美国哈佛医学院儿科Daniel E. Bauer研究组取得最新进展。他们通过人类HSC基因编辑分析ELANE中性粒细胞减少症（SCN）的致病性。2021年1月28日出版的《细胞-干细胞》杂志发表了这项成果。
他们在人类造血干细胞和祖细胞（HSPC）中进行了汇总CRISPR筛选，将ELANE突变与中性粒细胞成熟潜力相关联。早期外显子的高效基因编辑引起无意突变介导的衰变（NMD），克服了ELANE突变型SCN患者的HSPC中的中性粒细胞成熟停滞，并产生了正常的造血移植功能。
相反，模仿SCN相关突变的末端外显子移码等位基因避免了NMD，概括了中性粒细胞的成熟停滞，并建立了ELANE突变SCN的动物模型。出人意料的是，只有-1位插入或缺失（indels）会阻碍中性粒细胞的成熟，而-2位晚期外显子indels会抑制翻译并支持中性粒细胞的成熟。对主要HSPC的基因编辑可以有效的鉴定变异的致病性，以阐明疾病的分子机制，并鼓励对ELANE突变的中性粒细胞减少症采取普遍的治疗方法，恢复中性粒细胞的正常产生并保持HSPC的功能。
据了解，严重的先天性SCN是一种威胁生命的疾病，最常见的原因是ELANE基因的显性突变会干扰中性粒细胞的成熟。
附：英文原文
Title: Dissecting ELANE neutropenia pathogenicity by human HSC gene editing
Author: Shuquan Rao, Yao Yao, Josias Soares de Brito, Qiuming Yao, Anne H. Shen, Ruth E. Watkinson, Alyssa L. Kennedy, Steven Coyne, Chunyan Ren, Jing Zeng, Anna Victoria Serbin, Sabine Studer, Kaitlyn Ballotti, Chad E. Harris, Kevin Luk, Christian S. Stevens, Myriam Armant, Luca Pinello, Scot A. Wolfe, Roberto Chiarle, Akiko Shimamura, Benhur Lee, Peter E. Newburger, Daniel E. Bauer
Issue&Volume: 2021-01-28
Abstract: Severe congenital neutropenia (SCN) is a life-threatening disorder most often causedby dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen inhuman hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing ofearly exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturationarrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function. Conversely,terminal exon frameshift alleles that mimic SCN-associated mutations escaped NMD,recapitulated neutrophil maturation arrest, and established an animal model of ELANE-mutant SCN. Surprisingly, only 1 frame insertions or deletions (indels) impededneutrophil maturation, whereas 2 frame late exon indels repressed translation andsupported neutrophil maturation. Gene editing of primary HSPCs allowed faithful identificationof variant pathogenicity to clarify molecular mechanisms of disease and encouragea universal therapeutic approach to ELANE-mutant neutropenia, returning normal neutrophil production and preserving HSPC function.
DOI: 10.1016/j.stem.2020.12.015
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30599-3
Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
官方网址：https://www.cell.com/cell-stem-cell/home
投稿链接：https://www.editorialmanager.com/cell-stem-cell/default.aspx
本期文章：《细胞—干细胞》：Online/在线发表
