Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

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)...

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Detalles Bibliográficos
Autores: Martin, Carol-Anne, Sarlós, Kata, Logan, Clare V., Singh Thakur, Roshan, Parry, David A., Bizard, Anna H., Leitch, Andrea, Cleal, Louise, Shaukat Ali, Nadia, Al-Owain, Mohammed A., Allen, William, Altmüller, Janine|||0000-0003-4372-1521, Aza-Carmona, Miriam|||0000-0003-4448-9541, Barakat, Bushra A. Y., Barraza-García, Jimena, Begtrup, Amber, Bogliolo, Massimo|||0000-0001-8240-7784, Cho, Megan T., Cruz-Rojo, Jaime, Mundi Dhahrabi, Hassan Ali, Elcioglu, Nursel H., Gorman, Gráinne S.|||0000-0002-7585-3409, Jobling, Rebekah, Kesterton, Ian, Kishita, Yoshihito, Kohda, Masakazu, Quesne Stabej, Polona Le, Jassim Malallah, Asam, Nürnberg, Peter, Ohtake, Akira, Okazaki, Yasushi, Pujol Calvet, Maria Roser|||0000-0003-1840-5455, Ramírez de Haro, Ma. José|||0000-0003-1417-7731, Revah-Politi, Anya, Shimura, Masaru, Stevens, Paul, Taylor, Robert W.|||0000-0002-7768-8873, Turner, Lesley, Williams, Hywel, Wilson, Carolyn, Yigit, Gökhan, Zahavich, Laura, Alkuraya, Fowzan S.|||0000-0003-4158-341X, Surralles, Jordi|||0000-0002-4041-7519, Iglesias, Alejandro, Murayama, Kei, Wollnik, Bernd|||0000-0003-2589-0364, Dattani, Mehul, Heath, Karen E., Hickson, Ian D., Jackson, Andrew P.
Tipo de recurso: artículo
Fecha de publicación:2018
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:197195
Acceso en línea:https://ddd.uab.cat/record/197195
https://dx.doi.org/urn:doi:10.1016/j.ajhg.2018.07.001
Access Level:acceso abierto
Palabra clave:Topoisomerase III
RecQ helicases
BLM
Genomic instability
Double Holliday junction dissolution
Bloom syndrome
Descripción
Sumario: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.

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