Disease relevance of Tnnt2

• A hcTnT isoform, hcTnT(1), expressed during development and in heart disease but not in the normal adult heart, was expressed in transgenic (TG) mice (1-30% of total cTnT) [1].
• Patients with cTnT mutations generally exhibit mild or no hypertrophy, but a high frequency of sudden death at an early age [2].
• BACKGROUND: Transgenic mouse models expressing a missense mutation (R92Q) or a splice donor site mutation (trunc) in the cardiac troponin T (cTnT) model familial hypertrophic cardiomyopathy (FHC) in humans [3].
• Unlike mutations in the beta-MyHC gene, the prognostic significance of which reflect their hypertrophic expressivity, cTnT mutations are associated with a mild degree of hypertrophy, but a high incidence of sudden cardiac death [4].
• To test whether the predicted alterations in thin filament structure could lead to distinct cardiomyopathies in vivo, we developed transgenic mouse models expressing either the Arg-92-Trp or Arg-92-Leu cTnT proteins in the heart [5].

Psychiatry related information on Tnnt2

• These results support the hypothesis that cTnT isoform amino-terminal differences affect myofilament function and suggest that hcTnT(1) expression levels present during human development and in human heart disease can affect in vivo ventricular function [1].

High impact information on Tnnt2

• Unexpectedly, in addition to loss of Tnnt2 expression in sih mutant hearts, we observed a significant reduction in Tpma and Tnni3, and consequently, severe sarcomere defects [6].
• The thin filament protein cardiac troponin T (cTnT) is an important regulator of myofilament activation [7].
• Here we report a significant change in cardiac energetics in transgenic mice bearing the missense mutation R92Q within the tropomyosin-binding domain of cTnT, a mutation associated with a clinically severe form of familial hypertrophic cardiomyopathy [7].
• This functional domain of cTnT has recently been shown to be a crucial modulator of contractile function despite the fact that it does not directly interact with the ATP hydrolysis site in the myosin head [7].
• Multiple mutations in cardiac troponin T (cTnT) can cause familial hypertrophic cardiomyopathy (FHC) [8].

Biological context of Tnnt2

• No differences in isoform expression of tropomyosin, myosin heavy chain, essential and regulatory myosin light chains (MLC), TnI, or in posttranslational modifications of mouse cTnT, cTnI, or regulatory MLC were observed [1].
• In transgenic mice, expression of a LacZ gene driven by a rat cTnT promoter (-497 to +192 bp) was very similar to that of the endogenous cTnT gene, suggesting that this promoter contained regulatory elements sufficient for the control of tissue-specific cTnT expression during development [9].
• Our data provide the first evidence that ROCK-II phosphorylation of the Tn complex, most likely at cTnT, has an important role in functional effects of signaling through the Rho-A pathway [10].
• Sequencing data from the large sample of independent cDNAs demonstrated relationships among the expression of four alternatively-spliced exons of the cardiac TnT gene, producing seven classes of cDNAs encoding four protein isoforms differing in two variable regions [11].
• Transgenes were constructed by placing wild-type (R(92)) or mutant (Q(92)) full-length human cTnT cDNAs 3' into a 5.5-kb murine [alpha -myosin heavy chain (MyHC)] promoter injected into fertilized zygotes [12].

Anatomical context of Tnnt2

• In addition to a strong expression in the developing heart beginning at day 7.5 p.c (postcoitum), the cTnT transcript was detected at later stages in some skeletal muscles, where beginning at day 11.75 p.c. the fTnT and sTnT genes were also expressed [9].
• Unexpectedly, the cTnT transcript was persistently found in the developing bladder, where presumably smooth muscle is present [9].
• We also formed a complex of either WT cTnI or each of the mutants with cTnC, reconstituted the complex into the cTnT-treated myofibrils, and measured the Mg2+-ATPase activity as a function of pCa [13].
• Similar to a mouse FHC model expressing a truncated cTnT protein, the left ventricles of all R92Q lines are smaller than those of wild-type [8].
• Triton X-100 extraction of cardiac muscle fibers promoted production of the NH(2)-terminal truncated cardiac TnT (cTnT-ND), indicating a myofibril-associated proteolytic activity. mu-Calpain is a myofibril-associated protease and is known to degrade TnT [14].

Associations of Tnnt2 with chemical compounds

• To determine the specific functional effects of the cTnT PKC-dependent phosphorylation sites (Thr197, Ser201, Thr206, and Thr287) we first mutated these residues to glutamate (E) or alanine (A). cTnT was selectively mutated to generate single, double, triple, and quadruple mutants [15].
• This distance was insensitive to reconstitution of cTnI with cardiac troponin T (cTnT), cTnC, or cTnC and cTnT in the absence of bound regulatory Ca(2+) in cTnC [16].

Physical interactions of Tnnt2

• These data provide the first evidence of a significant function of a cTnT-binding domain on cTnI [17].

Other interactions of Tnnt2

• Different from the developmental cardiac TnT switch generated by alternative splicing of a single exon, the fTnT isoform transition is an additive effect of alternative splicing of multiple N-terminal-coding exons, especially exons 4, 8 and fetal that are expressed at higher frequencies in the neonatal than in the adult muscle [18].
• To study the functional consequences of this mutation, we examined a wild type and two I79N-transgenic mouse lines of human cardiac TnT driven by a murine alpha-myosin heavy chain promoter [19].

Analytical, diagnostic and therapeutic context of Tnnt2

• Western blot analysis of human or mouse homogenized muscle specimens showed no evidence for cardiac TnT and cTnI expression, despite strong signals for skeletal muscle troponin isoforms [20].
• We constructed normal (cTnT-Arg92) and mutant (cTnT-Gln92) transgenes, driven by a murine cTnT promoter, and produced three normal and five mutant transgenic lines, which were identified by PCR and Southern blotting [21].
• Here we report a truncated cardiac TnT produced during myocardial ischemia reperfusion [14].
• However, there are only few publications on correlations of cardiac troponin T (cTnT) with pathologically determined infarct size which are flawed by insufficient sample size [22].
• Using the murine coxsackievirus group B3 (CVB3) myocarditis model, the histopathologic findings and virus titers in mouse hearts were compared with the serum cTnT levels measured by ELISA at various time points [23].

References