The role of Septin6 Group in Murine and Human Hematopoiesis

（请保持文字，不要PDF） 标题：Septin 6组在小鼠和人造血中的作用 1 R01 DK137172-01 隔膜蛋白是高度保守的GT3蛋白，其调节多种细胞功能，包括胞质分裂、极性、细胞周期、囊泡运输、胞吐作用和扩散屏障的产生。我们最近发现了一名患有严重中性粒细胞减少症的非综合征新生儿（Renella，AJH 2022），该新生儿在SEPTIN 6基因的C端存在一种新的X连锁生殖系突变（SEPTIN 6 c.1282T>C p.428Glnext*9），与骨髓生成障碍相关。将生殖系突变编辑为正常男性CD 34+造血干细胞和祖细胞（HSC/P）表型模仿了临床综合征的关键病理特征，包括大的多核核细胞核和体外髓系祖细胞生长减少（初步数据）。已经提出C-末端在细丝稳定、成束和弯曲以及与其他septins的相互作用中起关键作用，并且计算机模拟表明，添加与SEPTIN 6 c.1282T>C p.428Glnext*9突变相关的9个氨基酸（aa）将通过干扰SEPTIN 6蛋白相互作用来改变功能。基于我们的首次发表，在西雅图发现了第二例重度中性粒细胞减少症患者，该患者在同一密码子中存在不同突变（SEPTIN 6 c.1282 T>A）（Mohamad，Allensbach，威廉姆斯，接受报告，ASH 2022）。虽然氨基酸取代不同，但建模预测SEPTIN 6变体采用相同的结构。这两个确定的患者有高度的骨髓四倍体的骨髓和难治性G-CSF。

(PLEASE KEEP IN WORD, DO NOT PDF) Title: The role of Septin6 Group in Murine and Human Hematopoiesis 1 R01 DK137172-01 Septins are highly conserved GTPase proteins which regulate a variety of cellular functions including cytokinesis, polarity, cell cycle, vesicle trafficking, exocytosis, and creation of diffusion barriers. We have recently identified a non-syndromic newborn with severe neutropenia (Renella, AJH 2022) with a novel X-linked germline mutation in the C-terminus of SEPTIN6 gene (SEPTIN6 c.1282T>C p.428Glnext*9) associated with dysmyelopoiesis. Editing the germline mutation into normal male CD34+ hematopoietic stem and progenitor cells (HSC/P) phenocopied key pathologic features of the clinical syndrome, including large, multinucleated nuclei and reduced myeloid progenitor growth in vitro (preliminary data). The C-terminus has been proposed to play a key role in filament stabilization, bundling and bending as well as interactions with other septins and in silico modeling suggest the addition of 9 amino acids (aa) associated with the SEPTIN6 c.1282T>C p.428Glnext*9 mutation would alter function by interfering with SEPTIN6 protein interactions. Based on our initial publication, a second patient with severe neutropenia has since been identified in Seattle with a distinct mutation in the same codon (SEPTIN6 c.1282T>A) (Mohamad, Allensbach, Williams, accepted for presentation, ASH 2022). While the aa substitution is different, modeling predicts that SEPTIN6 variants adopt the same structure. Both identified patients had a high degree of myeloid tetraploidy in the marrow and were refractory to G-CSF.