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Genetic Basis of Familial Interstitial Lung Disease

Misfolding or Function of Surfactant Protein C?

Divisions of Neonatology and Pulmonary Biology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio

We live in an age when the term "idiopathic" as a descriptor of disease diagnosis is increasingly being transformed into numbers of nucleotides or amino acid residues caused by mutations at specific genetic loci. Rare, stereotypic findings with a familial pattern of inheritance typify single gene mutations as the basis of observable clinical phenotypes encountered in medicine. In the current issue of AJRCCM (pp. 1322–1328) the accompanying article by Thomas and coworkers ("Heterozygosity for a surfactant protein c gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred") (1) provide perhaps incontrovertible evidence that mutations in the surfactant protein C (SP-C) gene cause dominantly inherited familial interstitial pneumonitis in extended sibships that are variably affected by severe lung disease. Modified by age, environmental, genetic, or infectious factors, these individuals suffer from "idiopathic" lung disease with variable histopathologic patterns, including desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, or usual interstitial pneumonitis. The findings by Thomas and coworkers (1) extend previous observations in younger individuals and their family members diagnosed with familial interstitial lung disease or idiopathic pulmonary fibrosis in childhood associated with a lack of SP-C or mutations in the SP-C gene (2, 3). The authors have identified heterozygous individuals bearing a wild-type and a mutant SP-C gene, the latter in which exon 5 + 128TA transversion results in a nonconservative substitution of a leucine by glutamine (L188Q) in the C-terminal domain of propeptide SP-C (proSP-C). This region of the proSP-C has been previously demonstrated to be critical for the proper folding and processing of proSP-C (4). Overexpression of the L188Q SP-C protein in mouse lung epithelial cells in vitro was cytotoxic (1), suggesting that the accumulation of the mutant protein might be involved in the pathogenesis of the pulmonary disorder. The variability in histopathologic pattern of interstitial lung disease among affected individuals may be further influenced by the nature and biology of the SP-C mutation, amounts of production of the active SP-C peptide, the inheritance of other genetic modifiers or exposure to environmental factors. Taken together, these findings support a model in which misfolded proSP-C or SP-C protein can cause type II alveolar cell injury to cause forms of interstitial lung disease. However, Amin and coworkers (3) described a family with similar lung pathologies in which expression of proSP-C and the active SP-C protein was undetectable. Therefore, the severe lung disease caused by abnormalities in SP-C can result from the absence of SP-C and proSP-C as well as the production of an abnormal proSP-C protein.

Targeted deletion of SP-C genes in transgenic mice resulted in the complete lack of proSP-C in type II cells and SP-C in the airspaces in vivo (5). A modest decrease in surfactant function associated with abnormalities in pulmonary mechanics was detected only at low lung volumes, and neither surfactant lipids nor proteins were overtly perturbed in the absence of SP-C. However, in an inbred strain of mice, SP-C (-/-) mice developed severe interstitial lung disease with features similar to those seen in patients with interstitial lung disease (Glasser SW, Detmer EA, Ikegami M, Ross GF, Wert SE, Na C-L, Stahlman MT, Whitsett JA, unpublished observations). Thus, both the presence and absence of proSP-C can be associated with interstitial lung disease. Because the active SP-C peptide was not detected in the patients described by Thomas and coworkers (1) and Nogee and coworkers (2), it is unclear whether the lack of the active SP-C peptide causes or contributes to the disease. A lack of SP-C in pulmonary surfactant per se may cause abnormal shear forces in the alveoli, in turn causing mechanical injury of the respiratory epithelium that may contribute to the pathogenesis of idiopathic pulmonary fibrosis. If this is the case, then replacement of surfactant containing SP-C represents a potential strategy for therapy of idiopathic pulmonary fibrosis. It remains unclear, however, whether the relatively modest changes in surfactant function in the absence of SP-C are sufficient to cause cellular injury leading to emphysema and pulmonary fibrosis. Do other proposed functions of SP-C or proSP-C, perhaps in the routing, processing, and trafficking of other proteins or lipids, contribute to the pathogenesis of lung disease in the absence or deficiency of SP-C?

The active SP-C peptide is perhaps the most hydrophobic protein yet encountered in the mammalian proteome, bearing a domain rich in valine, leucine, and isoleucine residues that form a stable -helical structure approximately spanning a phospholipid bilayer. The -helical SP-C peptide is membrane associated, palmitoylated, and readily forms insoluble random structures in aqueous environments (6). SP-C forms extended fibrillar structures that accumulate in lungs of patients with alveolar proteinosis (7). The structure, folding, and routing of proSP-C and SP-C are not unlike those of the prion protein, whose misrouting causes degenerative brain disease. Missense or short deletion mutations, as seen in the studies of Thomas and coworkers (1) and Nogee and coworkers (2), result in the production of a stable mRNA that produces an abundance of a misfolded protein that likely escapes from protein quality control systems. Accumulation of the abnormal proSP-C protein or protein complexes may cause type II epithelial cell injury. Furthermore, expression of a mutant SP-C protein directly caused a lethal lung disorder when expressed in transgenic mice (8), providing strong support for the concept that mutations in the SP-C gene-caused misfolding and misrouting of proSP-C, may contribute to the pathogenesis of lung disease in mice and patients expressing mutant proSP-C peptides.

The findings of Thomas and coworkers (1) have important implications for the diagnosis, prognosis, and therapy of idiopathic pulmonary fibrosis. Genetic diagnosis can now be made by analysis of the inherited SP-C mutations. Likewise, pathologic diagnosis may be facilitated by immunostaining or structural analysis of the proSP-C proteins or fragments isolated from lung tissue or bronchoalveolar lavage samples. Insights into the molecular and cellular basis for the lung disease caused by SP-C mutations should lead to new therapies for idiopathic pulmonary fibrosis. The finding that either lack of SP-C or misfolding/misrouting of proSP-C is a cause of familial pulmonary fibrosis should stimulate investigation to seek mutations in other genes whose polypeptide products are expressed by pulmonary epithelial cells that may cause lung disease by mechanisms similar to those caused by mutations in the SP-C gene.

REFERENCES

1. Thomas AQ, Lane K, Phillips J III, Prince M, Markin C, Speer M, Schwartz DA, Gaddipati R, Marney A, Johnson J, et al. Heterozygosity for a surfactant protein c gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med 2002;165:1322–1328.[Abstract/Free Full Text]
2. Nogee LM, Dunbar AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C (SP-C) gene associated with interstitial lung disease. N Engl J Med 2001;344:573–579.[Free Full Text]
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5. Glasser SW, Burhans MS, Korfhagen TR, Na C, Sly PD, Ross GF, Ikegami M, Whitsett JA. Altered stability of pulmonary surfactant in SP-C deficient mice. Proc Natl Acad Sci USA 2001;98:6366–6371.[Abstract/Free Full Text]
6. Baatz JE, Smyth KL, Whitsett JA, Baxter C, Absolom DR. Structure and functions of a dimeric form of surfactant protein SP-C: a Fourier transform infrared and surfactometry study. Chem Phys Lipids 1992;63:91–104.[CrossRef][Medline]
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8. Conkright JJ, Na C-L, Weaver TE. Overexpression of SP-C mature SP-C peptide causes neonatal lethality in transgenic mice. Am J Respir Cell Mol Biol 2002;26:85–90.[Abstract/Free Full Text]

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