Pyruvate kinase deficiency and <i>PKLR</i> gene mutations: Insights from molecular dynamics simulation analysis

作者全名："Wang, Yang; Liu, Jiaqi; Liu, Tao; An, Xizhou; Huang, Lan; Li, Jiacheng; Zhang, Yongjie; Xiang, Yan; Xiao, Li; Yi, Weijia; Qin, Jiebin; Liu, Lili; Wang, Cuilan; Yu, Jie"

作者地址："[Wang, Yang; Liu, Tao; An, Xizhou; Huang, Lan; Li, Jiacheng; Zhang, Yongjie; Xiang, Yan; Xiao, Li; Yi, Weijia; Qin, Jiebin; Yu, Jie] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Dept Hematol & Oncol,Childrens Hosp,Minist Educ,Ch, 136 Zhong Shan Er Lu, Chongqing 400014, Peoples R China; [Liu, Jiaqi] Shanghai Cinopath Med Testing Co Ltd, Shanghai 200000, Peoples R China; [Liu, Lili] North China Univ Sci & Technol, Dept Cardiovasc Med, Affiliated Hosp, Tangshan 063000, Peoples R China; [Wang, Cuilan] North China Univ Sci & Technol, Dept Neurol, Affiliated Hosp, Tangshan 063000, Peoples R China; [Yu, Jie] Chongqing Med Univ, Childrens Hosp, Dept Hematol & Oncol, 136 Zhong Shan Er Lu, Chongqing 400014, Peoples R China"

通信作者："Yu, J (通讯作者)，Chongqing Med Univ, Childrens Hosp, Dept Hematol & Oncol, 136 Zhong Shan Er Lu, Chongqing 400014, Peoples R China."

来源：HELIYON

ESI学科分类：　

WOS号：WOS:001197796100001

JCR分区：Q1

影响因子：3.4

年份：2024

卷号：10

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：Mutation; Pyruvate kinase deficiency; Pyruvate kinase; Molecular dynamics simulation

摘要："Pyruvate kinase deficiency is a rare hereditary erythrocyte enzyme disease caused by mutations in the pyruvate kinase liver and red blood cell gene. The clinical presentations of pyruvate kinase deficiency are significantly heterogeneous, ranging from just mild anemia to hemolytic crisis or even death. The proband in our study was a 2-year-old girl for severe skin and scleral icterus with progressive aggravation. We collected the family's data for further analysis. Whole exome genome sequencing of the pedigree revealed a novel compound heterozygous mutation, c.1097del (p.P366Lfs*12) and c.1493G > A (p.R498H), in the pyruvate kinase liver and red blood cell gene. Furthermore, molecular dynamics simulations were employed to uncover differences between the wild type and mutant pyruvate kinase liver and red blood cell proteins, focusing on structural stability, protein flexibility, secondary structure, and overall conformation. The combined bioinformatic tools were also utilised to assess the effects of the missense mutation on protein function. Thereafter, wild type and mutant plasmids were constructed and transfected into 293T cells, and Western blot assay was conducted to validate the impact of the mutations on the expression of pyruvate kinase liver and red blood cell protein. The data presented in our study enriches the genotype database and provides evidence for genetic counseling and molecular diagnosis of pyruvate kinase deficiency."

基金机构：Research Projects of Chongqing Municipal Health and Health Commission [2022WSJK005]; Intelligence Medicine Project of Chongqing Medical University [YJSZHYX202103]

基金资助正文：This work was supported by 2022 Research Projects of Chongqing Municipal Health and Health Commission (No. 2022WSJK005) and the Intelligence Medicine Project of Chongqing Medical University (YJSZHYX202103) .