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

E.A. Al-Mutairy, F. Imtiaz, M. Khalid, S. Al Qattan, S. Saleh, L. Mahmoud, M. Al-Saif, L. Al-Haj, A. Al-Enazi, A.M. AlJebreen, S. Mohammed, A. Mobeireek, K. Alkattan, M.A. Chisti, I.G. Luzina, M. Al-Owain, I. Weheba, A. Abdelsayed, K. Ramzan, J.L. Janssen, W. Conca, A. Alaiya, K.S. Collison, B.F. Meyer, S.P. Atamas, K.S. Khabar, J.D. Hasday, F. Al-Mohanna
European Respiratory Journal 2019; DOI: 10.1183/13993003.02041-2018
E.A. Al-Mutairy
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
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F. Imtiaz
4Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
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M. Khalid
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
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S. Al Qattan
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
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S. Saleh
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
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L. Mahmoud
5BioMolecular Medicine, KFSHRC, Riyadh, Saudi Arabia
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M. Al-Saif
5BioMolecular Medicine, KFSHRC, Riyadh, Saudi Arabia
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L. Al-Haj
5BioMolecular Medicine, KFSHRC, Riyadh, Saudi Arabia
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A. Al-Enazi
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
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A.M. AlJebreen
6Department of Radiology, KFSHRC, Riyadh, Saudi Arabia
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S. Mohammed
7Department of Pathology and Laboratory Medicine, KFSHRC, Riyadh, Saudi Arabia
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A. Mobeireek
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
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K. Alkattan
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
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M.A. Chisti
8Department of Dermatology, KFSHRC, Riyadh, Saudi Arabia
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I.G. Luzina
9University of Maryland School of Medicine, Baltimore, MD, USA
10Baltimore VA Medical Center, Baltimore, MD, USA
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M. Al-Owain
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
11Department of Medical Genetics, KFSHRC, Riyadh, Saudi Arabia
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I. Weheba
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
12National Research Centre, Cairo, Egypt
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A. Abdelsayed
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
13Ain Shams University, Cairo, Egypt
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K. Ramzan
4Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
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J.L. Janssen
14St. Joseph's Hospital& Department of Medicine, McMaster University, Ontario, Canada
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W. Conca
1Department of Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
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A. Alaiya
15Stem Cell Therapy Program, KFSHRC, Riyadh, Saudi Arabia
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K.S. Collison
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
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B.F. Meyer
4Department of Genetics, KFSHRC, Riyadh, Saudi Arabia
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S.P. Atamas
9University of Maryland School of Medicine, Baltimore, MD, USA
10Baltimore VA Medical Center, Baltimore, MD, USA
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K.S. Khabar
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
5BioMolecular Medicine, KFSHRC, Riyadh, Saudi Arabia
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J.D. Hasday
9University of Maryland School of Medicine, Baltimore, MD, USA
10Baltimore VA Medical Center, Baltimore, MD, USA
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F. Al-Mohanna
2Department of Cell Biology, KFSHRC, Riyadh, Saudi Arabia
3College of Medicine, Al-Faisal University, Riyadh, Saudi Arabia
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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

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

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.

This is a PDF-only article. Please click on the PDF link above to read it.

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An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13
E.A. Al-Mutairy, F. Imtiaz, M. Khalid, S. Al Qattan, S. Saleh, L. Mahmoud, M. Al-Saif, L. Al-Haj, A. Al-Enazi, A.M. AlJebreen, S. Mohammed, A. Mobeireek, K. Alkattan, M.A. Chisti, I.G. Luzina, M. Al-Owain, I. Weheba, A. Abdelsayed, K. Ramzan, J.L. Janssen, W. Conca, A. Alaiya, K.S. Collison, B.F. Meyer, S.P. Atamas, K.S. Khabar, J.D. Hasday, F. Al-Mohanna
European Respiratory Journal Jan 2019, 1802041; DOI: 10.1183/13993003.02041-2018

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An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13
E.A. Al-Mutairy, F. Imtiaz, M. Khalid, S. Al Qattan, S. Saleh, L. Mahmoud, M. Al-Saif, L. Al-Haj, A. Al-Enazi, A.M. AlJebreen, S. Mohammed, A. Mobeireek, K. Alkattan, M.A. Chisti, I.G. Luzina, M. Al-Owain, I. Weheba, A. Abdelsayed, K. Ramzan, J.L. Janssen, W. Conca, A. Alaiya, K.S. Collison, B.F. Meyer, S.P. Atamas, K.S. Khabar, J.D. Hasday, F. Al-Mohanna
European Respiratory Journal Jan 2019, 1802041; DOI: 10.1183/13993003.02041-2018
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