异合体THBS2致病变体导致埃勒斯-丹洛斯综合征,在人类和小鼠中具有突出的血管特征
Noam Hadar1,2, Omri Porgador1,2, Idan Cohen2
1The Morris Kahn Laboratory of Human Genetics at the National Institute of Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
European journal of human genetics : EJHG
|March 3, 2024
概括
一种与THBS2突变相关的新型埃勒斯-丹洛斯综合征 (EDS) 形式导致血管问题. 这一发现在小鼠中得到证实,强调了Thrombospondin-2的存在.
科学领域:
- 遗传学 是一个遗传学.
- 分子生物学分子生物学
- 病理学 病理学 病理学
背景情况:
- 埃勒斯-丹洛斯综合征 (EDS) 是一种遗传性结合组织疾病.
- 原蛋白和相关基因的突变导致EDS.
- 一种带有血管并发症的新型EDS变体需要进行表征.
研究的目的:
- 为了划出一种新的EDS形式,具有血管特征.
- 为了确定这种EDS变异的遗传原因.
- 在小鼠模型中验证研究结果.
主要方法:
- 三代血统的临床和本病学表型化.
- 基因分析以确定致病突变.
- 基因编辑CRISPR/Cas9以创建敲进 (KI) 鼠标模型.
- 形态学,组织学和传输电子显微镜 (TEM) 分析.
- 出血时间测定.
主要成果:
- 观察到一种新型的自体主导EDS表型,包括关节多动,脱,缩性痕,长时间出血和大动脉问题.
- 组织病理学揭示了无组织的原蛋白,异常的纤维细胞/内皮细胞以及改变的细胞外基质 (ECM).
- 鉴定了一种异构THBS2突变 (c.2686T>C,p.Cys896Arg).
- THBS2-KI小鼠表现出类似的表型特征,证实了突变的致病性.
- THBS2功能丧失会影响MMP2清除,导致ECM异常.
结论:
- 一种与血管并发症相关的新型EDS形式是由异合体THBS2误解突变引起的.
- 这种EDS变种呈现出古典式的特征和显著的血管参与.
- THBS2-KI小鼠模型重复了人类的表型,支持THBS2在连接组织和血管完整性中的作用.
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