A Novel Mutation of the KLK6 Gene in a Family With Knee Osteoarthritis

Yanzhi Ge; Chenfen Zhou; Xiujuan Xiao; Zhijiang Jin; Li Zhou; Zuxiang Chen; Fucun Liu; Qiang Yuan; Guoqing Zhang; Letian Shan; Peijian Tong

doi:10.3389/fgene.2021.784176

A Novel Mutation of the KLK6 Gene in a Family With Knee Osteoarthritis

Front Genet. 2021 Nov 11:12:784176. doi: 10.3389/fgene.2021.784176. eCollection 2021.

Authors

Yanzhi Ge¹, Chenfen Zhou², Xiujuan Xiao³, Zhijiang Jin⁴, Li Zhou¹, Zuxiang Chen¹, Fucun Liu⁵, Qiang Yuan³, Guoqing Zhang², Letian Shan¹, Peijian Tong¹

Affiliations

¹ The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.
² National Genomics Data Center, CAS Key Laboratory of Computational Biology, Bio-Med Big Data Center, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
³ College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
⁴ Department of Orthopaedics, The 9th People's Hospital of Hangzhou, Hangzhou, China.
⁵ Department of Orthopaedics, Changzheng Hospital, Second Military Medical University, Shanghai, China.

Abstract

To investigate the correlation between gene mutation and knee osteoarthritis (KOA), a whole-exome sequencing (WES) was applied to analyze blood samples of four KOA patients and two normal subjects in a family. Gene mutations were identified by gene-trapping and high-throughput sequencing analysis across the differences between the patients and normal subjects. The interactive gene network analysis on the retrieval of interacting genes (STRING) database and the KOA-related genes expression data sets was performed. A possibly detrimental and nonsynonymous mutation at the kallikrein-related peptidase 6 (KLK6) gene (rs201586262, c. C80A, P27H) was identified and attracted our attention. KLK6 belongs to the kallikrein family of serine proteases and its serum level is known as a prevalent biomarker in inflammatory and malignant diseases. KLK6 expresses in the extracellular compartment for matrix degradation, highlighting that KLK6 plays a role in the pathogenesis of KOA. By using the gene databases, the KOA-related genes were mined after de-duplication and IL6 was selected as the most relevant gene through interactive analysis of protein-protein interaction (PPI) network. The data suggested that KLK6 gene mutation and the related expression alteration of IL6 gene might determine the occurrence of hereditary KOA. The is the first study discovering the gene mutation of KLK6 as a factor of pathogenesis of KOA, especially the hereditary KOA.

Keywords: IL6; KLK6; knee osteoarthritis; mutation; whole-exome sequencing.