A loss-of-function mutation in the GTPase domain of MFN2, perverting mitochondrial dynamics, is associated with dilated cardiomyopathy

The p.Asn311Ser missense variant in the GTPase domain of MFN2 distorts mitofusin 2 conformation, weakens its interaction with PRKN and impairs mitophagy, causing mitochondrial fragmentation, reduced membrane potential, ATP production and oxygen consumption, with elevated cytosolic calcium and reactive oxygen species.

The authors screened MFN2 by whole-exome sequencing in 15 patients with dilated cardiomyopathy (5 familial and 10 sporadic cases). A rare de novo variant, c.932A>G (p.Asn311Ser), was identified in one patient, absent from 100 healthy controls, 1000 Genomes and IndiGenomes, with a very low frequency in gnomAD (0.0000081). Structural modelling predicted a highly deleterious effect with marked conformational distortion (RMSD = 8.95 Å), and molecular docking showed weakened interaction with PRKN, suggesting defective mitophagy. In stable H9c2 cardiomyoblast lines, the mutant protein was expressed at lower levels and was associated with mitochondrial clustering and fragmentation, reduced membrane potential, ATP production and oxygen consumption rate, together with increased cytosolic calcium and reactive oxygen species, activation of PI3K/AKT/mTOR signalling and overexpression of the hypertrophic markers Myh6, Nppa, Nfatc1 and Nfatc2.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The functional work is coherent and covers several converging axes, but it rests on a single patient and a non-human-cardiomyocyte cell line: this is a mechanistic argument, not a demonstration of association between MFN2 and dilated cardiomyopathy. In practice, MFN2 is already covered by any exome or genome ordered for cardiomyopathy, and the real question is annotation — whether to accept an isolated cardiac phenotype for a gene so far read through the Charcot-Marie-Tooth lens. I would therefore keep this as a variant of uncertain significance with functional support, pending further independent cases and the peer-reviewed version of this preprint.

Analysis by Dr Thibaut Benquey