Whole exome sequencing identified two novel mutations of ACD in Chinese patients with idiopathic pulmonary fibrosis

TL;DR

This study identifies two new mutations in the ACD gene in Chinese patients with idiopathic pulmonary fibrosis, linking them to telomere shortening and disease progression.

Contribution

The study reports the first ACD mutations associated with IPF in an Asian population, expanding the known mutation spectrum.

Findings

Two novel ACD mutations (c.884G>A/p.S295N and c.1074C>G/p.H358Q) were identified in Chinese IPF patients.

These mutations reduce TPP1 protein stability and expression, leading to telomere shortening.

The findings suggest a role for ACD mutations in IPF pathogenesis in Asian populations.

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive, age-related, and distinct form of fibrosing interstitial pneumonia with an unknown etiology. Previous studies have indicated that mutations in the ACD Shelterin Complex Subunit and Telomerase Recruitment Factor (ACD) gene are associated with the development of IPF. This study aims to investigate ACD mutations in Chinese patients with interstitial lung diseases (ILDs). A total of 124 ILD patients were enrolled in this study. Whole exome sequencing and Sanger sequencing were performed to identify genetic variants in these individuals. Mutant plasmids were constructed and transfected into the A549 cell line to conduct in vitro functional assays. Among the 124 patients, two novel ACD mutations (c.884G>A/p.S295N and c.1074C>G/p.H358Q) were identified in two Chinese families with a history of IPF. Functional analyses revealed that both mutations compromise the stability of the TPP1 protein, leading to reduced TPP1 expression. This downregulation subsequently decreases DKC1 expression, ultimately resulting in telomere shortening and contributing to IPF pathogenesis. To the best of our knowledge, this study represents the first report of ACD mutations in an Asian population with IPF. Our findings broaden the mutation and population spectrum of ACD deficiency.

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