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Eur Respir J. 2019 Jul 18;54(1). pii: 1802041. doi: 10.1183/13993003.02041-2018. Print 2019 Jul.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13.

Author information

1
Dept of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
2
Dept of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
3
College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia.
4
Dept of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
5
BioMolecular Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
6
Dept of Radiology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
7
Dept of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
8
Dept of Dermatology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
9
University of Maryland School of Medicine, Baltimore, MD, USA.
10
Baltimore VA Medical Center, Baltimore, MD, USA.
11
Dept of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
12
National Research Centre, Cairo, Egypt.
13
Ain Shams University, Cairo, Egypt.
14
St Joseph's Hospital and Dept of Medicine, McMaster University, Hamilton, ON, Canada.
15
Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
16
Dept of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia futwan@kfshrc.edu.sa.

Abstract

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.

Conflict of interest statement

Conflict of interest: E.A. Al-Mutairy 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: F.A. Imtiaz has nothing to disclose. Conflict of interest: M. 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: S. Al Qattan has nothing to disclose. Conflict of interest: S. Saleh has nothing to disclose. Conflict of interest: L.M. Mahmoud has nothing to disclose. Conflict of interest: M.M. Al-Saif has nothing to disclose. Conflict of interest: L. Al-Haj has nothing to disclose. Conflict of interest: A. Al-Enazi has nothing to disclose. Conflict of interest: A.M. AlJebreen has nothing to disclose. Conflict of interest: S.F. Mohammed has nothing to disclose. Conflict of interest: A.F. Mobeireek has nothing to disclose. Conflict of interest: K. Alkattan has nothing to disclose. Conflict of interest: M.A. Chisti has nothing to disclose. Conflict of interest: I.G. Luzina has nothing to disclose. Conflict of interest: M. Al-Owain has nothing to disclose. Conflict of interest: I. Weheba has nothing to disclose. Conflict of interest: A.M. Abdelsayed has nothing to disclose. Conflict of interest: K. Ramzan has nothing to disclose. Conflict of interest: L.J. Janssen has nothing to disclose. Conflict of interest: W. Conca has nothing to disclose. Conflict of interest: A. Alaiya has nothing to disclose. Conflict of interest: K.S. Collison has nothing to disclose. Conflict of interest: B.F. Meyer has nothing to disclose. Conflict of interest: S.P. Atamas has nothing to disclose. Conflict of interest: K.S. Khabar has nothing to disclose. Conflict of interest: J.D. Hasday has nothing to disclose. Conflict of interest: F. 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.

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