Mutations in Nuclear Genes Affecting mtDNA Stability

Autosomal dominant progressive external ophthalmoplegia (adPEO) and mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) are diseases caused by defective interplay of the mitochondrial and nuclear genome. Most of the adPEO patients carry mutations in one of three genes: ANT1 (muscle-heart specific isoform of mitochondrial adeni-nenucleotide translocator), Twinkle (mtDNA helicase), or POLG1 (catalytic subunit of mtDNA polymerase) [38]. On the molecular level adPEO is associated with multiple mtDNA mutations [39].AdPEO is clinically characterized by ophthalmoplegia (progressive muscle weakness affecting eye muscle), very often associated with ataxia, hypogonadism, severe depression, endocrine dysfunction, hearing loss, and peripheral neuropathy [39, 40]. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is associated with a loss of thymidine phosphorylase (TP) and is characterized by PEO, severe gastrointestinal syndrome, peripheral neuropathy, leukoen-cephalopathy, and mitochondrial dysfunction. Mitochondrial DNA analysis showed mtDNA deletions, mtDNA depletion, or both [41]. It is interesting to point out that TP is not a mitochondrial protein, and yet its dysfunction specifically affects mitochondrial function and mtDNA integrity.

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