Publication by Wang Y, et al (Am J Hum Genet. 2009;84:52-59.)

Commentary by Paul W. Noble, MD, of Duke University

Article Summary

Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84:52-59.

Background:

Approximately 1 case in 50 of idiopathic pulmonary fibrosis (IPF) is familial, with 15% of these familial cases attributable to mutations in telomerase components. Telomere shortening has been documented in leukocytes from patients with familial or sporadic pulmonary fibrosis.1,2 The surfactant proteins have been associated with IPF and an increased baseline serum concentration of SP-A is associated with increased 1-year mortality.3 SP-A is the major protein of pulmonary surfactant and assembles as an 18-subunit oligomer.

Study Design:

Wang et al4 performed a whole genome linkage analysis using single nucleotide polymorphism (SNP) markers on a large family with familial IPF and lung adenocarcinoma.

Results:

  • A region of chromosome 10 was linked to the disease. This region contains 118 annotated genes, including 2 genes for SP-A (SFTPA1, SFTPA2) and SP-D.
  • A mutation at codon 231 of SFTPA2 was identified which changed a conserved glycine to a valine (G231V). All individuals in the family with pulmonary fibrosis and/or lung cancer were heterozygous for this mutation, though it was not detected in more than 1000 ethnically matched control subjects from a cardiovascular health study.
  • In vitro studies suggest that the G231V variant SP-A2 protein is retained in the endoplasmic reticulum (ER) and is not normally secreted.
  • ER stress may play a role in familial IPF and possibly in development of lung cancer, which is observed at an elevated rate in patients with IPF.

Expert Commentary:

The paradigms of molecular pathogenesis of IPF have undergone re-evaluation over the last two decades. The failure of therapies that target the inflammatory and immune responses to demonstrate unequivocal improvement in lung function in patients with idiopathic usual interstitial pneumonia has resulted in questioning of the causal role of dysregulated immune responses as the primary pathogenic process in IPF. These clinical conundrums coupled with the recent landmark discovery that a percentage of patients with familial pulmonary fibrosis have defects in telomerase genes, has provided a genetic basis reinforcing the urgency of revising the molecular paradigm of relentless IPF.

One of the hallmarks of IPF is that fibrosis occurs only in the lung. This is in stark contrast to connective tissue disease-related interstitial pneumonias that occur in the context of scleroderma, rheumatoid arthritis, and polymyositis syndromes. This unique quality of IPF has led investigators to speculate for some time that abnormalities in surfactant and surfactant proteins could provide clues to the pathogenesis of IPF. Surfactant production is a unique feature of the lung and is critical for facilitating gas exchange. Alveolar type II cells are the essential producers of surfactant and surfactant proteins. Previous studies have provided evidence that mutations in surfactant proteins B and C are associated with pulmonary fibrosis in a small percentage of patients with familial pulmonary fibrosis.

References

  1. Armanios MY, Chen JJ, Cogan JD, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317-1326.
  2. Cronkhite JT, Xing C, Raghu G, et al Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178:729-737.
  3. Kinder BW, Brown KK, McCormack FX, et al. Serum surfactant protein-A is a strong predictor of early mortality in idiopathic pulmonary fibrosis. Chest. 2009;135(6):1557-1563.
  4. Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84:52-59.

Article Links

Wang Y, Kuan PJ, Xing C, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84:52-59.


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