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常染色体显性遗传Alport综合征致病基因 COL4A4杂合剪接突变的致病性分析及基因型-表型关联分析

wf(2023)

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Abstract
目的:探讨常染色体显性遗传Alport综合征(autosomal dominant Alport syndrome,ADAS)致病基因 COL4A4杂合剪接突变的致病机制及基因型与表型的关联,以加深对 COL4A4剪接突变的认识以及对ADAS表型异质性的理解。 方法:本研究为病例系列分析。从3家医院收集5个ADAS家系先证者及家系成员的临床资料。对从先证者中经全外显子组测序(whole exome sequencing,WES)发现的 COL4A4杂合剪接变异,通过RNA体内剪接或Minigene体外实验分析其对mRNA正常剪接的影响。 结果:在此5个ADAS家系患者中经WES发现了4个 COL4A4杂合剪接变异位点。家系1、家系2、家系3和家系4中多数患者呈孤立性镜下血尿或合并微量蛋白尿,个别患者合并显性蛋白尿、进入老年期后出现肾功能轻度减退。家系5中4例患者均呈快速肾功能进展,于28~41岁进展至终末期肾病。家系1、家系2患者携带的c.735+3A>G和家系3患者携带的c.694-1G>C均可引起 COL4A4的第12号外显子跳跃导致42 bp核苷酸框内缺失(c.694_735del),家系4中发现的c.2056+3A>G可引起 COL4A4的第26号外显子跳跃导致69 bp核苷酸框内缺失(c.1988_2056del)。家系5中发现的c.2716+5G>T可引起包括第29号外显子3’端100 bp缺失、第30号外显子跳跃和第31号外显子5’端89 bp缺失的360 bp核苷酸大片段框内缺失(c.2446_2805del)。 结论:COL4A4杂合剪接突变导致不同大小核苷酸框内缺失与ADAS表型存在一定关联。通过体内或体外实验明确 COL4A4剪接突变影响mRNA剪接的具体方式可能有助于分析ADAS基因型对表型的影响。
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Key words
Nephritis, hereditary,Mutation,Genetic association studies,Alport syndrome,Autosomal dominant inheritance,COL4A4,Splicing mutation
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