Wang Huaiyu, Zhu Changhua, Dong Linxin, Wu Baofeng, Liu Jingjing, Lin Lihang, Lin Daoyao, Chen Xiangqi, Xiao Xuemin
Department of Dermatology, The Union Hospital, Fujian Medical University, Fuzhou, China.
MyGenostics Inc., Beijing, China.
Front Genet. 2024 Nov 13;15:1365581. doi: 10.3389/fgene.2024.1365581. eCollection 2024.
The occurrence of pachyonychia congenita (PC) and acne inversa (AI) may be related to gene mutations. The aim of this study is to identify the genetic cause in a patient with PC and AI, and to explore the possible molecular mechanism of their co-occurrence.
The clinical data of the proband were collected, and the genomic DNA of the proband and unaffected parents were extracted. The variant sites of the proband were identified by whole-exome sequencing, and then the variant sites of the proband and his parents were verified by Sanger sequencing.
A heterozygous variant in gene was found in the patient, resulting in a missense amino acid variant (p.N92D). The variant was not found in his parents or 100 unrelated healthy controls. In addition, this variant was not found in the gnomad v4 database. The three-dimensional structure analysis of the protein suggested that the polarity of amino acids changed after the variant. After lentiviral plasmid transfection into HaCaT cells, the expression level of NOTCH signaling decreased in the constructed c.274A>G (p.Asn92Asp) of mutant cells compared to that in the wild-type. Subsequent verification confirmed that differences in the expression levels of p-PI3K, AKT and p-AKT between the groups were not statistically significant.
Although this variant has been reported previously, our findings could expand the spectrum of co-occurrence of PC and AI with gene variants, and elucidated the possible pathogenesis at the protein level, thereby laying a foundation for the genetic diagnosis and genetic counseling provided to individuals with PC.
先天性厚甲症（PC）和反向性痤疮（AI）的发生可能与基因突变有关。本研究旨在确定一名患有PC和AI的患者的遗传病因，并探讨它们共同发生的可能分子机制。
收集先证者的临床资料，提取先证者及其未受影响父母的基因组DNA。通过全外显子组测序确定先证者的变异位点，然后通过桑格测序验证先证者及其父母的变异位点。
在患者中发现基因中的一个杂合变异，导致错义氨基酸变异（p.N92D）。在其父母或100名无关健康对照中未发现该变异。此外，在gnomad v4数据库中也未发现该变异。蛋白质的三维结构分析表明，变异后氨基酸的极性发生了变化。将慢病毒质粒转染到HaCaT细胞中后，与野生型相比，在构建的突变细胞的c.274A>G（p.Asn92Asp）中NOTCH信号的表达水平降低。随后的验证证实，各组之间p-PI3K、AKT和p-AKT的表达水平差异无统计学意义。
虽然该变异先前已有报道，但我们的研究结果可能会扩大PC和AI与基因变异共同发生的范围，并在蛋白质水平上阐明可能的发病机制，从而为为患有PC的个体提供遗传诊断和遗传咨询奠定基础。
