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

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

Erdinc, Direnis (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Rodriguez-Luis, A. (author)

Fassad, M. R. (author)

Mackenzie, S. (author)

Watson, C. M. (author)

Valenzuela, Sebastian, 1993 (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Xie, Xie (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Menger, K. E. (author)

Sergeant, K. (author)

Craig, K. (author)

Hopton, S. (author)

Falkous, G. (author)

Poulton, J. (author)

Garcia-Moreno, H. (author)

Giunti, P. (author)

Aschoff, C. A. D. (author)

Saute, J. A. M. (author)

Kirby, A. J. (author)

Toro, C. (author)

Wolfe, L. (author)

Novacic, D. (author)

Greenbaum, L. (author)

Eliyahu, A. (author)

Barel, O. (author)

Anikster, Y. (author)

McFarland, R. (author)

Gorman, G. S. (author)

Schaefer, A. M. (author)

Gustafsson, Claes M, 1966 (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Taylor, R. W. (author)

Falkenberg, Maria, 1968 (author): Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology

Nicholls, T. J. (author)

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2023
2023
English.
In: Embo Molecular Medicine. - 1757-4676. ; 15:5

Related links:: https://gup.ub.gu.se...; show more...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

Topoisomerase 3 alpha (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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine (hsv//eng)

Keyword

Bloom syndrome
mitochondrial disease
mtDNA
TOP3A
topoisomerase-iii-alpha
impair mtdna replication
syndrome
gene-product
d-loop
essential component
syndrome protein
DNA
mutations
duplication
deletions
Research & Experimental Medicine

Publication and Content Type

ref (subject category)
art (subject category)

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...

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By the university: University of Gothenburg

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