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鉴定和描述一种罕见的MTTP变体,该变体是遗传性非酒精性脂肪肝疾病的基础
Jane I Grove1,2, Peggy C K Lo3,4, Nick Shrine5
1National Institute of Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & University of Nottingham, Nottingham, UK.
JHEP reports : innovation in hepatology
|July 24, 2023
概括
微体三糖转移蛋白 (MTP) 基因中的一种罕见的遗传变异会在缺乏常见危险因素的家庭中引起严重的非酒精性脂肪性肝病 (NAFLD). 这一发现为研究NAFLD机制和潜在治疗方法提供了新的模型.
科学领域:
- 遗传学 遗传学是一种遗传学.
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
背景情况:
- 非酒精性脂肪肝 (NAFLD) 影响全球25%的人口.
- 一个四代家庭呈现出渐进的NAFLD,肝硬化和肝细胞癌,尽管缺乏典型的危险因素,如肥胖和2型糖尿病.
研究的目的:
- 在一个没有共同的风险因素的家庭中识别导致严重NAFLD的遗传变异.
- 描述与已识别的变种相关的临床和代谢表型.
- 阐明背后的细胞机制变体诱导的肝病理.
主要方法:
- 外基因组测序和全基因组比较以确定因果变异.
- 在家庭成员中临床表型和食后代谢反应评估.
- 从诱导的多能干干细胞生成表达变异的肝细胞样细胞 (HLCs) 的生成和表征.
- 在CRISPR-Cas9基因编辑中恢复HLC中的野生型MTP功能.
- 使用成像,RNA分析和分子表达阵列评估HLC表型.
主要成果:
- 在微体三糖转移蛋白 (MTTP) 基因中发现了一种罕见的变异 (c.1691T>C p.I564T) 被确定为因果.
- 对于MTTP p.I564T的同卵性与进展性NAFLD有关,独立于代谢综合征或阿贝塔利蛋白质血症的特征.
- 变异表达的HLCs表现出降低的MTP活性和ApoB分泌,细胞质甘油三积累,ER压力和炎症.
结论:
- 罕见的MTTP p.I564T变体的同卵性导致进展性NAFLD,而没有其他表现为abetalipoproteinaemia.
- 这项研究为推动NAFLD严重进展的分子机制提供了新的见解.
- 鉴定的变体和细胞模型是未来NAFLD研究和治疗开发的宝贵工具.
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