Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.
Mutations in TOP3A Cause a Bloom Syndrome-like Disorder.
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DOI：
10.1016/j.ajhg.2018.07.001
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发表时间：
2018-08-02
影响因子：
9.8
通讯作者：
Jackson AP
中科院分区：
文献类型：
--
作者：
Martin CA;Sarlós K;Logan CV;Thakur RS;Parry DA;Bizard AH;Leitch A;Cleal L;Ali NS;Al-Owain MA;Allen W;Altmüller J;Aza-Carmona M;Barakat BAY;Barraza-García 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;Le Quesne Stabej P;Malallah AJ;Nürnberg 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;Iglesias A;Murayama K;Wollnik B;Dattani M;Heath KE;Hickson ID;Jackson AP
布卢姆综合征是由BLM双等位基因突变引起的，其特点是产前发作的生长缺陷、身材矮小、红斑性光敏性颧疹和增加的癌症易感性。在诊断上，一个标志性的特征是在细胞遗传学测试中增加姐妹染色单体交换（SCEs）的存在。在这里，我们描述了10例产前发病生长受限和小头畸形患者的TOP3A双等位基因突变。TOP3A编码拓扑异构酶IIIα (TopIIIα)，该酶作为BTRR复合物的一部分与BLM结合，并促进同源重组过程中产生的双Holliday连接的溶解。我们还在两个患有小头侏儒症的个体中发现了RMI1的纯合截断变体，该变体编码BTRR复合体的另一种成分。TOP3A突变显著降低了细胞中TopIIIα的水平，因此受试者细胞中SCE的发生率升高。未解决的DNA重组和/或复制中间体持续到有丝分裂，导致染色体分离缺陷和基因组不稳定，这最有可能解释在这些受试者和布鲁姆综合征中看到的生长限制。在一些双等位基因TOP3A突变的个体中，线粒体功能障碍的临床特征是明显的，这与最近报道的TopIIIα在线粒体DNA十烷化中的附加功能是一致的。综上所述，我们的研究结果表明，TOP3A突变是产前发病的身材矮小和细胞遗传学SCEs增加的另一个原因，并暗示BTRR复合物的十烷化活性在其发病机制中起作用。
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.
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影响因子：
3.9
作者：
Murray, Jennie E.;Bicknell, Louise S.;Yigit, Goekhan;Duker, Angela L.;van Kogelenberg, Margriet;Haghayegh, Sara;Wieczorek, Dagmar;Kayserili, Huelya;Albert, Michael H.;Wise, Carol A.;Brandon, January;Kleefstra, Tjitske;Warris, Adilia;van der Flier, Michiel;Bamforth, J. Steven;Doonanco, Kurston;Ades, Lesley;Ma, Alan;Field, Michael;Johnson, Diana;Shackley, Fiona;Firth, Helen;Woods, C. Geoffrey;Nuernberg, Peter;Gatti, Richard A.;Hurles, Matthew;Bober, Michael B.;Wollnik, Bernd;Jackson, Andrew P.
通讯作者：
Jackson, Andrew P.
影响因子：
30.8
作者：
Luo, GB;Santoro, IM;Bradley, A
通讯作者：
Bradley, A
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Goulaouic, H;Roulon, T;Riou, JF
通讯作者：
Riou, JF
影响因子：
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作者：
Janssen, Aniek;van der Burg, Marja;Medema, Rene H.
通讯作者：
Medema, Rene H.
影响因子：
11.4
作者：
Chan, Kok-Lung;North, Phillip S.;Hickson, Ian D.
通讯作者：
Hickson, Ian D.