Mitochondrial Complex V Deficiency via the ATPAF2 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 with this disorder 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. 2004; 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 ATPAF2-associated mitochondrial complex V deficiency (De Meirleir et al. 2014; Meulemans et al. 2009). The affected individual presented as a neonate with degenerative encephalopathy, dysmorphic features, lactic acidosis, developmental delay, and seizures.

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, ATP5E, ATPAF2, TMEM70, MT-ATP6, and MT-ATP8) are currently associated with disease. 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, ATP5E, 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 ATPAF2 gene (also referred to as Atp12p in the literature), encodes a chaperone protein thought to prevent aggregation of the F₁ alpha subunit prior to its integration into the mitochondrial ATP synthase complex (Wang et al. 2001; Ackerman 2002). To date, only one pathogenic variant, a homozygous missense change, has been documented as a cause of ATPAF2-associated mitochondrial complex V deficiency (De Meirleir et al. 2004; Meulemans et al. 2010).

ATPAF2-associated mitochondrial complex V deficiency has been described in only one patient to date (De Meirleir et al. 2004). Although we cannot precisely estimate clinical sensitivity at this time, defects in ATPAF2 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 ATPAF2 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).