Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

GOSgene, Carol-Anne Martin, Kata Sarlós, Clare V Logan, Roshan Singh Thakur, David A Parry, Anna H Bizard, Andrea Leitch, Louise Cleal, Nadia Shaukat Ali, Mohammed A Al-Owain, William Allen, Janine Altmüller, Miriam Aza-Carmona, Bushra A Y Barakat, Jimena Barraza-García, Amber Begtrup, Massimo Bogliolo, Megan T Cho, Jaime Cruz-RojoHassan Ali Mundi Dhahrabi, Nursel H Elcioglu, Gráinne S Gorman, Rebekah Jobling, Ian Kesterton, Yoshihito Kishita, Masakazu Kohda, Polona Le Quesne Stabej, Asam Jassim Malallah, Peter Nürnberg, Akira Ohtake, Yasushi Okazaki, Roser Pujol, Maria José Ramirez, Anya Revah-Politi, Masaru Shimura, Paul Stevens, Robert W Taylor, Lesley Turner, Hywel Williams, Carolyn Wilson, Gökhan Yigit, Laura Zahavich, Fowzan S Alkuraya, Jordi Surralles, Alejandro Iglesais, Kei Murayama, Bernd Wollnik, Mehul Dattani, Karen E Heath, Andrew P Jackson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
JournalAmerican Journal of Human Genetics
Early online date24 Jul 2018
Publication statusPublished - 2 Aug 2018


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