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A Novel Surfactant Protein C L55F Mutation Associated with Interstitial Lung Disease Alters Subcellular Localization of Prosp-C in A549 Cells

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A Novel Surfactant Protein C L55F Mutation Associated with Interstitial Lung Disease Alters Subcellular Localization of Prosp-C in A549 Cells nature publishing group Clinical Investigation Articles A novel surfactant protein C L55F mutation associated with interstitial lung disease alters subcellular localization of proSP-C in A549 cells Tingting Liu1, Kenji Sano2, Naoko Ogiwara2 and Norimoto Kobayashi1 BACKGROUND: Heterozygous mutations of SFTPC, the gene- the endoplasmic reticulum (ER), multivesicular bodies, lamel- encoding surfactant protein C (SP-C), result in interstitial lung lar bodies (LBs), and others (2). Mature SP-C is exclusively disease (ILD). However, characterization of mutations located produced by type II alveolar epithelial cells (AECs), packaged in the mature domain of precursor SP-C (proSP-C) is limited. into LBs, which are a subclass of lysosomal-like organelles, This study examined the molecular pathogenesis of such a and subsequently secreted to the alveolar surface. Meanwhile, mutation of ILD. phospholipids and proteins are endocytosed from the alveolar METHODS: We employed sequencing of SFTPC and estab- surface into early endosomes and routed back either to lyso- lished A549 cells stably expressing several proSP-C mutants. somes for degradation or LBs for recycling (3). Histopathology and transmission electron microscopy (TEM) Interstitial lung disease (ILD) in infants and children rep- of lung tissue from a pediatric patient with ILD were assessed. resents a heterogeneous group of respiratory disorders that Effects of mutant proSP-C were evaluated by western blotting, are mostly chronic and associated with higher morbidity and immunofluorescence, and TEM. mortality than those reported in adults (4–6). SP-C is critical RESULTS: Sequencing of SFTPC revealed a novel heterozygous in reducing alveolar surface tension at the air/liquid interface mutation, c.163C>T (L55F). In lung tissue, abnormal localiza- to prevent alveolar collapse at the end of expiration. Since the tion of proSP-C was observed by immunohistochemistry, and first report of an infant and mother with ILD due to a mutation small and dense lamellar bodies (LBs) in type II alveolar epithe- in the SFTPC gene (4), several additional mutations have been lial cells (AECs) were detected by TEM. TEM of A549 cells stably identified in ILD patients that were associated with abnormal expressing proSP-CL55F displayed abnormal cytoplasmic organ- expression of SP-C (7,8). The great majority of SFTPC muta- elles. ProSP-CL55F exhibited a band pattern similar to that of tions are located in the BRICHOS domain, and associated with proSP-CWT for processed intermediates. Immunofluorescence chronic accumulation of misfolded proSP-C (9,10). In contrast, studies demonstrated that proSP-CL55F partially colocalized in in vitro studies have shown that mutations located in the non- CD63-positive cytoplasmic vesicles of A549 cells, which was in BRICHOS region, such as proSP-CI73T, misdirected proSP-C to contrast to proSP-CWT. the plasma membrane, leading to the accumulation of abnor- CONCLUSION: We detected a novel c.163C>T mutation mally processed isoforms (11). Thus, mutations involving located in the mature domain of SFTPC associated with ILD different domains of proSP-C may represent different patho- that altered the subcellular localization of proSP-C in A549 cells. geneses of ILD. Although several mutations located within the mature domain of SFTPC have been recognized (7,8,12), the pathway and mechanism of such mutations remain unclear. he hydrophobic surfactant protein C (SP-C) is synthesized In the present study, we describe a novel heterozygous Tfrom the 191 or 197-amino-acid precursor SP-C (proSP- SFTPC mutation associated with ILD in a young Japanese girl. C), which is encoded by SFTPC on human chromosome Lung biopsy samples performed using transmission electron 8p21.3. ProSP-C is an integral membrane protein that contains microscopy (TEM) revealed abnormal subcellular organelles. four regions: a short cytoplasmic N-terminal domain (residues We also investigated whether the subcellular localization of 1–23), a mature SP-C region (residues 24–58) mainly com- novel proSP-CL55F was altered in A549 cells. posed of a transmembrane domain (residues 33–58), a non- BRICHOS region (residues 59–89), and a BRICHOS domain RESULTS (residues 90–197) (1). ProSP-C undergoes palmitoylation and Case Summary a series of proteolytic C- and N-terminal cleavages to yield a The patient was a young girl who had been delivered at full-term 3.7-kDa mature peptide within subcellular compartments of to nonconsanguineous parents without any apparent perinatal 1Department of Pediatrics, Shinshu University School of Medicine, Nagano, Japan; 2Department of Laboratory Medicine, Shinshu University School of Medicine, Nagano, Japan. Correspondence: Norimoto Kobayashi ([email protected]) Received 20 January 2015; accepted 2 July 2015; advance online publication 4 November 2015. doi:10.1038/pr.2015.178 Copyright © 2016 International Pediatric Research Foundation, Inc. Volume 79 | Number 1 | January 2016 Pediatric Research 27 Articles Liu et al. diseases. She presented with poor feeding at 2 mo of age and inflammation (Figure 1d) as compared with a control (Figure exhibited a failure to thrive. She was hospitalized at the age of 5 mo 1c). According to clinical features, biochemical indicators, and due to cough and tachypnea. High-resolution computed tomog- radiographic and pathological findings, she was given a diag- raphy at the age of 5 mo showed bilateral ground glass opacities nosis of ILD. She was treated with methylprednisolone pulse and minimal reticulation (Figure 1a). Histopathological evalu- therapy followed by oral prednisolone in addition to cyclospo- ation of her lung tissue by open-lung biopsy revealed type II rine and azathioprine. Due to her persistently elevated supple- AEC hyperplasia and alveolar interstitial fibrosis with obvious mentary oxygen requirement, the patient required conventional mechanical ventilation and hydroxychloroquine was added to a b her regimen. These treatments were associated with a slowing of her disease progression, and she was discharged at 2 y of age with home oxygen therapy. At the age of 10 y, her pulmonary function began to deteriorate rapidly. She successfully underwent living- donor right single-lobe lung transplantation from her mother soon afterwards (13). Three months after transplantation, high- resolution computed tomography demonstrated a well-inflated cd lung allograft without obvious atelectasis (Figure 1b). SFTPC Genetic Analysis Polymerase chain reaction (PCR) followed by direct sequenc- ing of SFTPC, SFTPB, and ATP-binding cassette subfamily A, member 3 (ABCA3) were performed, and three heterozygous substitutions at bases c.163, c.413, and c.557 were detected in SFTPC (Supplementary Figure S1 online). The c.163C>T Figure 1. Characteristics of interstitial lung disease in this patient. in exon 2 located at codon 55 in the mature transmembrane (a,b) High-resolution computed tomography (HRCT) images observed before domain resulted in a leucine to phenylalanine substitution (a) and after (b) right single-lobe lung transplantation. (a) HRCT image at 5 (p.L55F). Neither 61 healthy Japanese volunteers, nor the mo of age showed bilateral ground-glass pulmonary opacities, small cysts, and several thickened septae. (b) HRCT revealed normal right lung paren- patient’s parents, carried this c.163C>T mutation. chyma and a round tracheal shape after lung transplantation. (c) Normal lung The patient’s mother and several volunteers also possessed sub- tissue, hematoxylin and eosin. (d) The patient’s lung tissue showed interstitial stitutions of c.413C>A and c.557G>A, which have been described thickening, type II alveolar epithelial cell hyperplasia, and alveolar interstitial as common coding SNPs in previous studies (14). Paternal gene fibrosis with obvious inflammation consisting of lymphocytes, plasma cells, and macrophages, hematoxylin and eosin (scale bars = 100 μm). sequences were identical to those of healthy control volunteers. abef cdgh Figure 2. Immunohistochemical staining for precursor surfactant protein C (proSP-C) and electron microscopic images of type II alveolar epithelial cells (AECs). (a–d) Immunohistochemical staining of lung tissue samples for proSP-C. Immunostaining for proSP-C was detected in lung tissue specimens from a control (a) and the patient (c) at low-power magnification (scale bars = 100 μm). Solid boxes were magnified on the left for better resolution (right) (scale bars = 50 μm). (b) Normal staining for proSP-C in type II alveolar epithelial cells (AECs) of normal lung tissue. (d) Type II AECs of patient lung tissue showed abnormal focal brown staining of the cytoplasm adjacent to subcellular organelles. (e–h) Ultrastructure of type II AECs. Type II AECs of normal lung tissue (e) and the patient (g) at low-power magnification (scale bars = 2 μm). Solid boxes were magnified on the left for better resolution (right) (scale bars = 500 nm). (f) High-power magnification of normal lung type II AECs showed numerous lamellar bodies (LBs) filled with concentric lamellae having diameters of 1–2 μm. (h) High-power magnification of patient lung type II AEC showed multiple smaller condensed LBs with an electron-dense core (dark arrows). 28 Pediatric Research Volume 79 | Number 1 | January 2016 Copyright © 2016 International Pediatric Research Foundation, Inc. Novel SP-C mutation causing ILD Articles Lung Histology proSP-CWT (Figure 4a). According to quantitative analysis, the To evaluate whether the proSP-C mutation influenced the correlation of proSP-CL55F
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