Genetic disorders of the surfactant system: focus on adult disease

Abstract

Genes involved in the production of pulmonary surfactant are crucial for the development and maintenance of healthy lungs. Germline mutations in surfactant-related genes cause a spectrum of severe monogenic pulmonary diseases in patients of all ages. The majority of affected patients present at a very young age, however, a considerable portion of patients have adult-onset disease. Mutations in surfactant-related genes are present in up to 8% of adult patients with familial interstitial lung disease (ILD) and associate with the development of pulmonary fibrosis and lung cancer.High disease penetrance and variable expressivity underscore the potential value of genetic analysis for diagnostic purposes. However, scarce genotype–phenotype correlations and insufficient knowledge of mutation-specific pathogenic processes hamper the development of mutation-specific treatment options.This article describes the genetic origin of surfactant-related lung disease and presents spectra for gene, age, sex and pulmonary phenotype of adult carriers of germline mutations in surfactant-related genes.

Chronic lung diseases: entangled in extracellular matrix

“…The biomechanical environment within the lung tissue is the result of the complex mix of ECM components, the cross-linking of these components and the surfactant system that lines the alveolar epithelial surfaces [84]. Disruption of lung mechanics that results from surfactant system genetic disorders will not be covered in this review, rather the reader is referred to VAN MOORSEL et al [85]. The gas exchange units, the alveoli, are kept open through transpulmonary pressure from the air in the lungs.…”

Etiologic Classification of Diffuse Parenchymal (Interstitial) Lung Diseases

“…The “lung-only” conditions may occur at all ages and, nevertheless, are likely to have strong genetic etiology factors, as yet unknown to a large extent. Recently, several conditions previously thought to exclusively occur in childhood, e.g., SFTPC or ABCA3 deficiency, have been demonstrated to occur at all ages [ 32 ]. Up to now, in adults these conditions were lumped under interstitial idiopathic pneumonias ( Table 1 ).…”

Familial Pulmonary Fibrosis

“…Kindreds harboring SFTPC and SFTPA1/2 exhibit autosomal dominant inheritance, whereas inheritance of ABCA3 is autosomal recessive. 43 Surfactant-related gene variants have diverse molecular consequences depending on the gene and involved domain. The most common risk variant in SFTPC, encoding a missense mutation (I73T), causes altered surfactant protein C trafficking and proteostasis.…”