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| Item Type: | Article |
|---|---|
| Title: | Mutations in TOP3A cause a bloom syndrome-like disorder |
| Creators Name: | Martin, C.A. and Sarlós, K. and Logan, C.V. and Thakur, R.S. and Parry, D.A. and Bizard, A.H. and Leitch, A. and Cleal, L. and Ali, N.S. and Al-Owain, M.A. and Allen, W. and Altmüller, J. and Aza-Carmona, M. and Barakat, B.A.Y. and Barraza-García, J. and Begtrup, A. and Bogliolo, M. and Cho, M.T. and Cruz-Rojo, J. and Dhahrabi, H.A.M. and Elcioglu, N.H. and Gorman, G.S. and Jobling, R. and Kesterton, I. and Kishita, Y. and Kohda, M. and Le Quesne Stabej, P. and Malallah, A.J. and Nürnberg, P. and Ohtake, A. and Okazaki, Y. and Pujol, R. and Ramirez, M.J. and Revah-Politi, A. and Shimura, M. and Stevens, P. and Taylor, R.W. and Turner, L. and Williams, H. and Wilson, C. and Yigit, G. and Zahavich, L. and Alkuraya, F.S. and Surralles, J. and Iglesias, A. and Murayama, K. and Wollnik, B. and Dattani, M. and Heath, K.E. and Hickson, I.D. and Jackson, A.P. |
| 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: | Topoisomerase III, RecQ Helicases, BLM, Genomic Instability, Double Holliday Junction Dissolution, Bloom Syndrome |
| Source: | American Journal of Human Genetics |
| ISSN: | 0002-9297 |
| Publisher: | Cell Press |
| Volume: | 103 |
| Number: | 2 |
| Page Range: | 221-231 |
| Date: | 2 August 2018 |
| Official Publication: | https://doi.org/10.1016/j.ajhg.2018.07.001 |
| PubMed: | View item in PubMed |
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