PT - JOURNAL ARTICLE AU - Eid A. Al-Mutairy AU - Faiga Ahmad Imtiaz AU - Mohammed Khalid AU - Somaya Al Qattan AU - Soad Saleh AU - Linah Mahmood Mahmoud AU - Maher Mohammed Al-Saif AU - Latifa Al-Haj AU - Azizah Al-Enazi AU - Abdullah M. AlJebreen AU - Shamayel Faheem Mohammed AU - Abdullah Fahad Mobeireek AU - Khalid Alkattan AU - Muzamil Amin Chisti AU - Irina G. Luzina AU - Mohammed Al-Owain AU - Ihab Weheba AU - Abeer Mohamed Abdelsayed AU - Khushnooda Ramzan AU - Luke J. Janssen AU - Walter Conca AU - Ayodele Alaiya AU - Kate S. Collison AU - Brian F. Meyer AU - Sergei P. Atamas AU - Khalid S. Khabar AU - Jeffrey D. Hasday AU - Futwan Al-Mohanna TI - An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes <em>S100A3</em> and <em>S100A13</em> AID - 10.1183/13993003.02041-2018 DP - 2019 Jul 01 TA - European Respiratory Journal PG - 1802041 VI - 54 IP - 1 4099 - http://erj.ersjournals.com/content/54/1/1802041.short 4100 - http://erj.ersjournals.com/content/54/1/1802041.full SO - Eur Respir J2019 Jul 01; 54 AB - Background Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death.Methods 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts.Results The combination of a unique pattern of early-onset lung fibrosis (at 12–15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components.Conclusion Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.New evidence links an atypical form of pulmonary fibrosis with digenic mutations in the genes for calcium binding proteins S100A3 and S100A13. This implicates calcium homeostasis in the aetiology and pathogenesis of pulmonary fibrosis. http://bit.ly/2LyUQwb