Vitale Alessandra Maria, Conway de Macario Everly, Alessandro Riccardo, Cappello Francesco, Macario Alberto J L, Marino Gammazza Antonella
Department of Biomedicine, Neuroscience and Advanced Diagnosis, Section of Human Anatomy, University of Palermo, Palermo, Italy.
Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
Front Genet. 2020 Aug 18;11:969. doi: 10.3389/fgene.2020.00969. eCollection 2020.
Two chaperonopathies have been linked to mutations in the human (; ) gene, but other existing variants might cause diseases, even if there is no comprehensive information about this possibility. To fill this vacuum, which might be at the basis of misdiagnoses or simply ignorance of chaperonopathies in patients who would benefit by proper identification of their ailments, we searched the sequenced human genomes available in public databases to determine the range of missense mutations in the single gene. A total of 224 missense mutations were identified, including those already characterized. Detailed examination of these mutations was carried out to assess their possible impact on protein structure-function, considering: (a) the properties of individual amino acids; (b) the known functions of the amino acids in the human Hsp60 and/or in the highly similar bacterial ortholog GroEL; (c) the location of the mutant amino acids in the monomers and oligomers; and (d) structure-function relationships inferred from crystal structures. And we also applied a bioinformatics tool for predicting the impact of mutations on proteins. A portion of these genetic variants could have a deleterious impact on protein structure-function, but have not yet been associated with any pathology. Are these variants causing disease with mild clinical manifestations and are, therefore, being overlooked? Or are they causing overt disease, which is misdiagnosed? Our data indicate that more chaperonopathies might occur than is currently acknowledged and that awareness of chaperonopathies among medical personnel will increase their detection and improve patient management.
两种伴侣蛋白病已被证实与人类（；）基因的突变有关，但其他现有变体可能也会引发疾病，即便目前尚无关于这种可能性的全面信息。为填补这一空白（这可能是导致误诊的原因，或者仅仅是因为医疗人员对伴侣蛋白病缺乏了解，而这些患者若能得到正确诊断，病情将会得到改善），我们在公共数据库中搜索了已测序的人类基因组，以确定单个基因中错义突变的范围。我们共识别出224个错义突变，其中包括那些已经被鉴定过的突变。我们对这些突变进行了详细检查，以评估它们对蛋白质结构和功能可能产生的影响，评估时考虑了以下因素：（a）单个氨基酸的特性；（b）人类Hsp60和/或高度相似的细菌直系同源物GroEL中氨基酸的已知功能；（c）突变氨基酸在单体和寡聚体中的位置；（d）从晶体结构推断出的结构-功能关系。我们还应用了一种生物信息学工具来预测突变对蛋白质的影响。这些基因变体中的一部分可能会对蛋白质的结构和功能产生有害影响，但尚未与任何病理学相关联。这些变体是导致了临床表现轻微的疾病，因此被忽视了吗？还是它们导致了明显的疾病，却被误诊了？我们的数据表明，可能存在比目前所知更多的伴侣蛋白病，提高医疗人员对伴侣蛋白病的认识将有助于提高对它们的检测率，并改善患者的治疗效果。
