Boyling Alexandra, Perez-Siles Gonzalo, Kennerson Marina L
Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia.
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Front Genet. 2022 Mar 25;13:842860. doi: 10.3389/fgene.2022.842860. eCollection 2022.
A rare form of X-linked Charcot-Marie-Tooth neuropathy, CMTX3, is caused by an interchromosomal insertion occurring at chromosome Xq27.1. Interestingly, eight other disease phenotypes have been associated with insertions (or insertion-deletions) occurring at the same genetic locus. To date, the pathogenic mechanism underlying most of these diseases remains unsolved, although local gene dysregulation has clearly been implicated in at least two phenotypes. The challenges of accessing disease-relevant tissue and modelling these complex genomic rearrangements has led to this research impasse. We argue that recent technological advancements can overcome many of these challenges, particularly induced pluripotent stem cells (iPSC) and their capacity to provide access to patient-derived disease-relevant tissue. However, to date these valuable tools have not been utilized to investigate the disease-associated insertions at chromosome Xq27.1. Therefore, using CMTX3 as a reference disease, we propose an experimental approach that can be used to explore these complex mutations, as well as similar structural variants located elsewhere in the genome. The mutational hotspot at Xq27.1 is a valuable disease paradigm with the potential to improve our understanding of the pathogenic consequences of complex structural variation, and more broadly, refine our knowledge of the multifaceted process of long-range gene regulation. Intergenic structural variation is a critically understudied class of mutation, although it is likely to contribute significantly to unsolved genetic disease.
一种罕见的X连锁型夏科-马里-图斯神经病变，即CMTX3，是由发生在Xq27.1染色体上的染色体间插入引起的。有趣的是，其他八种疾病表型也与发生在同一基因座的插入（或插入-缺失）有关。迄今为止，尽管局部基因失调显然与至少两种表型有关，但这些疾病中大多数的致病机制仍未得到解决。获取与疾病相关的组织以及对这些复杂的基因组重排进行建模的挑战导致了这一研究僵局。我们认为，最近的技术进步可以克服其中许多挑战，特别是诱导多能干细胞（iPSC）及其提供获取患者来源的与疾病相关组织的能力。然而，迄今为止，这些有价值的工具尚未用于研究Xq27.1染色体上与疾病相关的插入。因此，以CMTX3作为参考疾病，我们提出了一种实验方法，可用于探索这些复杂的突变以及位于基因组其他位置的类似结构变异。Xq27.1处的突变热点是一个有价值的疾病范例，有可能增进我们对复杂结构变异致病后果的理解，更广泛地说，完善我们对远程基因调控多方面过程的认识。基因间结构变异是一类研究严重不足的突变，尽管它可能对未解决的遗传疾病有重大贡献。
