一种自体主导的儿童发病疾病,与VCP的病原变异有关
Annelise Y Mah-Som1, Jil Daw2, Diana Huynh3
1Genetics Training Program, Harvard Medical School and Brigham & Women's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
American journal of human genetics
|October 26, 2023
概括
含有瓦洛辛蛋白 (VCP) 的基因变异会导致儿童出现新的神经发育障碍,与成人发病的VCP蛋白质病症不同. 这项研究确定了与发育迟缓和智力障碍相关的新型VCP变体.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 神经科学是一个神经科学.
背景情况:
- 含有瓦洛辛的蛋白质 (VCP) 是一个AAA+ ATPase,对于依赖于全方位素的细胞功能至关重要.
- 致病性VCP变体与成人发病的多系统蛋白质病变 (MSP) 相关,影响肌肉,骨,认知和运动神经元.
研究的目的:
- 识别和描述与儿童发作的神经发育障碍相关的新型VCP变异.
- 研究这些变异对VCP蛋白活性和细胞过程的功能影响.
主要方法:
- 基因匹配器被用来识别具有VCP变异的个体.
- 三个外基因组测序和多基因面板被用于变体识别.
- 在体外功能测定和在模型中评估了变异对VCP ATPase活性和蛋白质功能的影响.
主要成果:
- 鉴定出13个异性VCP变异体 (12个新发,1个遗传) 的非相关个体.
- 变体包括误解,框架内删除,移和拼接更改.
- 功能性研究显示ATPase活性降低或过度激活,并预测了哈普洛缺陷,表明功能丧失机制.
结论:
- 这项研究扩大了VCP已知的疾病谱,包括儿童开始的神经发育障碍.
- 这些发现突出显示VCP是儿科神经发育条件中的重要基因.
- 已识别的变异提供了关于VCP相关疾病和潜在治疗点的见解.
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