Predominant cellular mitochondrial dysfunction in the TOP3A gene caused Bloom syndrome-like disorder

Abstract Background TOP3A is a subunit of the BLM-TOP3A-RMI1/2 complex, which promotes processing of double Holliday junction dissolution and also plays an important role in decatenation and segregation of human mtDNA. Recently, TOP3A mutations have been reported to cause Bloom syndrome-like disorder. However, whether the two function play equal roles in the disease pathogenesis is unclear. Results Beside the common clinical manifestations in the reported TOP3A-deficiency, our patients also exhibited liver lipid storage with hepatomegaly and elevated liver enzyme. In cellular and molecular biological studies, TOP3A deficiency decreased the cellular protein level of RMI1 and RMI2, and moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency. These changes were rescued by ectopic expression of either of the wildtype TOP3A or TOP3A-D479G. In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G. Conclusions Considering the severe disease course and the impact of the TOP3A-D479G mutation on the genome stability and mitochondrial metabolism, we propose that the impaired mitochondrial metabolism plays an important role in the pathogenesis of TOP3A-deficient Bloom-like disease.