O.24 Loss of function of MGME1, a novel player in mitochondrial DNA replication, causes a distinct autosomal recessive mitochondrial disorder

Mutations in genes involved in mitochondrial DNA (mtDNA) replication result in two molecular phenotypes of mitochondrial disorders, multiple mtDNA deletion and/or depletion syndromes, known collectively as mtDNA maintenance disorders. Disease mechanisms alter either the mtDNA replication machinery or the biosynthesis pathways of deoxyribonucleotides. We identified loss-of-function mutations in the orphan gene C20orf72, renamed as MGME1 (mitochondrial genome maintenance exonuclease 1), in 6 patients from 3 families originating from Lebanon, Italy, and Germany. The clinical phenotypes were almost identical and included upper eyelid ptosis, mild progressive external ophthalmoplegia, exercise intolerance, proximal and axial muscular weakness, muscle wasting, and profound emaciation. Intriguingly, all patients developed dyspnea, and respiratory failure usually required non-invasive ventilation. Cerebellar atrophy, gastrointestinal dysfunction, mental retardation, and cardiomyopathy were additional common symptoms. Muscle biopsies showed few ragged red and COX-negative fibers, respiratory chain dysfunction, multiple mtDNA deletions and mtDNA depletion. Furthermore, MGME1 mutations resulted in increased 7S DNA levels in patients‘ muscle and fibroblasts, which was also evident in MGME1-depleted cells. Patient fibroblasts failed to repopulate upon induced mtDNA depletion and accumulated replication intermediates similar to MGME1-depleted cells. MGME1 encodes a mitochondrial RecB-type exonuclease belonging to the PD-(D/E) XK nuclease superfamily. MGME1 preferentially cleaves single-stranded DNA with free 5′ DNA ends and processes flap-like substrates that contain RNA at the displaced 5′ arm thus resembling Okazaki fragments. In conclusion, MGME1 mutations affect mtDNA maintenance and result in a distinct mitochondrial disorder. MGME1 is the first identified mitochondrial exonuclease shown to be involved in replication and might play an additional role in mtDNA repair.