RT Journal Article
SR Electronic
T1 An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes <em>S100A3</em> and <em>S100A13</em>
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1802041
DO 10.1183/13993003.02041-2018
VO 54
IS 1
A1 Eid A. Al-Mutairy
A1 Faiga Ahmad Imtiaz
A1 Mohammed Khalid
A1 Somaya Al Qattan
A1 Soad Saleh
A1 Linah Mahmood Mahmoud
A1 Maher Mohammed Al-Saif
A1 Latifa Al-Haj
A1 Azizah Al-Enazi
A1 Abdullah M. AlJebreen
A1 Shamayel Faheem Mohammed
A1 Abdullah Fahad Mobeireek
A1 Khalid Alkattan
A1 Muzamil Amin Chisti
A1 Irina G. Luzina
A1 Mohammed Al-Owain
A1 Ihab Weheba
A1 Abeer Mohamed Abdelsayed
A1 Khushnooda Ramzan
A1 Luke J. Janssen
A1 Walter Conca
A1 Ayodele Alaiya
A1 Kate S. Collison
A1 Brian F. Meyer
A1 Sergei P. Atamas
A1 Khalid S. Khabar
A1 Jeffrey D. Hasday
A1 Futwan Al-Mohanna
YR 2019
UL http://erj.ersjournals.com/content/54/1/1802041.abstract
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