Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis

Heliyon · 14 authors, 4 centres

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TL;DR

A single pedigree with congenital hemolytic anemia was investigated by PKLR gene sequencing, which identified two novel compound heterozygous mutations (c.1097del p.P366Lfs*12 and c.1493G>A p.R498H), and molecular dynamics simulations plus in vitro experiments showed these mutations altered protein structure and reduced expression, supporting a loss-of-function mechanism for PKD.

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This study investigated a single pedigree with congenital hemolytic anemia. PKLR gene sequencing identified novel compound heterozygous loss-of-function mutations: a frameshift mutation (c.1097del p.P366Lfs*12) and a missense mutation (c.1493G>A p.R498H). Simulations revealed that R498H increased hydrophobicity, decreased intrinsically disordered residues, and reduced intermolecular forces in the A domain core. P366Lfs*12 resulted in early translation termination affecting the C domain subunit involved in tetramerization. Both mutations significantly altered global secondary structure, stability, compactness, and flexibility.

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other

SPECIALTY

hematology

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AI pipeline

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ORIGINAL PAPER

PMC10904247

Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis

Heliyon

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ABSTRACT

Abstract 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.P3 66Lfs *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. Keywords: Mutation, Pyruvate kinase deficiency, Pyruvate kinase, Molecular dynamics simulation

CITATION EXPORT

Yang Wang, Jiaqi Liu, Tao Liu et al.. Pyruvate kinase deficiency and PKLR gene mutations: Insights from molecular dynamics simulation analysis. Heliyon. (2024). https://doi.org/10.1016/j.heliyon.2024.e26368

AUTHORS

14 · 4 CENTRES

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

aDepartment of Hematology and Oncology, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Pediatrics, 136 Zhong shan er lu, Yu zhong district, Chongqing 400014, China
bShanghai Cinopath Medical Testing Co Ltd, Shanghai 200000, China
cDepartment of Cardiovascular Medicine, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China
dDepartment of Neurology, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, China