Mutations in the gene encoding SP-B result in severe, fatal neonatal lung disease, and mutations in the gene encoding SP-C are associated with chronic interstitial lung diseases in newborns, older children, and adults.
These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.
There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease.
ProSP-C contains a BRICHOS domain, in which many ILD-associated mutations are localized, and the BRICHOS domain can prevent SP-C from forming amyloid-like fibrils.
To identify possible starting points for therapeutic intervention, we stably transfected A549 alveolar epithelial cells with several proSP-C mutations previously found in patients suffering from ILD.
A 333-base deletion involving part of exon 4 and the adjacent intron of the gene encoding surfactant protein C was identified in a child with interstitial lung disease.
Mutations in the gene encoding surfactant protein C (SFTPC) have led to a broad range of phenotypes from neonatal respiratory distress syndrome to adult interstitial lung disease.
More than 20 mutations in the ER-lumenal CTC (C-terminal domain of proSP-C), are associated with ILD (interstitial lung disease), and some of the mutations cause intracellular accumulation of cytotoxic protein aggregates and a corresponding decrease in mature SP-C.
Recently, two seemingly dominant-negative mutations of the pro-SP-C-encoding gene (SFTPC, MIM 178620), were reported in families with vertically-inherited interstitial lung disease (Nogee et al.
While a lack of dimeric SP-B was found only in the sole subject with hereditary SP-B deficiency, low or absent SP-C was observed not only in surfactant dysfunction disorders but also in patients with other diffuse parenchymal lung diseases pathogenetically related to the alveolar surfactant region.
Patients with mutations in the pulmonary surfactant protein C (SP-C) gene develop interstitial lung disease and pulmonary exacerbations associated with viral infections including respiratory syncytial virus (RSV).
The BRICHOS domain was initially defined from sequence alignments of the Bri protein associated with familial dementia, chondromodulin associated with chondrosarcoma and surfactant protein C precursor (proSP-C) associated with respiratory distress syndrome and interstitial lung disease (ILD).
Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred.
These observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types.
Epithelial Expression of an Interstitial Lung Disease-Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice.
Conclusion Since ABCA3 mutations seem to be a heterogeneous entity with various phenotypes, we recommend genetic testing for mutations in SP-C and ABCA3 genes to be considered in children with unexplained interstitial lung disease.
A novel surfactant protein C mutation resulting in aberrant protein processing and altered subcellular localization causes infantile interstitial lung disease.