Research Paper Volume 11, Issue 3 pp 933—949

AluYb8 insertion polymorphism in the MUTYH gene impairs mitochondrial DNA maintenance and affects the age of onset of IPF

Wei Zhou1,4, , Jiapeng Sun1,4, , Wenwen Guo3, , Yi Zhuang1,2, , Lizhi Xu1,4, , Yaping Wang1,4, ,

  • 1 Department of Medical Genetics, Nanjing University School of Medicine, Nanjing, China
  • 2 Department of Respirology, Medical School Affiliated Drum Tower Hospital, Nanjing University, Nanjing, China
  • 3 Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
  • 4 Jiangsu Key Laboratory of Molecular Medicine, Nanjing University School of Medicine, Nanjing, Jiangsu, China

Received: May 10, 2018       Accepted: January 23, 2019       Published: February 4, 2019
How to Cite

Copyright: © 2019 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with an unknown etiology. Increased oxidative stress and mitochondrial dysfunction are thought to be involved in its pathogenesis. However, the effect of the AluYb8MUTYH polymorphism on IPF is not known.

Results: The mean age of onset for IPF in patients homozygous for the AluYb8MUTYH variant (P/P) was 66.5 years old, which was significantly earlier than that in patients with the wild-type (A/A, 70.45 years old). For the 97 male IPF patients with lung function data, the FVC% of the P/P patients was lower than that of the wild-type (A/A) or heterozygous (A/P) patients. The laboratory analysis indicated that an increased mtDNA content and impaired mitochondrial quality control were associated with the P/P genotype. We also confirmed that AluYb8 insertion into MUTYH caused decreased MUTYH1 expression in lung tissues.

Methods: We compared the lung function of IPF patients and observed the mtDNA content, mtDNA integrity and molecular expression of mitochondrial quality control among subjects with different AluYb8MUTYH genotypes. Additionally, immunoblotting and a reporter gene system were used to test whether altered mitochondrial MUTYH1 expression was linked to AluYb8MUTYH.

Conclusions: The AluYb8 insertion polymorphism in MUTYH impairs mtDNA stability and affects the age of onset of IPF.


IPF: idiopathic pulmonary fibrosis; mtDNA: mitochondrial DNA; UIP: usual interstitial pneumonia; ROS: reactive oxygen species; 8-oxoG: 8-oxo-7, 8-dihydroguanine; BER: base excision repair; MTS: mitochondrial targeting signal; FVC: forced vital capacity; FEV1: forced expiratory volume in 1 s; DLOC: diffusion capacity for carbon monoxide; SSB: single-strand break; mtQC: mitochondrial quality control; BAL: bronchoalveolar lavage; ECL: enhanced chemiluminescence..