The role of Septin6 Group in Murine and Human Hematopoiesis

Septin6 组在小鼠和人类造血中的作用

• 批准号: 10718515
• 负责人: DAVID A WILLIAMS
• 金额: $ 35.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718515
• 关键词: Adopted; Affect; Aging; Amino Acid Sequence Homology; Amino Acid Substitution; Amino Acids; Apoptosis; Awareness; Blood; Bundling; C-terminal; CD34 gene; CSF3 gene; Cell Cycle; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell division; Cell physiology; Cells; Clinical; Codon Nucleotides; Complex; Cytokinesis; Data; Diffusion; Engraftment; Exocytosis; Exons; Filament; GTP Binding Domain; Genes; Germ-Line Mutation; Growth; Guanosine Triphosphate Phosphohydrolases; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homing; Human; In Vitro; Individual; Link; Mammalian Cell; Marrow; Microfilaments; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; N-terminal; Nature; Neutropenia; Newborn Infant; Nucleotides; Pathologic; Pathway interactions; Patients; Phenocopy; Phenotype; Play; Proliferating; Proline; Proteins; Publications; Refractory; Regulation; Reporting; Role; Structure; Syndrome; Tetraploidy; Variant; Vesicle; Xenograft Model; cell motility; combinatorial; in silico; knock-down; male; member; mutant; negative affect; novel; predictive modeling; progenitor; trafficking

(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.

（请以 WORD 形式保存，请勿以 PDF 形式保存） 标题：Septin6 组在小鼠和人类造血中的作用 1 R01 DK137172-01 Septin 是高度保守的 GTP 酶蛋白，可调节多种细胞功能，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)，其 SEPTIN6 基因 C 末端存在新的 X 连锁种系突变 (SEPTIN6 c.1282T>C p.428Glnext*9)，与骨髓生成障碍相关。将种系突变编辑到正常男性 CD34+ 造血干细胞和祖细胞 (HSC/P) 中，复制了临床综合征的关键病理特征，包括大的多核细胞核和体外骨髓祖细胞生长减少（初步数据）。已提出 C 末端在细丝稳定、成束和弯曲以及与其他 septin 的相互作用中发挥关键作用，并且计算机模型表明添加与 SEPTIN6 c.1282T>C p.428Glnext*9 突变相关的 9 个氨基酸 (aa) 将通过干扰 SEPTIN6 蛋白相互作用来改变功能。根据我们最初发表的文章，西雅图第二名患有严重中性粒细胞减少症的患者在同一密码子中发现了明显的突变 (SEPTIN6 c.1282T>A)（Mohamad、Allensbach、Williams，接受演示，ASH 2022）。虽然 aa 替换不同，但建模预测 SEPTIN6 变体采用相同的结构。两名确诊患者的骨髓均具有高度的髓系四倍体，且对 G-CSF 耐药。