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

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

Yanzhi Ge  1 , Chenfen Zhou  2 , Xiujuan Xiao  3 , Zhijiang Jin  4 , Li Zhou  1 , Zuxiang Chen  1 , Fucun Liu  5 , Qiang Yuan  3 , Guoqing Zhang  2 , Letian Shan  1 , Peijian Tong  1
Affiliations

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

Yanzhi Ge et al. Front Genet. .

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.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer LZ declared a past collaboration with the authors LZ, LS to the handling editor.

Figures

FIGURE 1
FIGURE 1
Pedigrees of all participants in four generations of this study. Each individual was represented by a circle (if female) or a square (if male). Black shaded symbols denoted subjects diagnosed with KOA. Abbreviation: KOA, knee osteoarthritis.
FIGURE 2
FIGURE 2
Flow chart of mutation sites selection.
FIGURE 3
FIGURE 3
The location and distribution of KLK6. (A) The rs201586262 mutation of KLK6 protein. (B) The magnification of the rs201586262 mutational site. (C) The location of KLK6 gene on a chromosome. Note: Red color arrows represent a specific mutation site. (D) The distribution of KLK6 in the microenvironment. Note: The deeper the color, the higher confidence of the KLK6 expression.
FIGURE 4
FIGURE 4
(A) PPI network of KLK6-connected genes. (B) The relationship between KLK6-connected genes and four KOA-related genes databases. (C) The demo diagram showed the relationship between KLK6-connected genes and other databases. Note: Red color marked the crossed genes. Abbreviation: PPI, protein-protein interaction; KLK6, kallikrein-related peptidase six; KOA, knee osteoarthritis; PharmGKB, Pharmacogenomics Knowledgebase; OMIM, Online Mendelian Inheritance in Man.
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