Endogenous expression of mutant RagC in mice results in early-onset dilated cardiomyopathy with features of the Long-Olsen-Distelmaier syndrome

Endogenous heterozygous expression of mutant Rragc in mice causes early-onset dilated cardiomyopathy with decreased heart size, fibrosis, diastolic dysfunction, and aortic insufficiency.

• Why it matters: Long-Olsen-Distelmaier syndrome linked to de novo RRAGC mutations lacks a mammalian model to test how nutrient–Rag GTPase signaling drives early, severe cardiac disease.
• What they did: Mice engineered to express Rragc mutations orthologous to patient Serine 75 (Serine 74 in mice) were assessed for cardiac structure/function, then analyzed for RagC–TFEB transcriptional effects and neonatal mitochondrial signatures.
• The result: Mutant hearts show suppressed Tfeb transcriptional activity, impaired mitochondrial respiration, and disturbed complex IV multimerization/super-complex organization, supporting early postnatal metabolic dysfunction as a mechanism and rationale for early metabolic interventions.

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