Dominant rhabdomyolysis linked to a recurrent <i>ATP2A2</i> variant reducing SERCA2 function in muscle
Bibliographic record
Abstract
Rhabdomyolysis is an acute failure of cellular homeostasis resulting in muscle breakdown, triggered by trauma, infection, drugs or strenuous exercise. Recurrent rhabdomyolysis is often associated with genetic and metabolic defects of skeletal muscle. The sarcoendoplasmic reticulum Ca2+-ATPase 2 (SERCA2), encoded by the ATP2A2 gene, is an intracellular pump located in the sarcoplasmic and endoplasmic reticulum that is essential for maintaining intracellular calcium (Ca2+) homeostasis and is highly expressed in slow-twitch muscle. Heterozygous loss-of-function variants in ATP2A2 have previously been associated with dominant skin diseases, but not with rhabdomyolysis. In this study, we report a rare novel heterozygous missense variant in the ATP2A2 gene (c.1583G>A, p.R528Q) identified in 14 affected individuals from three unrelated families with recurrent rhabdomyolysis. Muscle biopsy revealed mild myopathic changes with fibre type uniformity, core-like structures and Z-band streaming, but normal levels of SERCA2 protein. Ca2+ imaging showed that sarcoplasmic reticulum Ca2+ reuptake mediated by SERCA was significantly slower in myotubes derived from patient fibroblasts carrying the c.1583G > A variant. We hypothesize that the ATP2A2 variant impairs SERCA2a function in slow-twitch muscle, disrupting SR Ca2+ reuptake and causing cytosolic Ca2+ overload following a trigger, leading to recurrent rhabdomyolysis. Morphant zebrafish embryos with atp2a2a knockdown showed morphological and functional muscle abnormalities, with a reduction in body length and trunk muscle area associated with a reduction in locomotor activity in zebrafish larvae. Co-injection of wild-type human SERCA2a mRNA, but not variant SERCA2a mRNA, resulted in complete rescue of the phenotype. This study reveals a novel association between a heterozygous ATP2A2 variant and autosomal dominant recurrent rhabdomyolysis. Both in vitro and in vivo studies provide evidence that the variant alters SERCA2 function, causing abnormal intracellular Ca2+ homeostasis in skeletal muscle, resulting in rhabdomyolysis. The work not only increases understanding of autosomal dominant rhabdomyolysis but also provides a diagnostic conclusion for three generations of affected individuals across the three families.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".