Use of a calcium-based therapeutic approach for the management of an atypical form of pulmonary fibrosis (PF) has been suggested, based on findings of coinheritance of mutations in the calcium-binding protein genes S100A3 and S100A13. A clinical investigation and genomic DNA analysis were conducted among a group of patients, their parents, and their unaffected relatives. Results of the study were published in the European Respiratory Journal.
Researchers evaluated a total of 13 patients who were born to consanguineous parents from 2 unrelated families who had interstitial lung disease. Of the 13 participants, respiratory failure developed in 9 people, who ultimately died. The researchers performed molecular genetic analyses on the patients’ whole blood or archived tissue. Additionally, cell biologic examinations were conducted on patient-derived fibroblasts.
A combination of a unique early onset lung fibrosis pattern (with symptoms beginning between 12 and 15 years of age) and distinct radiologic findings, including traction bronchiectasis; shrinkage of the secondary pulmonary lobules, primarily around the bronchovascular bundles; intralobular septal thickening; and early type 2 respiratory failure (ie, elevated blood carbon dioxide levels), exemplified a novel clinical subtype of familial PF.
Molecular genetic analysis of the families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, with both of these mutations segregating with the disorder in an autosomal recessive manner. Of note, family members who were either heterozygous carriers or wild-type normal for both of these variants were not affected.
Examination of patient-derived fibroblasts revealed significantly reduced expression of S100A3 and S100A13. Additional examination showed aberrant intracellular calcium homeostasis, differential expression of extracellular components, and mitochondrial dysregulation in cells isolated from patients with PF.
The investigators concluded that their findings help support the recommendation of using a calcium-based therapeutic approach when treating and managing PF — a disease that, to date, is incurable and is one of the leading indications for lung transplantation.
Al-Mutairy EA, Imtiaz F, Khalid M, et al. An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13 [published online May 9, 2019]. Eur Respir J. doi:10.1183/13993003.02041-2018