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

Abstract

BackgroundPulmonary 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.Methods13 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.ResultsThe 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.ConclusionOur 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.

Genome-wide analysis of DNA methylation identifies S100A13 as an epigenetic biomarker in individuals with chronic (≥ 30 years) type 2 diabetes without diabetic retinopathy

“…Mandinov et al reported that S100A13 mediates IL-6induced damage to the macrovasculature [18]. We speculate that significant demethylation of S100A13 in individuals with DR downregulates S100A13 and upregulates p38 MAPK and nuclear factor-kappa B through calcium signaling and the RAGE pathway, thus increasing the damage caused by hyperglycemia [17,[19][20][21][22][23]. Patients harboring hypomethylated S100A13 may require closer follow-up evaluation and more stringent blood glucose screening.…”

“…The S100A13 gene is involved in calcium ion homeostasis, energy metabolism, inflammation, apoptosis, regulation of proliferation, differentiation, and interactions with transcription factors and nucleic acids within cells and activates surface receptors, including the receptor for advanced glycation end-products and Toll-like receptor 4, G-protein-coupled receptors, scavenger receptors, or heparan sulfate proteoglycans and N-glycans [15,16]. Furthermore, S100A13 regulates calcium levels and fibroblast growth factor-1 and interleukin-1 alpha secretion through a noncanonical pathway [10,11,17]. Mandinov et al reported that S100A13 mediates IL-6induced damage to the macrovasculature [18].…”

Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer

“…Wang et al found CEBPD participated the integration of EMT and lipid metabolism signaling to promote lung adenocarcinoma metastasis [ 89 ]. S100A13 is a calcium binding protein gene [ 90 ], the digenic mutations of S100A13 would break calcium homeostasis, distort ECM and result in progression of lung fibrosis [ 91 ]. In addition, S100A13 is regarded as an angiogenic and prognostic biomarker in melanoma [ 92 ] and astrocytic gliomas [ 93 ].…”

The S100 Protein Family as Players and Therapeutic Targets in Pulmonary Diseases

“…Mutation of the S100A3 gene leads to the replacement of arginine with cysteine at the 77th position of the S100A3 protein along with a mutation of the S100A13 gene leading to decreased expression of both proteins. This is implicated in an atypical genetic variant of early onset interstitial pulmonary fibrosis [ 72 ]. The decreased expression of these proteins leads to abnormal calcium homeostasis intracellularly, decreased tolerability of oxidative stress, and altered expression of extracellular matrix proteins.…”