Mutations in the Surfactant Protein C Gene Associated With Interstitial Lung Disease

Abstract

The molecular basis for most forms of interstitial lung disease (ILD) is unknown. We recently identified a splicing mutation (c.460 + 1G > A) in the gene encoding surfactant protein C (SP-C) in two affected individuals with familial ILD. 1 Nogee LM Dunbar III, AE Wert SE et al. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001; 344: 573-579 Crossref PubMed Scopus (723) Google Scholar To test the hypothesis that SP-C mutations cause both sporadic and familial lung disease, we analyzed the SP-C gene sequence in infants with chronic lung diseases of unknown etiology. Mutations on one allele of the SP-C gene were identified in 11 of 34 patients evaluated. One infant had a mutation in the same location, but with a different nucleotide substitution (G > T) as the patients with the c.460 + 1G > A mutation. The clinical, histopathologic, and biochemical findings of these patients were similar, and included skipping of exon 4, expression of an aberrantly migrating proprotein corresponding to the size of the deletion, and reduced amounts of normal pro-SP-C. However, neither parent had a history of lung disease or carried the mutation. The occurrence of a de novo mutation functionally identical to a familial mutation in infants with the same phenotype strongly supports the hypothesis that the mutations were causally related to their lung disease. Missense SP-C mutations that resulted in amino-acid substitutions in residues highly conserved across species (P30 L, I73T, G100V, Y104H, P115 L, I126R, T187N, and L188R), as well as a frameshift mutation (140delA) associated with expression of a stable transcript, were identified in 10 other infants, 6 of whom had a family history of lung disease. None of the identified mutations were found on 100 control chromosomes, indicating that they are not common polymorphisms. We conclude that mutations in the SP-C gene are a cause of both familial and sporadic ILD. While the pathophysiologic mechanisms remain to be elucidated, the finding of mutations on one allele suggests a dominant negative effect on SP-C or pro-SP-C function or metabolism.