The role of Septin6 Group in Murine and Human Hematopoiesis

Septin6 组在小鼠和人类造血中的作用

基本信息

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
项目类别：
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

项目摘要

(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，并且在计算机模拟中表明添加了与 SEPTIN6 c.1282T>C p 相关的 9 个氨基酸 (aa) .428Glnext*9 突变会通过干扰 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。