RANGRF and Brugada Syndrome

RANGRF, which encodes the MOG1 protein, has been proposed as a susceptibility factor for Brugada syndrome, an autosomal dominant cardiac arrhythmia disorder associated with sudden cardiac death. Multiple case reports and family studies have identified rare variants in RANGRF; however, the overall genetic evidence remains inconclusive. In one Spanish family, a nonsense variant was detected in the index case and five additional relatives, yet baseline electrocardiograms were normal in most and flecainide challenge was required to unmask diagnostic features (PMID:24142675).

Genetic investigations have reported a coding variant, specifically c.249G>C (p.Glu83Asp), in a symptomatic patient with Brugada syndrome, supporting a potential gene‐disease link despite its rarity (PMID:21447824). The variant spectrum overall is limited, and segregation data remains sparse, with only a single family exhibiting borderline cosegregation. This limited genetic evidence challenges definitive pathogenic interpretation.

The disorder follows an autosomal dominant inheritance pattern, as evidenced by the family studies, where five additional affected relatives were identified. However, the incomplete penetrance and variable expressivity observed in carriers complicate clinical interpretation and underscore the need for cautious diagnostic decision‑making.

Beyond the genetic data, several functional studies have investigated the molecular role of MOG1 in cardiac physiology. These studies demonstrate that MOG1 is crucial for the proper trafficking and function of the cardiac sodium channel Nav1.5. Functional assays, including co‐immunoprecipitation and electrophysiologic recordings, reveal that disruptions in MOG1–Nav1.5 interactions can lead to decreased sodium current density, thereby providing moderate support for a mechanistic role in arrhythmogenesis (PMID:34843967; PMID:11509570).

Despite the supportive functional data, the genetic evidence remains limited, and the reported variants do not consistently segregate with disease phenotype in affected families. This dichotomy indicates that while MOG1 is mechanistically plausible as a contributor to Brugada syndrome pathogenesis, additional studies and larger cohorts are necessary to firmly establish its diagnostic utility.

Key take‑home: Although functional assays validate an important role for MOG1 in sodium channel regulation, the current genetic evidence supporting a causative association of RANGRF with Brugada syndrome is limited, and further studies are warranted before this gene can be routinely used for clinical diagnosis.

References

• Cardiology journal • 2014 • Brugada syndrome and p.E61X_RANGRF PMID:24142675
• Circulation. Cardiovascular genetics • 2011 • MOG1: a new susceptibility gene for Brugada syndrome PMID:21447824
• Heart rhythm • 2022 • Mechanistic insights into the interaction of cardiac sodium channel Nav1.5 with MOG1 and a new molecular mechanism for Brugada syndrome PMID:34843967
• The Journal of biological chemistry • 2001 • Interaction between Ran and Mog1 is required for efficient nuclear protein import PMID:11509570

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