The strongman trait: clinical and molecular characterization of a dominant herculean myalgic disorder
Bibliographic record
Abstract
Herculean strength has always fascinated humans. Several studies have suggested that muscular strength is a trait proposing that genetic factors contribute to the development of an increased strength phenotype. Most male French-Canadian settlers that came to Quebec during the French Regime (1608-1760) were soldiers chosen by merchants for their strength. This may have influenced the relative increase in carrier frequencies of certain alleles related to muscle strength that have been passed down through generations in Quebec. We recruited several French-Canadian families with individuals presenting a muscle disorder that we have called the Strongman trait (ST). Affected individuals present with a familial and personal history of superior strength, which is accompanied by myalgia, prolonged contractions and weakness after repetitive contractions as negative symptoms, and superior muscle strength and mass as positive findings. We identified an autosomal dominant mutation segregating in two families in an uncharacterized gene called DC-STAMP Domain Containing 2 (DCST2). By further exploring the function of DCST2, we found that it is localized to the sarcoplasmic reticulum (SR) and forms puncta that lie juxtaposed to the transverse-tubules (TT) in the I-band. We observed that DCST2 formed larger puncta in the muscle of a ST patient and it often colocalized with stromal interaction molecule 1 (STIM1) and ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 (SERCA1), a finding that was rarely observed in control muscles. We performed an unbiased approach through a proximity biotinylation (BioID) assay to identify some DCST2’s proximity interactors. Several proteins of the endoplasmic reticulum (ER) were identified as well as important proteins involved with cellular calcium handling. Two of the proteins involved with calcium handling with the highest scores in the BioID were STIM1 and coiled-coil domain containing 47 (CCDC47 or calumin). Considering that these two proteins have been described to have important roles as calcium sensors influencing ER calcium replenishing through the store-operated calcium entry (SOCE), we then performed cellular calcium assays to identify if the mutation in DCST2 could have an effect on cellular calcium transients. We observed that ST differentiating myoblasts elicited lower SR calcium release and we confirmed that this effect is probably due to a defective SERCA activity that is unable to properly reuptake calcium ions from the cytosol back to the SR. We also detected lower extracellular calcium entry by measuring calcium-release calcium activated (CRAC) channels activity. This result indicated that STIM1 is partially dysfunctional to allow proper extracellular calcium entry through the CRAC channels. We also detected that ST myoblasts presented a greater number of larger DCST2 puncta and that this number tended to increase when cells were exposed to calcium deficit stress. These larger DCST2 puncta also contained STIM1 and SERCA1 suggesting that DCST2 is probably involved in the dynamics of STIM1-SERCA1 multi-protein complex formation. DCST2-L759P found in the ST cells appears to lead to an improper complex formation impacting cellular calcium transients. We showed that ST patients that do not carry DCST2 mutations presented overlapping clinical and pathological (larger DCST2 puncta) features as ST patients carrying a DCST2 mutation, underlining that they could be used to support the ST diagnosis in a clinical setting. This thesis presents the original description of the ST phenotype and the identification of its first causal gene while concluding that calcium handling dysfunctions are responsible for this new Herculean myopathy
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 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) | 0.000 | 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 | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".