Mihovilovic M, ''et al.'' |title=A new human slow skeletal troponin T (TnTs) mRNA isoform derived from alternative splicing of a single gene. |journal=Biochem. Biophys. Res. Commun. |volume=199 |issue= 2 |pages= 841-7 |year= 1994 |pmid= 8135831 |doi= 10.1006/bbrc.1994.1305 }}
<ref name = "Feng_2009">{{cite journal | vauthors = Feng HZ, Wei B, Jin JP | title = Deletion of a genomic segment containing the cardiac troponin I gene knocks down expression of the slow troponin T gene and impairs fatigue tolerance of diaphragm muscle | journal = The Journal of Biological Chemistry | volume = 284 | issue = 46 | pages = 31798–806 | date = Nov 2009 | pmid = 19797054 | pmc = 2797250 | doi = 10.1074/jbc.M109.020826 }}</ref>
*{{cite journal | author=Novelli G, Gennarelli M, Sangiuolo F, ''et al.'' |title=Isolation and cloning by a polymerase chain reaction of a genomic DNA fragment of the human slow skeletal troponin (TNNT1) gene. |journal=Cell Biochem. Funct. |volume=11 |issue= 3 |pages= 187-91 |year= 1993 |pmid= 8403232 |doi= 10.1002/cbf.290110306 }}
 
*{{cite journal | author=Jha PK, Leavis PC, Sarkar S |title=Interaction of deletion mutants of troponins I and T: COOH-terminal truncation of troponin T abolishes troponin I binding and reduces Ca2+ sensitivity of the reconstituted regulatory system. |journal=Biochemistry |volume=35 |issue= 51 |pages= 16573-80 |year= 1997 |pmid= 8987992 |doi= 10.1021/bi9622433 }}
<ref name = "Gahlmann_1987">{{cite journal | vauthors = Gahlmann R, Troutt AB, Wade RP, Gunning P, Kedes L | title = Alternative splicing generates variants in important functional domains of human slow skeletal troponin T | journal = The Journal of Biological Chemistry | volume = 262 | issue = 33 | pages = 16122–6 | date = Nov 1987 | pmid = 2824479 }}</ref>
*{{cite journal | author=Stefancsik R, Jha PK, Sarkar S |title=Identification and mutagenesis of a highly conserved domain in troponin T responsible for troponin I binding: potential role for coiled coil interaction. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 3 |pages= 957-62 |year= 1998 |pmid= 9448267 |doi= }}
 
*{{cite journal | author=Jha PK, Sarkar S |title=A recombinant monocysteine mutant (Ser to Cys-155) of fast skeletal troponin T: identification by cross-linking of a domain involved in a physiologically relevant interaction with troponins C and I. |journal=Biochemistry |volume=37 |issue= 35 |pages= 12253-60 |year= 1998 |pmid= 9724539 |doi= 10.1021/bi980025z }}
<ref name = "Huang_1999a">{{cite journal | vauthors = Huang QQ, Chen A, Jin JP | title = Genomic sequence and structural organization of mouse slow skeletal muscle troponin T gene | journal = Gene | volume = 229 | issue = 1–2 | pages = 1–10 | date = Mar 1999 | pmid = 10095098 | doi=10.1016/s0378-1119(99)00051-7}}</ref>
*{{cite journal | author=Barton PJ, Cullen ME, Townsend PJ, ''et al.'' |title=Close physical linkage of human troponin genes: organization, sequence, and expression of the locus encoding cardiac troponin I and slow skeletal troponin T. |journal=Genomics |volume=57 |issue= 1 |pages= 102-9 |year= 1999 |pmid= 10191089 |doi= 10.1006/geno.1998.5702 }}
 
*{{cite journal | author=Mukherjea P, Tong L, Seidman JG, ''et al.'' |title=Altered regulatory function of two familial hypertrophic cardiomyopathy troponin T mutants. |journal=Biochemistry |volume=38 |issue= 40 |pages= 13296-301 |year= 1999 |pmid= 10529204 |doi= }}
<ref name = "Huang_1999b">{{cite journal | vauthors = Huang QQ, Jin JP | title = Preserved close linkage between the genes encoding troponin I and troponin T, reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of contractility | journal = Journal of Molecular Evolution | volume = 49 | issue = 6 | pages = 780–8 | date = Dec 1999 | pmid = 10594179 | doi=10.1007/pl00006600| bibcode = 1999JMolE..49..780H }}</ref>
*{{cite journal | author=Yuasa K, Michibata H, Omori K, Yanaka N |title=A novel interaction of cGMP-dependent protein kinase I with troponin T. |journal=J. Biol. Chem. |volume=274 |issue= 52 |pages= 37429-34 |year= 2000 |pmid= 10601315 |doi= }}
 
*{{cite journal | author=Johnston JJ, Kelley RI, Crawford TO, ''et al.'' |title=A novel nemaline myopathy in the Amish caused by a mutation in troponin T1. |journal=Am. J. Hum. Genet. |volume=67 |issue= 4 |pages= 814-21 |year= 2000 |pmid= 10952871 |doi= }}
<ref name = "Jin_2003">{{cite journal | vauthors = Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO | title = Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy | journal = The Journal of Biological Chemistry | volume = 278 | issue = 28 | pages = 26159–65 | date = Jul 2003 | pmid = 12732643 | doi = 10.1074/jbc.M303469200 }}</ref>
*{{cite journal | author=Schmidtmann A, Lohmann K, Jaquet K |title=The interaction of the bisphosphorylated N-terminal arm of cardiac troponin I-A 31P-NMR study. |journal=FEBS Lett. |volume=513 |issue= 2-3 |pages= 289-93 |year= 2002 |pmid= 11904166 |doi= }}
 
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
<ref name = "Jin_1998">{{cite journal | vauthors = Jin JP, Chen A, Huang QQ | title = Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development | journal = Gene | volume = 214 | issue = 1–2 | pages = 121–9 | date = Jul 1998 | pmid = 9651500 | doi=10.1016/s0378-1119(98)00214-5}}</ref>
 
<ref name = "Jin_2010">{{cite journal | vauthors = Jin JP, Chong SM | title = Localization of the two tropomyosin-binding sites of troponin T | journal = Archives of Biochemistry and Biophysics | volume = 500 | issue = 2 | pages = 144–50 | date = Aug 2010 | pmid = 20529660 | pmc = 2904419 | doi = 10.1016/j.abb.2010.06.001 }}</ref>
 
<ref name = "Jin_2008">{{cite journal | vauthors = Jin JP, Zhang Z, Bautista JA | title = Isoform diversity, regulation, and functional adaptation of troponin and calponin | journal = Critical Reviews in Eukaryotic Gene Expression | volume = 18 | issue = 2 | pages = 93–124 | pmid = 18304026 | year = 2008 | doi=10.1615/critreveukargeneexpr.v18.i2.10}}</ref>
 
<ref name = "Johnston_2000">{{cite journal | vauthors = Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schäffer AA, Francomano CA, Biesecker LG | title = A novel nemaline myopathy in the Amish caused by a mutation in troponin T1 | journal = American Journal of Human Genetics | volume = 67 | issue = 4 | pages = 814–21 | date = Oct 2000 | pmid = 10952871 | pmc = 1287886 | doi = 10.1086/303089 }}</ref>
 
<ref name = "Larsson_2008">{{cite journal | vauthors = Larsson L, Wang X, Yu F, Höök P, Borg K, Chong SM, Jin JP | title = Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease | journal = American Journal of Physiology. Cell Physiology | volume = 295 | issue = 3 | pages = C722–31 | date = Sep 2008 | pmid = 18579801 | pmc = 2544436 | doi = 10.1152/ajpcell.00110.2008 }}</ref>
 
<ref name = "Marra_2015">{{cite journal | vauthors = Marra JD, Engelstad KE, Ankala A, Tanji K, Dastgir J, De Vivo DC, Coffee B, Chiriboga CA | title = Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish | journal = Muscle & Nerve | volume = 51 | issue = 5 | pages = 767–72 | date = May 2015 | pmid = 25430424 | doi = 10.1002/mus.24528 }}</ref>
 
<ref name = "Martin_1981">{{cite journal | vauthors = Martin AF | title = Turnover of cardiac troponin subunits. Kinetic evidence for a precursor pool of troponin-I | journal = The Journal of Biological Chemistry | volume = 256 | issue = 2 | pages = 964–8 | date = Jan 1981 | pmid = 7451483 }}</ref>
 
<ref name = "Palm_2001">{{cite journal | vauthors = Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJ | title = Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region | journal = Biophysical Journal | volume = 81 | issue = 5 | pages = 2827–37 | date = Nov 2001 | pmid = 11606294 | pmc = 1301748 | doi = 10.1016/S0006-3495(01)75924-3 | bibcode = 2001BpJ....81.2827P }}</ref>
 
<ref name = "Perry_1998">{{cite journal | vauthors = Perry SV | title = Troponin T: genetics, properties and function | journal = Journal of Muscle Research and Cell Motility | volume = 19 | issue = 6 | pages = 575–602 | date = Aug 1998 | pmid = 9742444 | doi=10.1023/a:1005397501968}}</ref>
 
<ref name="Samson_1992">{{cite journal | vauthors = Samson F, de Jong PJ, Trask BJ, Koza-Taylor P, Speer MC, Potter T, Roses AD, Gilbert JR | title = Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis | journal = Genomics | volume = 13 | issue = 4 | pages = 1374–5 | date = Aug 1992 | pmid = 1505979 | pmc =  | doi = 10.1016/0888-7543(92)90077-6 }}</ref>
 
<ref name = "van_der_Pol_2014">{{cite journal | vauthors = van der Pol WL, Leijenaar JF, Spliet WG, Lavrijsen SW, Jansen NJ, Braun KP, Mulder M, Timmers-Raaijmakers B, Ratsma K, Dooijes D, van Haelst MM | title = Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree | journal = Molecular Genetics & Genomic Medicine | volume = 2 | issue = 2 | pages = 134–7 | date = Mar 2014 | pmid = 24689076 | pmc = 3960055 | doi = 10.1002/mgg3.52 }}</ref>
 
<ref name = "Vinogradova_2005">{{cite journal | vauthors = Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ | title = Ca(2+)-regulated structural changes in troponin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 14 | pages = 5038–43 | date = Apr 2005 | pmid = 15784741 | pmc = 555973 | doi = 10.1073/pnas.0408882102 | bibcode = 2005PNAS..102.5038V }}</ref>
 
<ref name = "Wei_2011">{{cite journal | vauthors = Wei B, Jin JP | title = Troponin T isoforms and posttranscriptional modifications: Evolution, regulation and function | journal = Archives of Biochemistry and Biophysics | volume = 505 | issue = 2 | pages = 144–54 | date = Jan 2011 | pmid = 20965144 | pmc = 3018564 | doi = 10.1016/j.abb.2010.10.013 }}</ref>
 
<ref name = "Wei_2014">{{cite journal | vauthors = Wei B, Lu Y, Jin JP | title = Deficiency of slow skeletal muscle troponin T causes atrophy of type I slow fibres and decreases tolerance to fatigue | journal = The Journal of Physiology | volume = 592 | issue = Pt 6 | pages = 1367–80 | date = Mar 2014 | pmid = 24445317 | pmc = 3961093 | doi = 10.1113/jphysiol.2013.268177 }}</ref>
 
}}
}}
{{refend}}


{{protein-stub}}
==External links==
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=nem  GeneReviews/NCBI/NIH/UW entry on Nemaline Myopathy]
 
{{Cytoskeletal Proteins}}

Latest revision as of 19:14, 26 June 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ensembl

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Wikidata
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Slow skeletal muscle troponin T (sTnT) is a protein that in humans is encoded by the TNNT1 gene.[1][2]

The TNNT1 gene is located at 19q13.4 in the human chromosomal genome, encoding the slow twitch skeletal muscle isoform of troponin T (ssTnT). ssTnT is an ~32-kDa protein consisting of 262 amino acids (including the first methionine) with an isoelectric point (pI) of 5.95. It is the tropomyosin binding and thin filament anchoring subunit of the troponin complex in the sarcomeres of slow twitch skeletal muscle fibers.[3][4][5] TNNT1 gene is specifically expressed in slow skeletal muscle of vertebrates, with one exception that dry land toad (Bufo) cardiac muscle expresses ssTnT other than cardiac TnT.[6]

Evolution

File:TnT TnI gene pairs.jpg

Three homologous genes have evolved in vertebrates, encoding three muscle type specific isoforms of TnT.[5] Each of the TnT isoform genes is linked to one of the three troponin I[7] isoform genes encoding the inhibitory subunit of the troponin complex, in chromosomal DNA to form three gene pairs: The fast skeletal muscle TnI (fsTnI)-fsTnT, ssTnI-cardiac (cTnT) and cTnI-ssTnT gene pairs. Sequence and epitope conservation studies suggested that genes encoding the muscle type specific TnT and TnI isoforms may have evolved from duplications of a fsTnI-like-fsTnT-like gene pair.[8] Evolutionary lineage of the three TnI-TnT gene pairs shows that cTnI-ssTnT is the newest[8] and most closely linked.[9]

Protein sequence alignment demonstrated that TNNT1 genes are highly conserved among vertebrate species (Fig. 2), especially in the middle and C-terminal regions, while the three muscle type isoforms are significantly diverged among vertebrate species.[4][5]

File:TNNT1 gene phylogenic tree.jpg

Alternative splicing

In mammalian and avian species, TNNT1 gene has a total of 14 exons, among which exon 5 encoding an 11-amino acid in the N-terminal region is alternatively spliced, generating a high molecular weight and a low molecular weight slow TnT splice forms (Jin, Chen et al. 1998).[10][11] Biochemical studies showed that TnT splice forms have detectable different molecular conformation in the middle and C-terminal regions, producing different binding affinities for TnI and tropomyosin.[4][5] The alternative splice forms of ssTnT play a role in skeletal muscle adaptation in physiologic and pathological conditions.[12] Alternative splicing at alternative acceptor sites of intron 5 generates a single amino acid difference in the N-terminal region of ssTnT,[11] of which functional significance has not been established.

Clinical significance

A nonsense mutation E180X in the exon 11 of TNNT1 gene causes Amish Nemaline Myopathy (ANM), which is a severe form of recessive nemaline myopathy originally found in the Old Order Amish population in Pennsylvania, USA.[13][14] Truncation of the ssTnT polypeptide chain by the E180X mutation deletes the tropomyosin-binding site 2[15] as well as the binding sites for TnI and troponin C (TnC) in the C-terminal region (Fig. 3). Consistent with the recessive phenotype, the truncated ssTnT is incapable of incorporation into the myofilaments and completely degraded in muscle cells.[16]

File:Skeletal troponin complex structure.tif

Tnnt1 gene targeted mouse studies reproduced the myopathic phenotypes of ANM.[17][18] ssTnT null mice showed significantly decreased type I slow fibers in diaphragm and soleus muscles with hypertrophy of type II fast fibers, increased fatigability, and active regeneration of slow fibers (Wei, Lu et al. 2014).[17]

Recent case reports identified three more mutations in TNNT1 gene to cause nemaline myopathies outside the Amish population. A nonsense mutation S108X in exon 9 was identified in a Hispanic male patient with severe recessive nemaline myopathy phenotype.[19] A Dutch patient with compound heterozygous TNNT1 gene mutations that cause exon 8 and exon 14 deletions also presents nemaline myopathy phenotypes.[20] A rearrangement in TNNT1 gene (c.574_577 delins TAGTGCTGT) leading to aberrant splicing that causes C-terminal truncation of the protein (L203 truncation) was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited nemaline Myopathy.[21]

Illustrated in Fig. 3, the S108X mutation truncates ssTnT protein to cause a loss of functional structures equivalent to that of E180X. The exon 8 deletion destructs the middle region tropomyosin-binding site 1.[15][22] The L203 truncation deletes the binding sites for TnI and TnC but preserves both tropomyosin-binding sites 1 and 2.[15] It remains to be invistigated whether this novel mutation is able to bind the actin-tropomyosin thin filament in vivo and how it causes recessive nemaline myopathy.

Alternative splicing of exon 5 produces high and low molecular weight splice forms of ssTnT. The low molecular ssTnT was significantly upregulated in type 1 (demyelination) but not type 2 (axon loss) Charcot-Marie-Tooth disease,[12] suggesting that structural modification of TnT in the myofilaments may contribute to adaptation to abnormalities in neuronal activation.

Interactions

TNNT1 has been shown to interact with PRKG1.[23]

[24] [25] [26]

Notes


References

  1. ↑ Samson F, de Jong PJ, Trask BJ, Koza-Taylor P, Speer MC, Potter T, Roses AD, Gilbert JR (Aug 1992). "Assignment of the human slow skeletal troponin T gene to 19q13.4 using somatic cell hybrids and fluorescence in situ hybridization analysis". Genomics. 13 (4): 1374–5. doi:10.1016/0888-7543(92)90077-6. PMID 1505979.
  2. ↑ "Entrez Gene: TNNT1 troponin T type 1 (skeletal, slow)".
  3. ↑ Perry SV (Aug 1998). "Troponin T: genetics, properties and function". Journal of Muscle Research and Cell Motility. 19 (6): 575–602. doi:10.1023/a:1005397501968. PMID 9742444.
  4. ↑ 4.0 4.1 4.2 Jin JP, Zhang Z, Bautista JA (2008). "Isoform diversity, regulation, and functional adaptation of troponin and calponin". Critical Reviews in Eukaryotic Gene Expression. 18 (2): 93–124. doi:10.1615/critreveukargeneexpr.v18.i2.10. PMID 18304026.
  5. ↑ 5.0 5.1 5.2 5.3 Wei B, Jin JP (Jan 2011). "Troponin T isoforms and posttranscriptional modifications: Evolution, regulation and function". Archives of Biochemistry and Biophysics. 505 (2): 144–54. doi:10.1016/j.abb.2010.10.013. PMC 3018564. PMID 20965144.
  6. ↑ Feng HZ, Chen X, Hossain MM, Jin JP (Aug 2012). "Toad heart utilizes exclusively slow skeletal muscle troponin T: an evolutionary adaptation with potential functional benefits". The Journal of Biological Chemistry. 287 (35): 29753–64. doi:10.1074/jbc.M112.373191. PMC 3436204. PMID 22778265.
  7. ↑ Dweck D, Sanchez-Gonzalez MA, Chang AN, Dulce RA, Badger CD, Koutnik AP, Ruiz EL, Griffin B, Liang J, Kabbaj M, Fincham FD, Hare JM, Overton JM, Pinto JR (Aug 2014). "Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy". The Journal of Biological Chemistry. 289 (33): 23097–111. doi:10.1074/jbc.M114.561472. PMC 4132808. PMID 24973218.
  8. ↑ 8.0 8.1 Chong SM, Jin JP (May 2009). "To investigate protein evolution by detecting suppressed epitope structures". Journal of Molecular Evolution. 68 (5): 448–60. Bibcode:2009JMolE..68..448C. doi:10.1007/s00239-009-9202-0. PMC 2752406. PMID 19365646.
  9. ↑ Huang QQ, Jin JP (Dec 1999). "Preserved close linkage between the genes encoding troponin I and troponin T, reflecting an evolution of adapter proteins coupling the Ca(2+) signaling of contractility". Journal of Molecular Evolution. 49 (6): 780–8. Bibcode:1999JMolE..49..780H. doi:10.1007/pl00006600. PMID 10594179.
  10. ↑ Gahlmann R, Troutt AB, Wade RP, Gunning P, Kedes L (Nov 1987). "Alternative splicing generates variants in important functional domains of human slow skeletal troponin T". The Journal of Biological Chemistry. 262 (33): 16122–6. PMID 2824479.
  11. ↑ 11.0 11.1 Huang QQ, Chen A, Jin JP (Mar 1999). "Genomic sequence and structural organization of mouse slow skeletal muscle troponin T gene". Gene. 229 (1–2): 1–10. doi:10.1016/s0378-1119(99)00051-7. PMID 10095098.
  12. ↑ 12.0 12.1 Larsson L, Wang X, Yu F, Höök P, Borg K, Chong SM, Jin JP (Sep 2008). "Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease". American Journal of Physiology. Cell Physiology. 295 (3): C722–31. doi:10.1152/ajpcell.00110.2008. PMC 2544436. PMID 18579801.
  13. ↑ Johnston JJ, Kelley RI, Crawford TO, Morton DH, Agarwala R, Koch T, Schäffer AA, Francomano CA, Biesecker LG (Oct 2000). "A novel nemaline myopathy in the Amish caused by a mutation in troponin T1". American Journal of Human Genetics. 67 (4): 814–21. doi:10.1086/303089. PMC 1287886. PMID 10952871.
  14. ↑ Jin JP, Brotto MA, Hossain MM, Huang QQ, Brotto LS, Nosek TM, Morton DH, Crawford TO (Jul 2003). "Truncation by Glu180 nonsense mutation results in complete loss of slow skeletal muscle troponin T in a lethal nemaline myopathy". The Journal of Biological Chemistry. 278 (28): 26159–65. doi:10.1074/jbc.M303469200. PMID 12732643.
  15. ↑ 15.0 15.1 15.2 Jin JP, Chong SM (Aug 2010). "Localization of the two tropomyosin-binding sites of troponin T". Archives of Biochemistry and Biophysics. 500 (2): 144–50. doi:10.1016/j.abb.2010.06.001. PMC 2904419. PMID 20529660.
  16. ↑ Martin AF (Jan 1981). "Turnover of cardiac troponin subunits. Kinetic evidence for a precursor pool of troponin-I". The Journal of Biological Chemistry. 256 (2): 964–8. PMID 7451483.
  17. ↑ 17.0 17.1 Feng HZ, Wei B, Jin JP (Nov 2009). "Deletion of a genomic segment containing the cardiac troponin I gene knocks down expression of the slow troponin T gene and impairs fatigue tolerance of diaphragm muscle". The Journal of Biological Chemistry. 284 (46): 31798–806. doi:10.1074/jbc.M109.020826. PMC 2797250. PMID 19797054.
  18. ↑ Wei B, Lu Y, Jin JP (Mar 2014). "Deficiency of slow skeletal muscle troponin T causes atrophy of type I slow fibres and decreases tolerance to fatigue". The Journal of Physiology. 592 (Pt 6): 1367–80. doi:10.1113/jphysiol.2013.268177. PMC 3961093. PMID 24445317.
  19. ↑ Marra JD, Engelstad KE, Ankala A, Tanji K, Dastgir J, De Vivo DC, Coffee B, Chiriboga CA (May 2015). "Identification of a novel nemaline myopathy-causing mutation in the troponin T1 (TNNT1) gene: a case outside of the old order Amish". Muscle & Nerve. 51 (5): 767–72. doi:10.1002/mus.24528. PMID 25430424.
  20. ↑ van der Pol WL, Leijenaar JF, Spliet WG, Lavrijsen SW, Jansen NJ, Braun KP, Mulder M, Timmers-Raaijmakers B, Ratsma K, Dooijes D, van Haelst MM (Mar 2014). "Nemaline myopathy caused byTNNT1 mutations in a Dutch pedigree". Molecular Genetics & Genomic Medicine. 2 (2): 134–7. doi:10.1002/mgg3.52. PMC 3960055. PMID 24689076.
  21. ↑ Abdulhaq UN, Daana M, Dor T, Fellig Y, Eylon S, Schuelke M, Shaag A, Elpeleg O, Edvardson S (2015). "Nemaline body myopathy caused by a novel mutation in Troponin T1 (TNNT1)". Muscle Nerve. 53: 564–9. doi:10.1002/mus.24885. PMID 26296490.
  22. ↑ Amarasinghe C, Jin JP (Jun 2015). "N-Terminal Hypervariable Region of Muscle Type Isoforms of Troponin T Differentially Modulates the Affinity of Tropomyosin-Binding Site 1". Biochemistry. 54 (24): 3822–30. doi:10.1021/acs.biochem.5b00348. PMID 26024675.
  23. ↑ Yuasa K, Michibata H, Omori K, Yanaka N (Dec 1999). "A novel interaction of cGMP-dependent protein kinase I with troponin T". The Journal of Biological Chemistry. 274 (52): 37429–34. doi:10.1074/jbc.274.52.37429. PMID 10601315.
  24. ↑ Jin JP, Chen A, Huang QQ (Jul 1998). "Three alternatively spliced mouse slow skeletal muscle troponin T isoforms: conserved primary structure and regulated expression during postnatal development". Gene. 214 (1–2): 121–9. doi:10.1016/s0378-1119(98)00214-5. PMID 9651500.
  25. ↑ Palm T, Graboski S, Hitchcock-DeGregori SE, Greenfield NJ (Nov 2001). "Disease-causing mutations in cardiac troponin T: identification of a critical tropomyosin-binding region". Biophysical Journal. 81 (5): 2827–37. Bibcode:2001BpJ....81.2827P. doi:10.1016/S0006-3495(01)75924-3. PMC 1301748. PMID 11606294.
  26. ↑ Vinogradova MV, Stone DB, Malanina GG, Karatzaferi C, Cooke R, Mendelson RA, Fletterick RJ (Apr 2005). "Ca(2+)-regulated structural changes in troponin". Proceedings of the National Academy of Sciences of the United States of America. 102 (14): 5038–43. Bibcode:2005PNAS..102.5038V. doi:10.1073/pnas.0408882102. PMC 555973. PMID 15784741.

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