PT  - JOURNAL ARTICLE
AU  - Zaman, Mashiat
AU  - Sharma, Govinda
AU  - Almutawa, Walaa
AU  - Soule, Tyler GB
AU  - Sabouny, Rasha
AU  - Joel, Matt
AU  - Mohan, Armaan
AU  - Chute, Cole
AU  - Joseph, Jeffrey T
AU  - Pfeffer, Gerald
AU  - Shutt, Timothy E
TI  - The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation
AID  - 10.26508/lsa.202402921
DP  - 2025 Jun 01
TA  - Life Science Alliance
PG  - e202402921
VI  - 8
IP  - 6
4099  - http://www.life-science-alliance.org/content/8/6/e202402921.short
4100  - http://www.life-science-alliance.org/content/8/6/e202402921.full
SO  - Life Sci. Alliance2025 Jun 01; 8
AB  - Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient’s pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient’s myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.