PDF(Pubmed)
Abstract：
Idiopathic congenital nystagmus (ICN) manifests as involuntary and periodic eye movements. To identify the genetic defect associated with X-linked ICN, Whole Exome Sequencing (WES) was conducted in two affected families. We identified two frameshift mutations in FRMD7, c.1492dupT/p.(Y498Lfs*15) and c.1616delG/p.(R539Kfs*2). Plasmids harboring the mutated genes and qPCR analysis revealed mRNA stability, evading degradation via the NMD pathway, and corroborated truncated protein production via Western-blot analysis. Notably, both truncated proteins were degraded through the proteasomal (ubiquitination) pathway, suggesting potential therapeutic avenues targeting this pathway for similar mutations. Moreover, we conducted a comprehensive analysis, summarizing 140 mutations within the FRMD7 gene. Our findings highlight the FERM and FA structural domains as mutation-prone regions. Interestingly, exons 9 and 12 are the most mutated regions, but 90% (28/31) mutations in exon 9 are missense while 84% (21/25) mutations in exon 12 are frameshift. A predominant occurrence of shift code mutations was observed in exons 11 and 12, possibly associated with the localization of premature termination codons (PTCs), leading to the generation of deleterious truncated proteins. Additionally, our conjecture suggests that the loss of FRMD7 protein function might not solely drive pathology; rather, the emergence of aberrant protein function could be pivotal in nystagmus etiology. We propose a dependence of FRMD7 protein normal function primarily on its anterior domain. Future investigations are warranted to validate this hypothesis.
摘要：
特发性先天性眼球震颤（ICN）表现为不自主和周期性的眼球运动。为了确定与X连锁ICN相关的遗传缺陷，在两个受影响的家庭中进行全外显子组测序(WES)。我们在FRMD7中鉴定了两个移码突变，c.1492dupT/p。（Y498Lfs*15）和c.1616delG/p。（R539Kfs*2）。携带突变基因的质粒和qPCR分析显示mRNA稳定性，通过NMD途径逃避降解，并通过蛋白质印迹分析证实了截短的蛋白质生产。值得注意的是,两种截短的蛋白质都通过蛋白酶体（泛素化）途径降解，提出了针对类似突变的潜在治疗途径。此外，我们进行了全面的分析，总结了FRMD7基因中的140个突变。我们的发现强调了FERM和FA结构域是易发生突变的区域。有趣的是,外显子9和12是突变最多的区域，但外显子9中90%(28/31)的突变是错义的，而外显子12中84%(21/25)的突变是移码的。在外显子11和12中观察到移位代码突变的主要发生，可能与过早终止密码子（PTC）的定位有关，导致有害的截短蛋白质的产生。此外,我们的猜想表明，FRMD7蛋白功能的丧失可能不仅仅是驱动病理；相反，异常蛋白质功能的出现可能是眼球震颤病因的关键。我们提出FRMD7蛋白正常功能的依赖性主要取决于其前结构域。未来的调查有必要验证这一假设。
