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对MED12 c.887G>A的定性和定量分析导致X链接的欧多综合征中的误解和拼接变异

Sumihito Togi^1,2, Hiroki Ura^1,2, Yo Niida^1,2

¹Center for Clinical Genomics, Kanazawa Medical University Hospital, Uchinada, Ishikawa, Japan.

American journal of medical genetics. Part A

|April 24, 2024

概括

这项研究表明,MED12误解变异导致异常的mRNA拼接,导致男性严重的X链接Ohdo综合征. 对于理解变异效应和患者表型,mRNA分析至关重要.

科学领域:

遗传学遗传学是一种遗传学.
分子生物学分子生物学
人类疾病人类疾病

背景情况:

病原体变体MED12呈现出多样化的表型,特别是在男性中,通常涉及误解突变.
这些误解变体对信使RNA (mRNA) 拼接的影响在很大程度上仍未被探索.

研究的目的:

为了研究一个特定的MED12误解变体 (NM_005120.3:c.887G>A p.
为了将观察到的拼接异常与受影响的男性兄弟姐妹的严重临床表型相关联.
强调mRNA分析在理解变体致病性方面的重要性.

主要方法:

具有智力障碍和多种先天性异常的日本兄弟姐妹的表型特征.
基因分析以确定MED12基因中的致病变体.
基于远程PCR的向RNA测序 (逆转录长安普利康测序),以定性和定量评估MED12mRNA拼接.
在携带母体的X染色体无活化研究.

主要成果:

在受影响的兄弟姐妹中发现了一种已知的MED12误解变异,c.887G>A p.
发现误解变异导致异常拼接,特别是在MED12mRNA的约30%中,在第7个外体 (r.847_888del) 中发生了42bp的框架内删除.
携带母体表现出携带突变异位基因的X染色体100%不活化.

结论:

确定的MED12误解变异诱导了显著的mRNA拼接缺陷,导致男性严重的X链接Ohdo综合征表型.
对于全面解释误解变异效应而言,mRNA水平分析至关重要,超出了简单的氨基酸替代.
这一发现表明,由于拼接变化而导致MED12蛋白功能的降低可能解释了受影响的男性的严重临床表现.

关键词:

与MED12相关的疾病一个X染色体不活化.与X相关的欧多综合征.基因型表型相关性相关性拼接变体的拼接变体有针对性的RNA测序.

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