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首页> 外文期刊>Human mutation >Characterization of mutation spectrum and identification of novel mutations in ATP7B ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications
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Characterization of mutation spectrum and identification of novel mutations in ATP7B ATP7B gene from a cohort of Wilson disease patients: Functional and therapeutic implications

机译：来自威尔逊病患者群体突变谱和ATP7B ATP7B基因鉴定的突变谱和鉴定的特征：功能性和治疗意义

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Abstract Wilson disease (WD), a copper metabolism disorder, occurs due to the presence of mutations in the gene encoding ATP7B, a protein that primarily facilitates hepatic copper excretion. A better understanding of spectrum and functional significance of ATP7B variants is critical to formulating targeted and personalized therapies. Henceforth, we screened and sequenced 21 exons of ATP7B gene from 50 WD patients and 60 healthy subjects. We identified 28 variants comprising, seven novels in 20% alleles, while eight variations affecting 23% alleles were first time reported in Indian cohort. The c.813CA, p.(Cys271*) (10%) was the most frequent mutation. Bioinformatics analysis revealed five of seven novel variants viz. c.1600CA, p.(Pro534Thr); c.1616CA, p.(Pro539His); c.1924GT, p.(Asp642Tyr); c.2168GC, p.(Arg723Thr); c.2174GC, p.(Arg725Thr) resulted in protein misfolding. Sequence conservation analysis of ATP7B regions containing novel variants documented an evolutionarily conserved nature. Functional analysis of these novel variants in five different cell lines lacking inherent ATP7B expression demonstrated sensitivity to CuCl 2 ‐treatment, experiencing augmented cellular copper retention and decreased copper excretion as well as ceruloplasmin secretion to that of wildtype‐ ATP7B expressing cells. Interestingly, pharmacological chaperone 4‐phenylbutyrate, a clinically approved compound, partially restored protein function of ATP7B mutants. These findings might enable novel treatment strategies in WD by clinically enhancing the protein expression of mutant ATP7B with residual copper export activity.
机译：摘要由于编码ATP7B的基因中的突变存在，铜代谢障碍发生铜代谢疾病（WD），主要促进肝铜排泄的蛋白质。更好地理解ATP7B变体的频谱和功能性意义对于制定靶向和个性化疗法至关重要。从此，我们从50名WD患者和60名健康受试者筛查和测序21个ATP7B基因外显子。我们鉴定了28种变体，其中七种小说在20％等位基因中，而影响23％等位基因的八种变异首次在印度队列中报告。 C.813C＆ a，p。（cys271 *）（10％）是最常见的突变。生物信息学分析揭示了七种新型变种的五种viz。 C.1600C＆ a，p。（pro534th）; C.1616C＆ a，p。（pro539his）; C.1924G＆ t，p。（asp642tyr）; C.2168G＆ c，p。（arg723th）; C.2174G＆ C，p。（Arg725Thr）导致蛋白质误用。含有新型变体的ATP7B区域的序列守恒分析记录了一种进化保守的性质。在缺乏固有的ATP7B表达中的五种不同细胞系中这些新型变体的功能分析表明了与CuCl 2-处理的敏感性，经历增强的细胞铜保留和降低铜排泄以及表达细胞的野生型 - ATP7B的分泌。有趣的是，药理伴侣4-苯基丁酯，临床批准的化合物，ATP7B突变体的部分恢复的蛋白质功能。这些发现可能通过临床上增强突变体ATP7B与残留铜出口活动的蛋白质表达来实现新的治疗策略。

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