Abstract
Background: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown etiology, can be progressive resulting in distortion of extracellular matrix (ECM), inflammation, fibrosis and eventual death.
Patients and methods: Thirteen 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 (12–15 years old), 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 CO2 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 are 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.
Footnotes
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Conflict of interest: Dr. Abdelsayed has nothing to disclose.
Conflict of interest: Dr. Alanazi has nothing to disclose.
Conflict of interest: Dr. AlJebreen has nothing to disclose.
Conflict of interest: Dr. Mobeireek has nothing to disclose.
Conflict of interest: Dr. Alaiya has nothing to disclose.
Conflict of interest: Dr. Meyer has nothing to disclose.
Conflict of interest: Dr. Almutairy reports In addition, Dr. Almutairy has a patent METHOD FOR TREATING PULMONARY FIBROSIS USING S100A3 PROTEIN pending, and a patent The use of S100A13 in the diagnosis and treatment of pulmonary fibrosis pending.
Conflict of interest: Dr. Imtiaz has nothing to disclose.
Conflict of interest: Dr. Hasday has nothing to disclose.
Conflict of interest: Dr. Collison has nothing to disclose.
Conflict of interest: Dr. Alsaif has nothing to disclose.
Conflict of interest: Dr. Al-Owain has nothing to disclose.
Conflict of interest: Dr. Khalid reports In addition, Dr. Khalid has a patent METHOD FOR TREATING PULMONARY FIBROSIS USING S100A3 PROTEIN pending, and a patent The use of S100A13 in the diagnosis and treatment of pulmonary fibrosis pending.
Conflict of interest: Dr. Shamayel has nothing to disclose.
Conflict of interest: Dr. S. A. Khabar has nothing to disclose.
Conflict of interest: Dr. Atamas has nothing to disclose.
Conflict of interest: Dr. Conca has nothing to disclose.
Conflict of interest: Dr. Weheba has nothing to disclose.
Conflict of interest: Dr. Ramzan has nothing to disclose.
Conflict of interest: Dr. Al-Haj has nothing to disclose.
Conflict of interest: Dr. Mahmoud has nothing to disclose.
Conflict of interest: Dr. Saleh has nothing to disclose.
Conflict of interest: Dr. Al Qattan has nothing to disclose.
Conflict of interest: Dr. Al-Mohanna reports In addition, Dr. Al-Mohanna has a patent METHOD FOR TREATING PULMONARY FIBROSIS USING S100A3 PROTEIN pending, and a patent The use of S100A13 in the diagnosis and treatment of pulmonary fibrosis pending.
Conflict of interest: Dr. Luke has nothing to disclose.
Conflict of interest: Dr. Irina has nothing to disclose.
Conflict of interest: Dr. Chisti has nothing to disclose.
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