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在TBXT的突变导致人类和小鼠的先天性脊椎形

Shuxia Chen¹, Yunping Lei², Yajun Yang³

¹Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Key Laboratory of Reproduction Regulation of NPFPC, Institute of Reproduction and Development, Fudan University, Shanghai 200438, China; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.

Journal of genetics and genomics = Yi chuan xue bao

|September 26, 2023

概括

在T-box转录因子T (TBXT) 基因的新奇突变导致人类和小鼠的先天性脊椎形 (CVMs). 这项研究确定了TBXT.

科学领域:

遗传学是一个遗传学.
发展生物学发展生物学
人类疾病人类疾病

背景情况:

T-box转录因子T (TBXT) 对于中皮形成和轴骨发育至关重要.
与TBXT相关的人类先天性脊椎形 (CVMs) 尚不清楚.
之前对TBXT功能的研究主要利用模型生物.

研究的目的:

为了研究一个特定的TBXT突变 (c.596A>G,p.Q199R) 在人类CVM中的作用.
在哺乳动物模型中确定TBXT p.Q199R突变的致病性.
阐明TBXT相关的CVM背后的分子机制.

主要方法:

基于家族的基因分析,以确定CVM患者的TBXT突变.
在体外功能测试以评估p.Q199R突变对TBXT蛋白的影响.
生成和分析一个Q199R敲入小鼠模型来研究CVM在生物体内.

主要成果:

在四代的15名CVM患者中发现了一种异构的TBXTc.596A>G (p.Q199R) 突变,与表型共同分离.
实验室研究表明,p.Q199R突变改变了TBXT的核细胞质比,增强了DNA结合,但降低了转录活性.
在Q199R敲入小鼠模型中,表现出CVM表型,包括尾部异常和同卵性小鼠的严重脊椎形.

结论:

TBXT p.Q199R突变是致病的,并导致人类的CVM.
这项研究为TBXT在人类CVM遗传病因学中的作用提供了体内证据.
这些发现突出了TBXT作为轴骨发育和CVM病变的重要基因.

关键词:

原始的脊椎形是先天性的.功能丧失突变是指功能丧失的突变.我们的基因是T基因.在TBXT TBXT TBXT

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