Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.
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DOI：
10.1038/s41467-022-34349-8
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发表时间：
2022-11-04
影响因子：
16.6
通讯作者：
Stewart, Grant S.
中科院分区：
文献类型：
--
作者：
Grange, Laura J.;Reynolds, John J.;Ullah, Farid;Isidor, Bertrand;Shearer, Robert F.;Latypova, Xenia;Baxley, Ryan M.;Oliver, Antony W.;Ganesh, Anil;Cooke, Sophie L.;Jhujh, Satpal S.;McNee, Gavin S.;Hollingworth, Robert;Higgs, Martin R.;Natsume, Toyoaki;Khan, Tahir;Martos-Moreno, Gabriel A.;Chupp, Sharon;Mathew, Christopher G.;Parry, David;Simpson, Michael A.;Nahavandi, Nahid;Yuksel, Zafer;Drasdo, Mojgan;Kron, Anja;Vogt, Petra;Jonasson, Annemarie;Seth, Saad Ahmed;Gonzaga-Jauregui, Claudia;Brigatti, Karlla W.;Stegmann, Alexander P. A.;Kanemaki, Masato;Josifova, Dragana;Uchiyama, Yuri;Oh, Yukiko;Morimoto, Akira;Osaka, Hitoshi;Ammous, Zineb;Argente, Jesus;Matsumoto, Naomichi;Stumpel, Constance T. R. M.;Taylor, Alexander M. R.;Jackson, Andrew P.;Bielinsky, Anja-Katrin;Mailand, Niels;Le Caignec, Cedric;Davis, Erica E.;Stewart, Grant S.
胚胎发育是由DNA复制、细胞分裂和分化的严格调控决定的。DNA修复和复制基因的突变破坏了这种平衡，导致了以小头畸形、身材矮小和染色体断裂为特征的神经发育疾病。在这里，我们在11例小头畸形、身材矮小、心脏异常和贫血的患者中发现了RAD18-SLF1/2-SMC5/6基因组稳定途径的两个组成部分SLF2和SMC5的双等位基因变异。患者来源的细胞表现出独特的染色体不稳定表型，包括节段性和双着丝粒染色体，并具有镶嵌杂色超倍体。为了表明这些节段性染色体的重要性，我们将这种疾病命名为阿特尔-S综合征。对阿泰-S综合征细胞的分析显示，复制压力水平升高，部分原因是通过G-四链DNA结构复制的能力降低，以及姐妹染色单体凝聚力的丧失。总之，这些数据加强了SLF2和SMC5/6复合体之间的功能联系，突出了这一途径在维持基因组稳定方面的独特作用。SMC5/6复合体对基因组稳定性至关重要。在这里，作者发现SLF2和SMC5的突变是导致阿特利S综合征的原因，该综合征的特征是小头畸形、身材矮小、贫血、染色体分段和镶嵌杂色超倍体。
Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability. The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.
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DOI：
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发表时间：
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影响因子：
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作者：
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