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 bone marrow 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 that 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.

中文翻译：

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由于 SEPT6 种系突变导致的先天性 X 连锁中性粒细胞减少伴骨髓增生异常和体细胞四倍体

Septins 在哺乳动物细胞分裂和胞质分裂中发挥关键作用，但以前没有涉及人类种系疾病。一名男婴患有严重的中性粒细胞减少症和进行性骨髓细胞生成障碍，具有四倍体骨髓前体细胞。未发现中性粒细胞减少症或骨髓衰竭的已知遗传病因。然而，来自患者的种系样本的下一代测序揭示了 X 连锁基因SEPT6中的一种新的、从头种系停止丢失突变，导致骨髓粒细胞前体细胞和巨核细胞中的 SEPT6 染色减少。患者皮肤成纤维细胞衍生的诱导多能干细胞 (iPSC) 产生的骨髓集落减少，特别是粒细胞谱系。CRISPR/Cas9 敲入患者突变或完全敲除SEPT6在非患者来源的 iPSC 或人骨髓细胞系中不耐受，但SEPT6敲除在红细胞系中成功，所得克隆显示多核化倾向。计算机分析预测，突变蛋白会阻碍平行和反平行排列中 SEPT6 卷曲螺旋的二聚化，进而可能损害细丝形成。这些数据证明了SEPT6在骨髓祖细胞染色体分离中的关键作用，这可以解释非整倍体和骨髓细胞生成异常的异常倾向。