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角膜环状皮样瘤(RDC)、虹膜发育不全(IH)和Axenfeld-Rieger综合征(ARS)都是常染色体显性遗传病,都可以由于一个转录因子PITX2的突变引起.在3种疾病中,RDC的症状最轻,IH其次,ARS最重.将分别引起RDC,IH和ARS的错义突变R62H,R84W和T68P定点地引入PITX2野生型cDNA序列中进行分子功能的比较研究.结果证明,3种突变体蛋白都可以在真核细胞中稳定表达,并且都定位在细胞核中.EMSA和转录激活研究显示,3种突变体功能保留情况不同,R62H在三者中保留了最多的活性,R84W也保留了小部分功能,而T68P则完全丧失了DNA结合和转录激活能力.这一结果证实了前人提出的假设,即PITX2突变体残留活性的多少决定了疾病表型的严重程度.
Corneal loop-like dermoid tumors (RDC), iris hypoplasia (IH), and Axenfeld-Rieger syndrome (ARS) are autosomal dominant genetic disorders that are both caused by mutations in one transcription factor, PITX2. Of the three diseases , The symptom of RDC was the lightest, followed by IH and ARS was the heaviest.The molecular motifs of the PITX2 wild-type cDNAs were respectively introduced into the wild-type cDNA sequences of R62H, R84W and T68P which caused the RDC, IH and ARS respectively.The results showed that, All 3 kinds of mutant proteins can be stably expressed in eukaryotic cells and both located in the nucleus.EMSA and transcriptional activation studies showed that the three kinds of mutants retained different functions and R62H retained the most activity in all three.The R84W But also retained a small part of the function, while T68P completely lost the ability of DNA binding and transcriptional activation.This result confirmed the previous hypothesis that the residual activity of PITX2 mutant determines the severity of disease phenotype.