M.I.3 Nuclear genes involved in mitochondrial syndromes

Abstract

Maternally inherited mitochondrial DNA encodes only 13 subunits of the respiratory complexes. All other proteins involved in a functional respiratory chain are nucleus-encoded and imported into mitochondria. Because of the extreme complexity of OXPHOS, the number of candidate disease genes is enormous, and tends to coincide with the size of the mitochondrial proteome itself (>1000 gene products). Important advancements have recently been made in three main areas: (a) defects associated with mtDNA instability; (b) defects of mtDNA translation; (c) defects of coenzyme Q biosynthesis. The first group comprises Mendelian traits characterized by either the accumulation of multiple mtDNA deletions or tissue-specific mtDNA depletion. Mutations in polymerase gamma, the core enzyme of mtDNA replication, and in several other factors related to mtDNA maintenance, are responsible for a continuum clinical spectrum ranging from autosomal dominant or recessive PEO, to spino-cerebellar ataxia with epilepsy, to Alpers’ syndrome. The second group comprises severe encephalopathies caused by mutations in mitochondrial translation factors, but also a peculiar multisystemic disease characterized by mitochondrial myopathy with lactic acidosis and sideroblastic anemia. MLASA is caused by mutations in pseudouridylate synthase 1, an isomerase that converts uridine into pseudouridine of both cytosolic and mitochondrial tRNAs. The third group consists of primary CoQ10 deficiency, a potentially treatable condition with a clinical spectrum that encompasses at least five major phenotypes. Mutations in the CoQ10 biosynthetic genes, COQ2, PDSS1, and PDSS2, have been identified in children with severe multisystemic disease, while the other forms still await genetic characterization.