Disease relevance of TNNT2

• Mutations of the gene (TNNT2) encoding the thin-filament contractile protein cardiac troponin T are responsible for 15% of all cases of familial hypertrophic cardiomyopathy, the leading cause of sudden death in young athletes [1].
• OBJECTIVES: We performed genetic investigations of cardiac troponin T (TNNT2) and troponin C (TNNC1) in 235 consecutive patients with idiopathic dilated cardiomyopathy (DCM) to evaluate prevalence of mutations and associated disease expression in affected families [2].
• Mutations in the human cardiac troponin T gene (TNNT2) are associated with familial hypertrophic cardiomyopathy (FHC) linked to chromosome 1q3 (CMH2) [3].
• TNNT2 R278C was present in a woman with severe HC, but a sister and a daughter were mutation carriers and did not have hypertrophy [4].
• BACKGROUND: Mutations in the cardiac beta-myosin heavy chain (MYH7) and cardiac troponin T (TNNT2) genes are reportedly responsible for up to 40% of familial cases with hypertrophic cardiomyopathy (HC) [4].

Psychiatry related information on TNNT2

• Certainly, cTnT measurement can be incorporated into a clinical decision-making strategy to assign patients to investigation and management pathways [5].

High impact information on TNNT2

• TNNT2 mutations can also lead to dilated cardiomyopathy, a leading cause of heart failure [1].
• CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy [6].
• CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI) [6].
• RESULTS--Sensitivity of the rapid cTnT assay increased from 33% within 2 hours from the onset of chest pain to 86% after 8 hours (P < .001); specificity ranged from 86% to 100% during the same time intervals [7].
• PATIENTS--A cohort of 100 patients admitted for evaluation of chest pain who had sufficient blood samples at presentation for measurement of creatine kinase, creatine kinase MB fraction, and rapid cTnT as well as adequate clinical data to establish the diagnosis of MI [7].

Chemical compound and disease context of TNNT2

• In contrast, a missense mutation R94L in the vicinity of the strong tropomyosin-binding region associated with hypertrophic cardiomyopathy (HCM) resulted in an increase in the Ca(2+) sensitivity of force generation, as in the case of the other HCM-causing mutations in cTnT reported previously [8].
• Biochemical markers, including total creatine kinase (total CK), creatine kinase-MB (CK-MB), the MB isoforms, and myoglobin, as well as the troponins--cardiac troponin T (cTnT) and cardiac troponin I (cTnI)--are all used for assessment of the suspected acute myocardial infarction (AMI) patient [9].
• Addition of heparin ( approximately 100 IU/mL) to serial samples from nine acute myocardial infarction patients produced mean cTnT losses of 33% at 1-12 h after onset of chest pain, 17% at 13-48 h, and 7% after 48 h [10].
• This study compared troponin I (cTnI) to troponin T (cTnT) in a population admitted to General Medicine Divisions in whom acute myocardial infarction (AMI) was suspected; 98 consecutive patients were included [11].
• CONCLUSIONS: We found no clinically significant cardiac toxicity from the use of intravenous terbutaline for severe asthma as measured by serum cTnT elevations [12].

Biological context of TNNT2

• Because mutational hot spots offer unique possibilities for analysis of genotype-phenotype correlations, new missense mutations that could define such hot spots in TNNT2 were looked for in unrelated French families with familial hypertrophic cardiomyopathy [13].
• We characterized the genomic structure of 15 TNNT2 exons spliced into the adult isoform [3].
• The disease expression associated with TNNC1 and TNNT2 mutations was severe with complete penetrance [2].
• Three polymorphic short tandem repeat elements (D1S477, D1S2622, and D1S1723), useful for FHC pedigree analyses at CMH2, were shown to be physically tightly linked to TNNT2 [3].
• Currently it is not possible to predict the phenotype in carriers of mutations in these genes, although it is widely accepted that mutations in the MYH7 gene predispose to severe HC, whereas TNNT2 mutations are frequently linked to sudden cardiac death (SCD) in spite of minimal hypertrophy [4].

Anatomical context of TNNT2

• Hybridization of the cloned cDNAs to genomic DNA identifies a single-copy gene, and using somatic cell hybrid analysis, we have mapped the corresponding gene locus (designated TNNT2) to the long arm of chromosome 1 (1cen-qter) [14].
• We have previously cloned the first human cardiac troponin T (cTnT) cDNA and showed the differential expression of cTnT in cardiac and skeletal muscle during ontogenic development [15].
• In this work we located the human cTnT gene by means of fluorescent in situ hybridization to 1q32 and, by sequencing thirteen cDNAs isolated from a human fetal heart cDNA library, identified three new isoforms resulting from specific combinations of three variable regions in human cTnT cDNA [15].
• The average soluble cTnT and cTnI pools in right atrial appendages of 11 patients with right atrial and right ventricular pressures within reference values were comparable and were approximately 8% of total myocardial troponin content [16].
• However, the studies on cardiac troponin T (cTnT) which is more sensitive and specific to myocardium after stroke are relatively scarce [17].

Associations of TNNT2 with chemical compounds

• In occasional heparin-plasma samples immunochemical measurement of cTnT may give exceptionally low values [18].
• We have investigated the utility of myoglobin, creatine kinase (CK)-MB isoforms and creatine kinase MB mass (CK-MBm) in early diagnosis of MI using cardiac troponin T (cTnT) positivity as a reference [19].
• Specificity for cTnT was 96% [78-100] in patients with renal impairment (creatinine > 150 mumol/l), 95% [75-100] in continuous ambulatory peritoneal dialysis patients, but in hemodialysis patients it was 75% [53-92] for short-term hemodialysis (< 1 year) and 46% [24-68] for long-term hemodialysis (> 1 year) [20].
• A mutation was identified in exon 11 and is predicted to substitute a phenylalanine-for-serine mutation at residue 179 (Ser(179)Phe) in cTnT [21].
• However, the TnI isoforms had greater effects on the Ca(2+) dissociation rate of site II than the cTnT isoforms [22].

Physical interactions of TNNT2

• This study was initiated with exons 9 and 11 of TNNT2 because of their crucial role in the binding ability of cardiac troponin T to alpha-tropomyosin, and continued with analyses in other regions of the gene [23].

Enzymatic interactions of TNNT2

• Together with the observations that cTnI is a good substrate for cGK I and is effectively phosphorylated in the presence of cTnT in vitro, these findings suggest that TnT functions as an anchoring protein for cGK I and that cGK I may participate in the regulation of muscle contraction through phosphorylation of TnI [24].

Regulatory relationships of TNNT2

• Pretreatment of the heparin plasma samples either with heparinase or protamine cannot completely reverse the heparin-induced decrease in cTnT and cTnI levels and therefore addition of these reagents to the commercial test systems could not significantly improve the performance of the assay [25].

Other interactions of TNNT2

• In MYH7 vs. TNNT2, mean age at diagnosis was late (P<0.03), penetrance was incomplete in adults (56 vs. 100%), and mean age at major cardiac event was higher (P<0.04) [26].
• The reverse-transcribed cDNAs were amplified by PCR using oligonucleotide primers specific for cTnT, sTnT, and cTnI sequences (GenBank accession numbers X74819, m19308, and X54163, respectively) [27].
• On admission serum myoglobin, and cardiac troponin T (cTnT) were measured [28].
• These results suggested that MYH7 and MYBPC3 were the predominant genes responsible for HCM, and TNNT2 mutation less proportionally contributed to Chinese HCM [29].
• BACKGROUND: Genotype-phenotype correlative studies have implicated 8 particular mutations that cause hypertrophic cardiomyopathy (HCM) as "benign defects," associated with near-normal survival: N232S, G256E, F513C, V606M, R719Q, and L908V of beta-myosin heavy chain (MYH7); S179F of troponin T (TNNT2); and D175N of alpha-tropomyosin (TPM1) [30].

Analytical, diagnostic and therapeutic context of TNNT2

• METHODS: Comprehensive screening of MYBPC3, MYH7 and TNNT2 was performed in 88 unrelated HCM patients by denaturing high-performance liquid chromatography and automatic sequencing [31].
• However, no cTnI mRNA expression was found in healthy or diseased skeletal muscle specimens. cTnT mRNA expression in both heart and diseased skeletal muscles corresponded with cTnT isoform expression, respectively, as determined by Western blot analysis [27].
• The odds ratio for the development of acute graft failure after heart transplantation was 42.7 for donors with cTnI >1.6 microg/L and 56.9 for donors with cTnT >0.1 microg/L [32].
• Three main regions of alternative splicing within the cTnT coding region were identified using reverse-transcriptase polymerase chain reaction (RT-PCR) [33].
• In the peroperative and postoperative period all classical markers were elevated, in contrast to cTnI and cTnT, because of the concomitant skeletal muscle damage [34].

References