Molecular Insights into Arrhythmogenic Right Ventricular Cardiomyopathy Caused by Plakophilin-2 Missense Mutations
Bibliographic record
Abstract
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disorder mainly caused by dominant mutations in several components of the cardiac desmosome including plakophilin-2 (PKP2), the most prevalent disease gene. Little is known about the underlying genetic and molecular mechanisms of missense mutations located in the armadillo (ARM) domains of PKP2, as well as their consequences on human cardiac pathology. METHODS AND RESULTS: We focused on in vivo and in vitro studies of the PKP2 founder mutation c.2386T>C (p.C796R), and demonstrated in cardiac tissue from 2 related mutation carriers a patchy expression pattern ranging from unchanged to totally absent immunoreactive signals of PKP2 and other desmosomal proteins. In vitro expression analysis of mutant PKP2 in cardiac derived HL-1 cells revealed unstable proteins that fail to interact with desmoplakin and are targeted by degradation involving calpain proteases. Bacterial expression, crystallization, and structural modeling of mutated proteins impacting different ARM domains and helices of PKP2 confirmed their instability and degradation, resulting in the same remaining protein fragment that was crystallized and used to model the entire ARM domain of PKP2. CONCLUSIONS: The p.C796R and other ARVC-related PKP2 mutations indicate loss of function effects by intrinsic instability and calpain proteases mediated degradation in in vitro model systems, suggesting haploinsufficiency as the most likely cause for the genesis of dominant ARVC due to mutations in PKP2.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".