Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability

Abstract

Topoisomerase 3α (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi‐allelic pathogenic variants in BLM , encoding a nuclear‐binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult‐onset mitochondrial disease resulting from bi‐allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory‐motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom‐like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult‐onset mitochondrial disease and more severe variants causing a Bloom‐like syndrome with mitochondrial dysfunction in childhood. image We report cases of adult‐onset mitochondrial disease causes by pathological variants in the topoisomerase TOP3A, which localises both to mitochondria and the nucleus. We propose that different variants result in different disease outcomes related to the mitochondrial or nuclear forms of the enzyme. Pathological variants in TOP3A cause adult‐onset mitochondrial disease. Pathological TOP3A variants cause mitochondrial genome instability and muscle mitochondrial dysfunction. TOP3A variants affect the DNA binding, relaxation and ssDNA decatenation functions of the protein, and impair mtDNA replication. The severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants associated with mitochondrial disease and more severe variants associated with Bloom syndrome.