Summary
A medRxiv preprint identifies a MYOF missense variant associated with arrhythmogenic cardiomyopathy and describes a calcium-handling mechanism in patient-derived heart cells and mice. The findings point to the MYOF–CaV1.2 pathway as a potential therapeutic target, but remain preclinical.
A medRxiv preprint reports that a variant in MYOF, the gene encoding the calcium-binding protein myoferlin, can cause arrhythmogenic cardiomyopathy (ACM). The researchers identified the same heterozygous missense variant, p.G1654S, in one ACM family and three unrelated cases, then connected it to abnormal calcium handling and a higher burden of arrhythmias in patient-derived heart cells.
The study also found related disease features in mice with one disrupted copy of Myof. In the patient-derived cells, the arrhythmias were rescued by the calcium-channel drug verapamil, identifying the MYOF–CaV1.2 pathway as a possible therapeutic target. The report is a preprint, and its treatment implications remain at the laboratory stage.
A different genetic route to arrhythmogenic cardiomyopathy
ACM is an inherited heart-muscle disease associated with fibrofatty remodelling and sudden cardiac death. It is often linked to defects in desmosomes, the protein structures that help neighbouring heart-muscle cells attach to one another. The researchers note that around 40% of ACM cases remain genetically unexplained, creating a need to investigate genes outside the desmosomal system.
Whole-exome sequencing led the team to the p.G1654S change in MYOF. The variant was found in an ACM family and subsequently in three unrelated cases. Myoferlin is involved in cardiomyocytes, the muscle cells that contract to pump blood, but its role in ACM had not been defined in the report's starting model.
The researchers propose that the variant disrupts myoferlin function by causing the altered protein to pair with normal myoferlin and undergo accelerated breakdown in lysosomes, cellular compartments involved in protein degradation. This reduced myoferlin activity was associated with impaired handling of calcium ions inside the heart cells.
Calcium signals are central to each heartbeat: changes in calcium concentration help initiate and regulate contraction. The study found that myoferlin interacts with CaV1.2, a voltage-gated calcium channel that helps calcium enter cardiomyocytes. Disruption of this interaction was associated with a higher arrhythmia burden in the patient-derived cells.
Evidence from patient-derived cells and mice
The team generated cardiomyocytes from induced pluripotent stem cells carrying the patient variant. These cells showed altered myoferlin stability, disrupted calcium handling and increased arrhythmic activity. Correcting the MYOF variant at the genomic level rescued the reported cellular abnormalities, strengthening the link between p.G1654S and the observed phenotype.
The researchers also examined heterozygous Myof knockout mice, which have one functional and one disrupted copy of the gene. These animals developed systolic dysfunction, meaning reduced pumping performance, together with cardiac fibrosis. The mouse findings provide an in-vivo model consistent with the abnormalities seen in the engineered human heart cells.
Verapamil pharmacologically rescued the arrhythmias in the patient-derived cardiomyocytes. This result supports the study's proposed mechanism and makes CaV1.2 a candidate target for further investigation. It does not constitute evidence that verapamil treats MYOF-associated ACM in people: the supplied report describes cell and mouse experiments rather than a human treatment trial.
The work therefore adds MYOF to the genetic and mechanistic landscape of ACM while connecting the gene to calcium-channel regulation rather than only to structural cell adhesion. The report is a medRxiv preprint, and the abstract does not provide the full experimental sample sizes or quantitative effect estimates needed to assess the strength and reproducibility of each result.