Mitochondrial Complex V Deficiency via the ATP5F1E (ATP5E) Gene

Mitochondrial complex V deficiency is considered the rarest oxidative phosphorylation (OXPHOS) complex disorder, accounting for approximately one percent of all OXPHOS disease (Rodenburg 2011). Although patients share a similar biochemical phenotype, with a significant decrease in the activity of mitochondrial complex V, the phenotypic disease spectrum can be broad (Hejzlarová et al. 2014; Jonckheere et al. 2012). Defects in complex V-associated nuclear genes often result in a severe, neonatal-onset mitochondrial encephalopathy and/or cardiomyopathy. To date, only a single patient has been described with ATP5F1E-associated mitochondrial complex V deficiency (Mayr et al. 2010). The affected individual first presented as a neonate with lactic acidosis and 3-methylglutaconic aciduria; by the second decade of life, the patient exhibited severe peripheral neuropathy, ataxia, nystagmus, and mild intellectual impairment.

Mitochondrial complex V deficiency is caused by defects in the mitochondrial adenosine triphosphate (ATP) synthase, the fifth multi-subunit oxidative phosphorylation (OXPHOS) complex (Jonckheere et al. 2012; Hejzlarová et al. 2014). Although over 20 genes have been implicated in the assembly, structure, and function of the mitochondrial ATP synthase, variants in only six of these genes (ATP5A1, ATP5F1E, ATPAF2, TMEM70, MT-ATP6, and MT-ATP8) have been linked to disease to date. Depending on the cellular localization of the affected gene, this disorder may have an autosomal recessive or maternal mode of inheritance. Causative variants in the nuclear genes (ATP5A1, ATP5F1E, ATPAF2, and TMEM70) are inherited in an autosomal recessive manner. In contrast, causative variants in the MT-ATP6 or MT-ATP8 genes, which are encoded by the mitochondrial genome, are inherited in a maternal manner.

The ATP5F1E gene encodes subunit ε of the F₁ catalytic complex in the mitochondrial ATP synthase. Although the exact function of this protein is still unclear, ATP5E may play a role in F₁ complex assembly (Havlíčková et al. 2010). To date, only one pathogenic variant, a homozygous missense change, has been documented as a cause of ATP5F1E-associated mitochondrial complex V deficiency (Mayr et al. 2010).

ATP5F1E-associated mitochondrial complex V deficiency has been described in only one patient to date (Mayr et al. 2010). Although we cannot precisely estimate clinical sensitivity at this time, defects in ATP5F1E appear to be a rare cause of mitochondrial complex V deficiency. In contrast, defects in TMEM70 appear to be the most frequent cause of this disorder (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac/index.php).

This test provides full coverage of all coding exons of the ATP5F1E gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).