Diseases caused by nuclear genes affecting mtDNA stability

Am J Med Genet. Spring 2001;106(1):53-61. doi: 10.1002/ajmg.1379.


Diseases caused by nuclear genes that affect mitochondrial DNA (mtDNA) stability are an interesting group of mitochondrial disorders, involving both cellular genomes. In these disorders, a primary nuclear gene defect causes secondary mtDNA loss or deletion formation, which leads to tissue dysfunction. Therefore, the diseases clinically resemble those caused by mtDNA mutations, but follow a Mendelian inheritance pattern. Several clinical entities associated with multiple mtDNA deletions have been characterized, the most frequently described being autosomal dominant progressive external ophthalmoplegia (adPEO). MtDNA depletion syndrome (MDS) is a severe disease of childhood, in which tissue-specific loss of mtDNA is seen. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or mtDNA depletion. Recent reports of thymidine phosphorylase mutations in MNGIE and adenine nucleotide translocator mutations in adPEO have given new insights into the mechanisms of mtDNA maintenance in mammals. The common mechanism underlying both of these gene defects could be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. Future studies on MNGIE and adPEO pathogenesis, and identification of additional gene defects in adPEO and MDS will provide further understanding about the mammalian mtDNA maintenance and the crosstalk between the nuclear and mitochondrial genomes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Blotting, Southern
  • Cell Nucleus / metabolism*
  • DNA / genetics*
  • DNA, Mitochondrial / genetics*
  • Gene Deletion
  • Humans
  • Mitochondrial Diseases / diagnosis*
  • Mitochondrial Diseases / genetics*
  • Models, Biological
  • Muscles / cytology
  • Muscles / ultrastructure


  • DNA, Mitochondrial
  • DNA