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Am J Hum Genet. 2018 Aug 2;103(2):221-231. doi: 10.1016/j.ajhg.2018.07.001. Epub 2018 Jul 26.

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.

Author information

1
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
2
Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
3
Dubai Hospital, Al Khaleej Street, Al Baraha, PO Box 7272, Dubai.
4
Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
5
Fullerton Genetics Center, Asheville, NC 28803, USA.
6
Cologne Center for Genomics, University of Cologne, 50931 Cologne, Germany.
7
Institute of Medical and Molecular Genetics and Skeletal dysplasia multidisciplinary Unit, Hospital Universitario La Paz, Universidad Autónoma de Madrid, IdiPaz, Madrid 28046, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28029, Spain.
8
GeneDx, 207 Perry Parkway, Gaithersburg, MD 20877, USA.
9
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28029, Spain; Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain.
10
Department of Pediatric Endocrinology & Dysmorphology, Hospital 12 Octubre, Madrid 28041, Spain.
11
Department of Pediatric Genetics, Marmara University Medical School, Istanbul 34722, Turkey.
12
UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
13
Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, School of Medical Education, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
14
The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
15
Cytogenetics Department, Viapath Analytics, Guy's Hospital, London SE1 9RT, UK.
16
Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
17
Department of Pediatrics, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495, Japan.
18
Institute for Genomic Medicine, Columbia University Medical Center, New York, NY 10032, USA.
19
Center for Medical Genetics, Department of Metabolism, Chiba Children's Hospital, 579-1, Heta-cho, Midori-ku, Chiba 266-0007, Japan.
20
Memorial University of Newfoundland, St. John's, NL A1C 5S7, Canada.
21
Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
22
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
23
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28029, Spain; Department of Genetics and Microbiology, Universitat Autònoma de Barcelona, Bellaterra 08193, Spain; Department of Genetics and Biomedical Research Institute Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona 08041, Spain.
24
Department of Pediatrics, Division of Clinical Genetics, Columbia University Medical Center, New York, NY 10032, USA.
25
Center for Chromosome Stability and Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark. Electronic address: iandh@sund.ku.dk.
26
MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: andrew.jackson@igmm.ed.ac.uk.

Abstract

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects' cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis.

KEYWORDS:

BLM; Bloom syndrome; RecQ helicases; double Holliday junction dissolution; genomic instability; topoisomerase III

PMID:
30057030
PMCID:
PMC6080766
[Available on 2019-02-02]
DOI:
10.1016/j.ajhg.2018.07.001
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