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

ABSTRACT: Topoisomerase 3 (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 eleven individuals from nine 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 a Bloom-like syndrome, upon mtDNA maintenance and upon 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.

SUBMITTER: Ms. Direnis Erdinc

PROVIDER: S-SCDT-10_15252-EMMM_202216775 | biostudies-other |

REPOSITORIES: biostudies-other

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