Abstract

Papillon Lefevre syndrome (PLS) manifests with palmoplantar keratoderma, combined with a rapidly progressive periodontitis associated with mutations in Cathepsin C (CTSC) gene. This article reports a 15-year old male proband with typical PLS traits having a novel compound heterozygote with p.Q49X mutation in exon 1 and p.Y259C missense mutation in exon 6 of CTSC gene respectively. The exon 1 mutation, p.Q49X, (found in proband’s mother) was located in exclusion domain and exon 6 mutation, p.Y259C (found in proband’s father), was present in peptidase C1A, papain C-terminal domain. Interestingly, missense mutation p.Y259C identified in this study was found to be not reported so far. Upon computational analysis, this missense mutation was found to be lethal. Moreover, our protein modelling approach using mutant protein revealed the presence of monomeric structure on contrary to the tetrameric structure of the wild type protein. In addition, in vitro functional characterization of mutant p.Y259C expressed in HEK293 cells showed a significant reduction in CTSC activity (0.015 ± 0.009 mU/ml) when compared with wild type protein (0.21 ± 0.008 mU/ml). Thus, in this study, we have demonstrated that the pathogenic missense mutant p.Y259C might cause PLS by impaired CTSC function.

中文翻译：

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Papillon-Lefèvre综合征（PLS）在组织蛋白酶C基因的排他和肽酶C1A域中具有新型复合杂合突变。

摘要

Papillon Lefevre综合征（PLS）表现为掌plant角化病，并伴有与组织蛋白酶C（CTSC）基因突变相关的快速进行性牙周炎。本文报道了一个具有典型PLS性状的15岁男性先证者，在CTSC外显子1的p.Q49X突变和p.Y259C错义突变的新型复合杂合子基因分别。外显子1突变p.Q49X（在先证者的母亲中发现）位于排斥域中，外显子6突变p.Y259C（在先证者的父亲中发现）存在于木瓜蛋白酶C末端域肽酶C1A中。有趣的是，该研究中发现的错义突变p.Y259C迄今未见报道。通过计算分析，发现这种错义突变是致命的。而且，我们使用突变蛋白的蛋白质建模方法揭示了与野生型蛋白的四聚体结构相反的单体结构的存在。另外，与野生型蛋白（0.21±0.008mU / ml）相比，HEK293细胞中表达的突变体p.Y259C的体外功能表征显示CTSC活性显着降低（0.015±0.009mU / ml）。因此，在这项研究中