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在人类神经管缺陷中识别和功能分析罕见的HECTD1误解变异

Elias Oxman¹, Huili Li², Hong-Yan Wang³

¹Center for Genetic Medicine Research, Children's Research Institute, Children's National Research and Innovation Campus, Children's National Hospital, Washington, DC, 20012, USA.

|March 7, 2024

概括

罕见的HECTD1基因变异与人类神经管缺陷 (NTD) 有关. 这些变异会损害HECTD1的功能.

科学领域:

遗传学遗传学是一个
发展生物学发展生物学
生物化学生物化学

背景情况:

神经管缺陷 (NTD) 是一种严重的中枢神经系统形.
在小鼠模型中,HECTD1,一种E3泛素酶,对于神经管闭合至关重要.
之前的工作将细胞外热冲击蛋白90 (eHSP90) 的分泌与Hectd1突变体中的NTD联系起来.

研究的目的:

研究HECTD1序列变异在人类NTDs中的作用.
评估已识别的HECTD1变异对eHSP90分泌的功能影响.

主要方法:

在中国队列中针对性下一代测序 (352例NTD病例,224例对照).
在HEK293T细胞中进行功能测试,以评估蛋白质表达和eHSP90调控.
对HECTD1保存和对突变不耐受性的分析.

主要成果:

在NTD病例中发现了五种罕见的HECTD1误解变异.
这五种变体都显著降低了HECTD1对eHSP90分泌的调节.
一种变体 (A1084T) 显示蛋白质表达显著减少.

结论:

这项研究首次确定了HECTD1序列变异与人类NTD之间的关联.
在NTD患者中发现的HECTD1变体在调节eHSP90分泌时表现出功能受损.
这些发现强调了HECTD1作为NTD病变发生的潜在遗传因素.

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