Identification of early interstitial lung disease in an individual with genetic variations in ABCA3 and SFTPC

Abstract

A man with usual interstitial pneumonia (age of onset 58 years) was previously found to have an Ile73Thr (I73T) surfactant protein C (SFTPC) mutation. Genomic DNA from the individual and two daughters (aged 39 and 43 years) was sequenced for the I73T mutation and variations in ATP-binding cassette A3 (ABCA3). All three had the I73T SFTPC mutation. The father and one daughter (aged 39 years) also had a transversion encoding an Asp123Asn (D123N) substitution in ABCA3. The daughters were evaluated by pulmonary function testing and high-resolution CT (HRCT). Neither daughter had evidence of disease, except for focal subpleural septal thickening on HRCT scan in one daughter (aged 39 years). This daughter underwent bronchoscopy with transbronchial biopsies revealing interstitial fibrotic remodeling. These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.

Figure 1.

Pedigree demonstrating carrier status of the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation. The proband (I-1) carried both variations and died of idiopathic pulmonary fibrosis (IPF) at age 62 years; he had previously had a surgical lung biopsy that revealed usual interstitial pneumonia (UIP). He had three daughters, two of whom were screened for both mutations and for evidence of early interstitial lung disease (ILD). One daughter carried only the SFTPC mutation (II-1), whereas the other daughter carried both mutations (II-2). Both daughters who participated in this study were completely asymptomatic and had normal physical examinations and pulmonary function tests (PFTs). The daughter who carried both mutations had early ILD detected by high-resolution CT (HRCT) scan and on transbronchial biopsies. ABCA3 = adenosine triphosphate binding cassette A3 gene; SFTPC = surfactant protein C gene.

Figure 2.

HRCT image of the chest. HRCT scanning of the chest was performed using prone positioning. One asymptomatic daughter (aged 39 years) had evidence of interstitial thickening in the lower lobes in a few areas suggestive of early interstitial pneumonia (arrows). Overall, these findings were mild and most of the lung fields appeared normal. Standard positioning image shown for orientation. These mild abnormalities did not resolve with prone positioning. See Figure 1 legend for expansion of abbreviation.

Figure 3.

Hematoxylin and eosin-stained lung tissue obtained at transbronchial biopsy from an asymptomatic individual who was heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation. Multiple foci of interstitial fibrosis are present; associated inflammation is variable. Anthracotic pigment (arrows) marks respiratory bronchioles. Original magnification ×25 (A). Alveolar tissue involved by interstitial fibrosis (fine arrows); focus of dense scar with associated lymphoplasmacytic inflammation (heavy arrows). Original magnification ×62.5 (B). Linear alveolar septal fibrosis with lymphocytic infiltrate (fine arrows); single paucicellular collagen deposit (open arrow). Original magnification ×62.5 (C). A single fibroblastic focus is present. Original magnification ×62.5 (D). See Figure 1 legend for expansion of abbreviations.

Figure 4.

Electron microscopic images of lung tissue obtained at transbronchial biopsy from an asymptomatic individual heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation. Bands of collagen were prominent in the lung interstitium (asterisks). Type 2 alveolar epithelial cells demonstrated the presence of poorly developed lamellar bodies (large arrows), which had a more solid core rather than the typical lamellar whorls seen with mature lamellar bodies and the accumulation of numerous small vesicles in the cytoplasm (small arrows). See Figure 1 legend for expansion of abbreviations.

Figure 5.

Immunohistochemistry (IHC) for components of the unfolded protein response (UPR) from lung tissue obtained at transbronchial biopsy from an asymptomatic individual heterozygous for both the Ile73Thr SFTPC mutation and Asp123Asn ABCA3 variation (same individual in Fig 2-4). IHC for immunoglobulin-binding protein (BiP) revealed positive staining in alveolar epithelial cells in areas of affected lung and in normal appearing alveolar tissue adjacent to affected lung (A). IHC for x-box binding protein 1 revealed positive staining in epithelial cells lining areas of affected lung (B). Arrows point to immunostain-positive cells. Original magnification ×100. See Figure 1 legend for expansion of abbreviations.