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The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The combination of a unique pattern of early-onset lung fibrosis (at 12\u201315\u2005years 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<jats:italic>S100A3<\/jats:italic>and a novel truncating mutation in<jats:italic>S100A13<\/jats:italic>, 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our data demonstrate that digenic inheritance of mutations in<jats:italic>S100A3<\/jats:italic>and<jats:italic>S100A13<\/jats:italic>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.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.02041-2018","type":"journal-article","created":{"date-parts":[[2019,5,9]],"date-time":"2019-05-09T12:25:44Z","timestamp":1557404744000},"page":"1802041","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein 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