Genetic Link Found in Pulmonary Fibrosis

June 30, 2002 – Cincinnati, Ohio -- Idiopathic interstitial pneumonias due to misprocessing of SP-C

Genetic basis of interstitial pneumonias in three families described mutations in the gene encoding surfactant protein C in an infant with a family history of interstitial lung disease. The mother had had a diagnosis of DIP at 1 year of age and had been treated with corticosteroids through age 15 yrs. The maternal grandfather had died of life-long interstitial lung disease of unknown cause. The infant developed tachypnea and cyanosis at 6 weeks of age, associated with hyperinflation and increased interstitial markings on chest x-ray. An open lung biopsy from the infant revealed a cellular or nonspecific interstitial pneumonia.  

The mother developed worsening respiratory failure after delivery and died. Her lung biopsy revealed areas of diffuse fibrosis and honeycombing, with patch areas of mild interstitial lymphocytic infiltration, macrophage accumulation and areas of superimposed alveolar damage. Immmunostaining for SP-C revealed deficiency of the protein in the infant and the mother, but the misprocessed SP-C precursor was readily detected in alveolar type II cells of both patients. Restriction analysis confirmed the presence of this mutation in the patient and the mother. SP-C products of reverse transcriptase PCR revealed the presence of a truncated RNA lacking exon 4 in both the infant and the mother.

A large kindred composed of 32 members in five generations reported by Thomas et al had 14 members affected by pulmonary fibrosis. Pathological data was available for 9 members, including 3 children with NSIP, 5 adults with UIP and one adult with ‘fibrocystic pulmonar dysplasia”. Expression of the mutant SP-C in mouse lung epithelial cells resulted in reduced growth and the formation of intracellular inclusions consistent with misfolded protein aggregates. The fact that heterozygotes for SP-C mutations can develop ILD suggest that mutant SP-C can interfere with the function of endogenous SP-C in a dominant negative fashion. Furthermore, the finding that not all patients who are heterozygous for SP-C mutations within a given family are affected indicates that environmental factors or genetic modifiers play an important role in the pathogenesis of ILD. The finding that the same genetic mutation can result in NSIP in children and UIP in adults suggests that NSIP may be a precursor for UIP. Structure and function of SP-C-The association between SP-C deficiency and interstitial lung disease highlights the importance of the respiratory epithelium in the pathogenesis of interstitial lung disease.

Summary

Collectively the data indicate that expression of a dominantly inherited mutant proSP-C protein or the deletion of the SP-C gene can cause fibrotic lung disease. Cell injury due to misfolding and misprocessing of the SP-C precursor may result in primary injury to the alveolar epithelium and secondary fibrosis, or, alternatively, SP-C deficiency may result in surfactant dysfunction and altered alveolar surface tension forces that ultimately causes interstitial pneumonia. Although the data clearly indicate that SP-C mutations cause some forms of familial interstitial pneumonia, and additional studies will be required to determine if non-familial IIPs are associated with deficiency or dysfunction of SP-C.

Frank McCormack, M.D. Division of Pulmonary and Critical Care Medicine University of Cincinnati