Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6.
Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6.
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DOI：
10.1002/ajh.26382
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发表时间：
2022-01-01
影响因子：
12.8
通讯作者：
Williams DA
中科院分区：
文献类型：
--
作者：
Renella R;Gagne K;Beauchamp E;Fogel J;Perlov A;Sola M;Schlaeger T;Hofmann I;Shimamura A;Ebert BL;Schmitz-Abe K;Markianos K;Murphy K;Sun L;Rockowitz S;Sliz P;Campagna DR;Springer TA;Bahl C;Agarwal S;Fleming MD;Williams DA
隔膜蛋白在哺乳动物细胞分裂和胞质分裂中起关键作用，但以前没有涉及生殖系人类疾病。一名男婴患有严重的中性粒细胞减少症和进行性骨髓生成障碍与四倍体骨髓前体细胞被确定。没有发现中性粒细胞减少或骨髓衰竭的已知遗传病因，但是，对患者生殖细胞样本的下一代测序显示，X连锁基因SEPT 6中存在一种新的、从头发生的生殖细胞停止丢失突变，导致BM粒细胞前体细胞和巨核细胞中SEPT 6染色减少。患者皮肤成纤维细胞衍生的诱导多能干细胞（iPSC）产生减少的髓样集落，特别是粒细胞谱系。患者突变的CRISPR/Cas9敲入或SEPT 6的完全敲除在非患者来源的iPSC或人骨髓细胞系中是不耐受的，但SEPT 6敲除在红系细胞系中是成功的，并且所得克隆揭示了多核化的倾向。计算机模拟分析预测，突变的蛋白质阻碍了SEPT 6卷曲螺旋在平行和反平行排列中的二聚化，这反过来又会损害细丝的形成。这些数据表明SEPT 6在骨髓祖细胞中的染色体分离中的关键作用，这可以解释非整倍性和骨髓生成障碍的不寻常倾向。
Septins play key roles in mammalian cell division and cytokinesis but have not previously been implicated in a germline human disorder. A male infant with severe neutropenia and progressive dysmyelopoiesis with tetraploid myeloid precursors was identified. No known genetic etiologies for neutropenia or bone marrow failure were found. However, next-generation sequencing of germline samples from the patient revealed a novel, de novo germline stop-loss mutation in the X-linked gene SEPT6 that resulted in reduced SEPT6 staining in BM granulocyte precursors and megakaryocytes. Patient skin fibroblast-derived induced pluripotent stem cells (iPSCs) produced reduced myeloid colonies, particularly of the granulocyte lineage. CRISPR/Cas9 knock-in of the patient’s mutation or complete knock-out of SEPT6 was not tolerated in non-patient derived iPSCs or human myeloid cell lines, but SEPT6 knock-out was successful in an erythroid cell line and resulting clones revealed a propensity to multinucleation. In silico analysis predicts the mutated protein hinders the dimerization of SEPT6 coiled coils in both parallel and antiparallel arrangements, which could in turn impair filament formation. These data demonstrate a critical role for SEPT6 in chromosomal segregation in myeloid progenitors that can account for the unusual predisposition to aneuploidy and dysmyelopoiesis.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
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82.9
作者：
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通讯作者：
Steidl, Ulrich
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5.8
作者：
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通讯作者：
Strelkov, Sergei V.
影响因子：
4
作者：
Caudron, Fabrice;Yadav, Smita
通讯作者：
Yadav, Smita
影响因子：
5.8
作者：
Feng, Jianxing;Meyer, Clifford A.;Zhang, Yong
通讯作者：
Zhang, Yong