Mutations in TOP3A Cause a Bloom Syndrome-like Disorder
Por:
Martin, CA, Sarlos, K, Logan, CV, Thakur, RS, Parry, DA, Bizard, AH, Leitch, A, Cleal, L, Ali, NS, Al-Owain, MA, Allen, W, Altmueller, J, Aza-Carmona, M, Barakat, BAY, Barraza-Garcia, J, Begtrup, A, Bogliolo, M, Cho, MT, Cruz-Rojo, J, Dhahrabi, HAM, Elcioglu, NH, Gosgene, Gorman, GS, Jobling, R, Kesterton, I, Kishita, Y, Kohda, M, Stabej, PLQ, Malallah, AJ, Nuernberg, P, Ohtake, A, Okazaki, Y, Pujol, R, Ramirez, MJ, Revah-Politi, A, Shimura, M, Stevens, P, Taylor, RW, Turner, L, Williams, H, Wilson, C, Yigit, G, Zahavich, L, Alkuraya, FS, Surralles, J, Iglesais, A, Murayama, K, Wollnik, B, Dattani, M, Heath, KE, Hickson, ID, Jackson, AP
Publicada:
2 ago 2018
Resumen:
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 (TopIII alpha), 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 TopIII alpha, 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 TopIII alpha 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.
Filiaciones:
Martin, CA:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Sarlos, K:
Univ Copenhagen, Dept Cellular & Mol Med, Ctr Chromosome Stabil & Ctr Hlth, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Logan, CV:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Thakur, RS:
Univ Copenhagen, Dept Cellular & Mol Med, Ctr Chromosome Stabil & Ctr Hlth, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Parry, DA:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Bizard, AH:
Univ Copenhagen, Dept Cellular & Mol Med, Ctr Chromosome Stabil & Ctr Hlth, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Leitch, A:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Cleal, L:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Ali, NS:
Dubai Hosp, Khaleej St,Al Baraha,Box 7272, Dubai, U Arab Emirates
Al-Owain, MA:
King Faisal Specialist Hosp & Res Ctr, Dept Med Genet, Riyadh 11211, Saudi Arabia
Allen, W:
Fullerton Genet Ctr, Asheville, NC 28803 USA
Altmueller, J:
Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany
Aza-Carmona, M:
Univ Autonoma Madrid, Hosp Univ La Paz, Inst Med & Mol Genet, IdiPaz, Madrid 28046, Spain
Univ Autonoma Madrid, Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit, IdiPaz, Madrid 28046, Spain
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Barakat, BAY:
Dubai Hosp, Khaleej St,Al Baraha,Box 7272, Dubai, U Arab Emirates
Barraza-Garcia, J:
Univ Autonoma Madrid, Hosp Univ La Paz, Inst Med & Mol Genet, IdiPaz, Madrid 28046, Spain
Univ Autonoma Madrid, Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit, IdiPaz, Madrid 28046, Spain
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Begtrup, A:
GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA
Bogliolo, M:
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Cho, MT:
GeneDx, 207 Perry Pkwy, Gaithersburg, MD 20877 USA
Cruz-Rojo, J:
Hosp 12 Octubre, Dept Pediat Endocrinol & Dysmorphol, E-28041 Madrid, Spain
Dhahrabi, HAM:
Dubai Hosp, Khaleej St,Al Baraha,Box 7272, Dubai, U Arab Emirates
Elcioglu, NH:
Marmara Univ, Sch Med, Dept Pediat Genet, TR-34722 Istanbul, Turkey
Gosgene:
UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England
Gorman, GS:
Newcastle Univ, Sch Med Educ, Inst Neurosci, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England
Jobling, R:
Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Kesterton, I:
Guys Hosp, Viapath Analyt, Cytogenet Dept, London SE1 9RT, England
Kishita, Y:
Juntendo Univ, Grad Sch Med, Intractable Dis Res Ctr, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan
Kohda, M:
Juntendo Univ, Grad Sch Med, Intractable Dis Res Ctr, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan
Stabej, PLQ:
UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England
Malallah, AJ:
Dubai Hosp, Khaleej St,Al Baraha,Box 7272, Dubai, U Arab Emirates
Nuernberg, P:
Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany
Ohtake, A:
Saitama Med Univ, Fac Med, Dept Pediat, 38 Morohongo, Moroyama, Saitama 3500495, Japan
Okazaki, Y:
Juntendo Univ, Grad Sch Med, Intractable Dis Res Ctr, Bunkyo Ku, 2-1-1 Hongo, Tokyo 1138421, Japan
Pujol, R:
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Ramirez, MJ:
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Revah-Politi, A:
Columbia Univ, Med Ctr, Inst Genom Med, New York, NY 10032 USA
Shimura, M:
Chiba Childrens Hosp, Dept Metab, Ctr Med Genet, Midori Ku, 579-1 Heta Cho, Chiba 2660007, Japan
Stevens, P:
Guys Hosp, Viapath Analyt, Cytogenet Dept, London SE1 9RT, England
Taylor, RW:
Newcastle Univ, Sch Med Educ, Inst Neurosci, Wellcome Ctr Mitochondrial Res, Newcastle Upon Tyne, Tyne & Wear, England
Turner, L:
Mem Univ Newfoundland, St John, NF A1C 5S7, Canada
Williams, H:
UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England
Wilson, C:
Fullerton Genet Ctr, Asheville, NC 28803 USA
Yigit, G:
Univ Med Ctr Gottingen, Inst Human Genet, D-37073 Gottingen, Germany
Zahavich, L:
Hosp Sick Children, Toronto, ON M5G 1X8, Canada
Alkuraya, FS:
King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi Arabia
Surralles, J:
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Univ Autonoma Barcelona, Dept Genet & Microbiol, Bellaterra 08193, Spain
Hosp Santa Creu & Sant Pau, Dept Genet, Barcelona 08041, Spain
Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau, Barcelona 08041, Spain
Iglesais, A:
Columbia Univ, Med Ctr, Div Clin Genet, Dept Pediat, New York, NY 10032 USA
Murayama, K:
Chiba Childrens Hosp, Dept Metab, Ctr Med Genet, Midori Ku, 579-1 Heta Cho, Chiba 2660007, Japan
Wollnik, B:
Univ Med Ctr Gottingen, Inst Human Genet, D-37073 Gottingen, Germany
Dattani, M:
UCL, Great Ormond St Inst Child Hlth, 30 Guilford St, London WC1N 1EH, England
Heath, KE:
Univ Autonoma Madrid, Hosp Univ La Paz, Inst Med & Mol Genet, IdiPaz, Madrid 28046, Spain
Univ Autonoma Madrid, Hosp Univ La Paz, Skeletal Dysplasia Multidisciplinary Unit, IdiPaz, Madrid 28046, Spain
Ctr Invest Biomed Red Enfermedades Raras, Madrid 28029, Spain
Hickson, ID:
Univ Copenhagen, Dept Cellular & Mol Med, Ctr Chromosome Stabil & Ctr Hlth, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark
Jackson, AP:
Univ Edinburgh, MRC Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
Green Published, Hybrid Gold, Green Accepted
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