The strongman trait: clinical and molecular characterization of a dominant herculean myalgic disorder
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».