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. 2022 Jul 6;8(4):e200007.
doi: 10.1212/NXG.0000000000200007. eCollection 2022 Aug.

Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases

Guido Primiano  1 , Alessandra Torraco  1 , Daniela Verrigni  1 , Andrea Sabino  1 , Enrico Bertini  1 , Rosalba Carrozzo  1 , Gabriella Silvestri  1 , Serenella Servidei  1
Affiliations

Novel TOP3A Variant Associated With Mitochondrial Disease: Expanding the Clinical Spectrum of Topoisomerase III Alpha-Related Diseases

Guido Primiano et al. Neurol Genet. .

Abstract

Objectives: Topoisomerase III alpha plays a key role in the dissolution of double Holliday junctions and is required for mitochondrial DNA (mtDNA) replication and maintenance. Sequence variants in the TOP3A gene have been associated with the Bloom syndrome-like disorder and described in an adult patient with progressive external ophthalmoplegia. The purpose of this report is to expand the clinical phenotype of the TOP3A-related diseases and clarify the role of this gene in primary mitochondrial disorders.

Methods: A 44-year-old woman was referred to our hospital because of exercise intolerance and creatine kinase increase. Muscle biopsy and a targeted next-generation sequencing (NGS) analysis were performed.

Results: A histopathologic assessment documented a mitochondrial myopathy, and a molecular analysis revealed a novel homozygous variant in the TOP3A gene associated with multiple mtDNA deletions.

Discussion: This case suggests that TOP3A is one of the several nuclear genes associated with mtDNA maintenance disorder and expands the spectrum of its associated phenotypes, ranging from a clinical condition defined Bloom syndrome-like disorder to canonical mitochondrial syndromes.

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Figures

Figure 1
Figure 1. Clinical, Muscle Biopsy, and Muscle CT Findings
(A) Physical examination showing a narrow face with a prominent nose due to the scarcity of subcutaneous fat. Serial skeletal muscle sections (deltoid) documenting (B) mild variation in fiber size with linear “cracks” (hematoxylin and eosin stain) and classic (C) ragged-red or (D) ragged-blue fibers, respectively, on modified Gomori trichrome and succinate dehydrogenase staining, which appeared (E) pale with COX stain (magnification 10×); Oil Red-O stain did not document lipid accumulation (figure not shown); (F) CT showing minor symmetrical degenerative changes and hypotrophy of the muscles of the posterior thigh compartment (arrowheads) and mild involvement of the paraspinal and gluteal muscles (arrows).
Figure 2
Figure 2. Molecular Studies of the Family Included in the Study and the Clinical Spectrum of TOP3A-Related Disease
(A) Long-range PCR showing multiple mitochondrial DNA (mtDNA) deletions in the index patient (Pt) in comparison with a control (Ctrl) and a patient positive for “common mtDNA deletion” (common Δ); (B) Electropherograms encompassing the mutated genomic region in TOP3A for patient (Pt, II.2), father (I.1) and mother (I.2), the heterozygous member of the family (II.3 and II.5), and the wild-type brother (II.4); (C) Protein alignments showing aminoacid residue conservation across the vertebrates; (D) pedigree of the family, in black the proband; (E) TOP3A domain organization: MTS: mitochondrial targeting sequence (AA 1-20); TOPRIM: topoisomerase/primase domain (AA 35-169); TOPA (AA 172-569); GRF ZF (AA 895-939); in black, a representation of the previously reported mutations; in red, the mutation reported in this article.
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References

    1. Wang Y, Lyu YL, Wang JC. Dual localization of human DNA topoisomerase IIIalpha to mitochondria and nucleus. Proc Natl Acad Sci U S A. 2002;99(19):12114-12119. doi: 10.1073/pnas.192449499 - DOI - PMC - PubMed
    1. Nicholls TJ, Nadalutti CA, Motori E, et al. . Topoisomerase 3α is required for decatenation and segregation of human mtDNA. Mol Cell. 2018;69(1):923.e6. doi: 10.1016/j.molcel.2017.11.033 - DOI - PMC - PubMed
    1. Martin CA, Sarlós K, Logan CV, et al. . Mutations in TOP3A cause a Bloom syndrome-like disorder. Am J Hum Genet. 2018;103(2):221-231. doi: 10.1016/j.ajhg.2018.07.001 - DOI - PMC - PubMed
    1. Jiang W, Jia N, Guo C, et al. . Predominant cellular mitochondrial dysfunction in the TOP3A gene-caused Bloom syndrome-like disorder. Biochim Biophys Acta Mol Basis Dis. 2021;1867(6):166106. doi: 10.1016/j.bbadis.2021.166106 - DOI - PubMed
    1. Thompson K, Collier JJ, Glasgow RIC, et al. . Recent advances in understanding the molecular genetic basis of mitochondrial disease. J Inherit Metab Dis. 2020;43(1):36-50. doi: 10.1002/jimd.12104 - DOI - PMC - PubMed