Abstract
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, ENDOG has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic ENDOG variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient’s muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient’s clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient’s fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of ENDOG variants with mitochondrial myopathy.
Highlights
Endonuclease G (ENDOG) is a nuclear-encoded nuclease, member of the conserved DNA/RNA non-specific ββα-Me-finger nuclease family [1]
Quantitative polymerase chain reaction (PCR) showed a reduction of 50% in the expression levels of the mRNA of ENDOG in fibroblasts, and cDNA sequencing on the full-length ENDOG transcript confirmed the biallelic and balanced expression of both missense and frameshift variants (Figure S5)
We examined the possible involvement of ENDOG in mitochondrial DNA (mtDNA) replication and concluded that its role in this process can be replaceable or may be largely compensated by other factors or players, at least in fibroblasts
Summary
Endonuclease G (ENDOG) is a nuclear-encoded nuclease, member of the conserved DNA/RNA non-specific ββα-Me-finger nuclease family [1]. Given its spatial closeness to mtDNA, as well as its ability to cleave nucleic acids (DNA, RNA and hybrid molecules) at double-stranded (dG)n·(dC)n and single-stranded (dC)n tracts tested in vitro [1], ENDOG is an excellent candidate to be involved in mtDNA replication initiation, mtRNA processing and mtDNA maintenance and homeostasis [5]. It has been reported to be involved in several biological processes, including apoptosis, paternal mitochondrial elimination in early embryogenesis and autophagy. Previous studies have reported a possible role of ENDOG as one of the apoptotic nucleases that move from the mitochondria to the nucleus, leading to DNA fragmentation [6]. None of the ENDOG null models (yeast, worm or mouse) provide convincing evidence of significant effects on apoptosis [7–9], or in paternal mitochondrial elimination and mitophagy [10].
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