Familial hypertrophic cardiomyopathy-related cardiac troponin C mutation L29Q affects Ca<sup>2+</sup>binding and myofilament contractility
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Bibliographic record
Abstract
The cardiac troponin C (cTnC) mutation, L29Q, has been found in a patient with familial hypertrophic cardiomyopathy. We previously showed that L29, together with neighboring residues, Asp2, Val28, and Gly30, plays an important role in determining the Ca(2+) affinity of site II, the regulatory site of mammalian cardiac troponin C (McTnC). Here we report on the Ca(2+) binding characteristics of L29Q McTnC and D2N/V28I/L29Q/G30D McTnC (NIQD) utilizing the Phe(27) --> Trp (F27W) substitution, allowing one to monitor Ca(2+) binding and release. We also studied the effect of these mutants on Ca(2+) activation of force generation in single mouse cardiac myocytes using cTnC replacement, together with sarcomere length (SL) dependence. The Ca(2+)-binding affinity of site II of L29Q McTnC(F27W) and NIQD McTnC(F27W) was approximately 1.3- and approximately 1.9-fold higher, respectively, than that of McTnC(F27W). The Ca(2+) disassociation rate from site II of L29Q McTnC(F27W) and NIQD McTnC(F27W) was not significantly different than that of control (McTnC(F27W)). However, the rate of Ca(2+) binding to site II was higher in L29Q McTnC(F27W) and NIQD McTnC(F27W) relative to control (approximately 1.5-fold and approximately 2.0-fold respectively). The Ca(2+) sensitivity of force generation was significantly higher in myocytes reconstituted with L29Q McTnC (approximately 1.4-fold) and NIQD McTnC (approximately 2-fold) compared with those reconstituted with McTnC. Interestingly, the change in Ca(2+) sensitivity of force generation in response to an SL change (1.9, 2.1, and 2.3 mum) was significantly reduced in myocytes containing L29Q McTnC or NIQD McTnC. These results demonstrate that the L29Q mutation enhances the Ca(2+)-binding characteristics of cTnC and that when incorporated into cardiac myocytes, this mutant alters myocyte contractility.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it