Progressive Lung Disease and Surfactant Dysfunction with a Deletion in Surfactant Protein C Gene

Abstract

Mutations in the surfactant protein (SP)-C gene are responsible for familial and sporadic interstitial lung disease (ILD). The consequences of such mutations on pulmonary surfactant composition and function are poorly understood. To determine the effects of a mutation in the SP-C gene on surfactant, we obtained lung tissue at the time of transplantation from a 14-mo-old infant with progressive ILD. An in-frame 9-bp deletion spanning codons 91-93 in Exon 3 of the SP-C gene was present on one allele; neither parent carried this deletion. SP-C mRNA was present in normal size and amount. By immunofluorescence, proSP-C was aggregated within alveolar Type II cells in a compartment separate from SP-B. In airway surfactant, there was little or no mature SP-B or SP-C; SP-A content was increased. Minimum surface tension was increased (20 mN/m, normal < 5 mN/m). Type II cells contained normal and disorganized appearing lamellar bodies by electron microscopy. This spontaneous deletion on one allele of the SP-C gene was associated with sporadic ILD and abnormalities in surfactant composition and function. We propose that a dominant negative effect on surfactant protein metabolism and function results from aggregation of misfolded proSP-C and subsequent cell injury and inflammation.

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

“…These alterations are distinct from those observed in SP-B or ABCA3 deficiency 3,6 and appear specific in both our observations and the literature. 15,28 In SP-C-deficient mice, LBs and extracellular surfactant are similar to controls, 35 suggesting that the human disease is not primarily caused by SP-C haploinsufficiency itself. However, even though human SP-C mutations are mono-allelic and both the wild-type and the mutated alleles are transcribed, mature SP-C peptide is not (or barely) detected in lung tissue and bronchoalveolar lavage fluid.…”

“…2 The typical presentation of SP-C defects consists of dyspnea, cough or wheezing with an onset between 2 and 12 months of age, gradual cyanosis and failure to thrive. 8,20,23,28 In this paper the youngest subject, a 28-week preterm triplet carrying the p.(Pro173His) mutation was identified by comparing RDS severity with his two siblings with wild-type SP-C alleles. Conversely, in the literature, SP-C mutations have been found in adults with familial idiopathic pulmonary fibrosis 29 and in adults 14-68 year-old in one pedigree, 30 Figure 1 Lung tissue morphology and surfactant protein immunohistochemistry.…”

Pulmonary Neuroendocrine Cell Hyperplasia Associated With Surfactant Protein C Gene Mutation

“…Mutations in SFTPC can lead to chronic ILD in both adults and children [6][7][8]. Known mutations of SFTPC are transmitted in an autosomal dominant pattern with variable penetrance [4,9] but can also occur de novo without known mutations in other family members [7,10,11].…”

The Importance of Surfactant on the Development of Neonatal Pulmonary Diseases

“…The age and pathology presentation are variable, and the pathological findings depend on age, clinical progression, and presence of infections. 6,24,46 Recently, mutations of the transport protein ABCA3 have been associated with respiratory failure in full-term newborns, with a recessive autosomic inheritance. The protein ABCA3 is a member of the ATP-dependent transporter family, as is the cystic fibrosis transmembrane conductance regulator and multiple-drug-resistant protein known for transporting a variety of ligands, ions, proteins, peptides, carbohydrates, and lipids.…”