Inherited mitochondrial diseases of DNA replication

Abstract

Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17.

Figure 1

Schematic diagram of human pol γ protein showing locations of disease-causing amino acid substitutions and polymorphisms. The protein is arranged with the exonuclease domain in the first third, followed by a long linker region, with the polymerase domain in the C-terminal third. The disease substitutions are represented by boxes: Light blue boxes, autosomal dominant PEO; light green boxes, autosomal recessive mutations; gray boxes, sporadic PEO; pink boxes, Alpers syndrome; yellow boxes, ataxia-neuropathy-like syndromes; and orange boxes, male infertility. Striped boxes represent disease substitutions found in more than one disease. Red arrows depict the nonsynonymous polymorphic amino acid changes.

Figure 2

Schematic diagram of the mitochondrion, showing enzyme pathways that cause mtDNA mutations or depletion when disrupted. Gene products associated with MDS or mtDNA mutations are in green boxes.