Homozygous c.820G>A variant in MGME1 contributes to multi-systemic mitochondrial dysfunction in an Indian patient cohort

Mitochondrial DNA (mtDNA) maintenance disorders arise from defects in mtDNA replication or repair, frequently resulting in extensive deletions or depletion of mtDNA. Mitochondrial genome maintenance exonuclease 1 (MGME1) is a nuclear-encoded nuclease essential for mtDNA replication and genome stability, and biallelic pathogenic variants in MGME1 cause mitochondrial DNA depletion syndrome 11. Here, we report a novel homozygous MGME1 missense variant c.820G>A (p. Ala274Thr) in five affected individuals from unrelated South Indian families presenting with proximal myopathy, chronic progressive external ophthalmoplegia, and cardiac and renal involvement. Patient-derived cells exhibited a significant reduction in mtDNA copy number, consistent with impaired mtDNA maintenance. Mechanistic analyses combining imaging-based and biochemical approaches demonstrated that the MGME1 variant disrupts both mtDNA replication and repair. Functional characterization further revealed defective oxidative phosphorylation and reduced mitochondrial membrane potential, confirming mitochondrial dysfunction. Collectively, our findings establish the pathogenicity of this novel MGME1 variant and expand the clinical and molecular spectrum of MGME1-associated mitochondrial disease, linking impaired mtDNA replication to multisystemic mitochondrial dysfunction. Graphical abstract summarySchematic overview of mitochondrial DNA (mtDNA) replication in wild-type and MGME1 mutant conditions. In wild-type cells, the coordinated activity of the mitochondrial replication machinery (TWNK, POLG, LIG3, TFAM, and MGME1) maintains mtDNA integrity and supports normal oxidative phosphorylation and ATP production. In contrast, the MGME1 mutation disrupts mtDNA replication and processing, leading to replication defects, mtDNA depletion, and mitochondrial dysfunction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/725852v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@50187forg.highwire.dtl.DTLVardef@78799borg.highwire.dtl.DTLVardef@177e7c6org.highwire.dtl.DTLVardef@1118c68_HPS_FORMAT_FIGEXP M_FIG C_FIG