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

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 <i>ACD Shelterin Complex Subunit and Telomerase Recruitment Factor</i> (<i>ACD</i>) gene are associated with the development of IPF. This study aims to investigate <i>ACD</i> 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 <i>in vitro</i> functional assays. Among the 124 patients, two novel <i>ACD</i> 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 <i>ACD</i> mutations in an Asian population with IPF. Our findings broaden the mutation and population spectrum of ACD deficiency.