Mutations in TOP3A Cause a Bloom Syndrome-like Disorder
Martin, Carol-Anne (University of Edinburgh. MRC Institute of Genetics and Molecular Medicine)
Sarlós, Kata (University of Copenhagen. Department of Cellular and Molecular Medicine)
Logan, Clare V. (University of Edinburgh. MRC Institute of Genetics and Molecular Medicine)
Singh Thakur, Roshan (University of Copenhagen. Department of Cellular and Molecular Medicine)
Parry, David A. (University of Copenhagen. Department of Cellular and Molecular Medicine)
Bizard, Anna H. (University of Copenhagen. Department of Cellular and Molecular Medicine)
Leitch, Andrea (University of Edinburgh. MRC Institute of Genetics and Molecular Medicine)
Cleal, Louise (University of Edinburgh. MRC Institute of Genetics and Molecular Medicine)
Shaukat Ali, Nadia (Dubai Hospital, Al Khaleej Street)
Al-Owain, Mohammed A. (King Faisal Specialist Hospital and Research Center. Department of Medical Genetics)
Allen, William (Fullerton Genetics Center, Asheville)
Altmüller, Janine (University of Cologne. Cologne Center for Genomics)
Aza-Carmona, Miriam (Universidad Autónoma de Madrid. Instituto de Genética Médica y Molecular-INGEMM)
Barakat, Bushra A. Y. (Dubai Hospital, Al Khaleej Street, Al Baraha)
Barraza-García, Jimena (Universidad Autónoma de Madrid. Instituto de Genética Médica y Molecular-INGEMM)
Begtrup, Amber (GeneDx, 207 Perry Parkway, Gaithersburg)
Bogliolo, Massimo (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Cho, Megan T. (GeneDx, 207 Perry Parkway, Gaithersburg)
Cruz-Rojo, Jaime (Hospital Universitario 12 de Octubre (Madrid))
Mundi Dhahrabi, Hassan Ali (Dubai Hospital, Al Khaleej Street, Al Baraha)
Elcioglu, Nursel H. (University Medical School. Department of Pediatric Genetics)
Gorman, Gráinne S. (Newcastle University. Institute of Neuroscience)
Jobling, Rebekah (The Hospital for Sick Children)
Kesterton, Ian (Cytogenetics Department, Viapath Analytics)
Kishita, Yoshihito (Juntendo University. Intractable Disease Research Center)
Kohda, Masakazu (Juntendo University. Intractable Disease Research Center)
Quesne Stabej, Polona Le (UCL Great Ormond Street Institute of Child Health)
Jassim Malallah, Asam (Dubai Hospital, Al Khaleej Street)
Nürnberg, Peter (University of Cologne. Cologne Center for Genomics)
Ohtake, Akira (Saitama Medical University. Department of Pediatrics)
Okazaki, Yasushi (Juntendo University. Intractable Disease Research Center)
Pujol i Calvet, M. Roser (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Ramírez de Haro, Ma. José (María José) (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Revah-Politi, Anya (University Medical Center. Institute for Genomic Medicine)
Shimura, Masaru (Chiba Children's Hospital. Department of Metabolism)
Stevens, Paul (Cytogenetics Department, Viapath Analytics)
Taylor, Robert W. (Newcastle University. Wellcome Centre for Mitochondrial Research)
Turner, Lesley (Memorial University of Newfoundland)
Williams, Hywel (UCL Great Ormond Street Institute of Child Health)
Wilson, Carolyn (Fullerton Genetics Center)
Yigit, Gökhan (University Medical Center Göttingen. Institute of Human Genetics)
Zahavich, Laura (The Hospital for Sick Children)
Alkuraya, Fowzan S. (King Faisal Specialist Hospital and Research Centre (Aràbia Saudita))
Surrallés Calonge, Jordi (Universitat Autònoma de Barcelona. Departament de Genètica i de Microbiologia)
Iglesias, Alejandro (Columbia University Medical Center. Department of Pediatrics)
Murayama, Kei (Chiba Children's Hospital. Department of Metabolism)
Wollnik, Bernd (University Medical Center Göttingen. Institute of Human Genetics)
Dattani, Mehul (UCL Great Ormond Street Institute of Child Health)
Heath, Karen E. (Universidad Autónoma de Madrid. Instituto de Genética Médica y Molecular-INGEMM)
Hickson, Ian D. (University of Copenhagen. Department of Cellular and Molecular Medicine)
Jackson, Andrew P. (University of Edinburgh. MRC Institute of Genetics and Molecular Medicine)
GOSgene UCL Great Ormond Street Institute of Child Health

Date:	2018
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 prenatalonset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIa), 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 TopIIIa, 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 TopIIIa 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.
Grants:	Ministerio de Economía y Competitividad SAF2015-66831-R Ministerio de Economía y Competitividad SAF2017-84646-R Ministerio de Economía y Competitividad SAF2015-64152-R European Commission 281847
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Topoisomerase III ; RecQ helicases ; BLM ; Genomic instability ; Double Holliday junction dissolution ; Bloom syndrome
Published in:	American journal of human genetics, Vol. 103, Issue 2 (August 2018) , p. 221-231, ISSN 0002-9297

DOI: 10.1016/j.ajhg.2018.07.001
PMID: 30057030

11 p, 1.2 MB

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