Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

Matsumura, Yoshihiro; Ban, Nobuhiro; Inagaki, Nobuya

doi:10.1152/ajplung.90352.2008

Cited by 72 publications

(83 citation statements)

References 39 publications

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“…To determine whether p.R288K and p.R1474W impair ATP hydrolysis (type II mutation), we extracted membrane protein from adenoviral-transduced A549 cells, performed a colorimetric ATPase assay, and compared results to a previously characterized ATP hydrolysis mutation, p.E292V (20). We found that, similar to p.E292V, both p.R288K (80% reduction, P , 0.0001) and p.R1474W (75% reduction, P = 0.0012) encoded ABCA3 proteins with significantly reduced ATPase activity compared with wild type (Figure 4).…”

Section: Atpase Assaymentioning

confidence: 99%

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Wambach

Yang

Wegner

et al. 2016

Am J Respir Cell Mol Biol

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Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome and childhood interstitial lung disease. As most ABCA3 mutations are rare or private, determination of mutation pathogenicity is often based on results from in silico prediction tools, identification in unrelated diseased individuals, statistical association studies, or expert opinion. Functional biologic studies of ABCA3 mutations are needed to confirm mutation pathogenicity and inform clinical decision making. Our objective was to functionally characterize two ABCA3 mutations (p.R288K and p.R1474W) identified among term and latepreterm infants with respiratory distress syndrome with unclear pathogenicity in a genetically versatile model system. We performed transient transfection of HEK293T cells with wild-type or mutant ABCA3 alleles to assess protein processing with immunoblotting. We used transduction of A549 cells with adenoviral vectors, which concurrently silenced endogenous ABCA3 and expressed either wildtype or mutant ABCA3 alleles (p.R288K and p.R1474W) to assess immunofluorescent localization, ATPase activity, and organelle ultrastructure. Both ABCA3 mutations (p.R288K and p.R1474W) encoded proteins with reduced ATPase activity but with normal intracellular localization and protein processing. Ultrastructural phenotypes of lamellar body-like vesicles in A549 cells transduced with mutant alleles were similar to wild type. Mutant proteins encoded by ABCA3 mutations p.R288K and p.R1474W had reduced ATPase activity, a biologically plausible explanation for disruption of surfactant metabolism by impaired phospholipid transport into the lamellar body. These results also demonstrate the usefulness of a genetically versatile, human model system for functional characterization of ABCA3 mutations with unclear pathogenicity.Keywords: surfactant; childhood interstitial lung disease; neonatal respiratory distress; respiratory distress syndrome ATP-binding cassette transporter A3 (ABCA3), a member of a large family of proteins that hydrolyze ATP to transport substances across biologic membranes, is encoded by an 80-kb gene (ABCA3; NM_001089.2, Gene ID 21) and consists of 1,704 amino acids with two membranespanning domains and two nucleotide binding domains. ABCA3 is expressed in alveolar type II cells, localizes to the membranes of lamellar bodies, and transports phospholipids into the lamellar body, where surfactant, a complex protein-phospholipid mixture that reduces surface tension and prevents alveolar collapse at end expiration, is assembled and stored (1-3). ABCA3 is also required for lamellar body biogenesis (4).Biallelic loss-of-function (nonsense, frameshift) mutations in ABCA3 result in severe, progressive neonatal respiratory distress syndrome (RDS) that is lethal by 1 year of age without lung transplantation (5). However, for individuals with missense, T.C., F.V.W., A.H., B.P.H., and F.S.C.; drafting and revising the manuscript for important intellectual content-J.A.W., P.Y....

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Section: Atpase Assaymentioning

confidence: 99%

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Wambach

Yang

Wegner

et al. 2016

Am J Respir Cell Mol Biol

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“…Recessive loss-of-function mutations in ABCA3 present as lethal surfactant deficiency in the newborn, whereas other recessive mutations in ABCA3 can result in interstitial lung disease in older children [4]. Previous studies showed that homozygous or compound heterozygous ABCA3 mutations led to abnormal processing and/or trafficking of the ABCA3 protein [5], alterations in ABCA3 protein functions such as ATPase activity [6], or impaired lipid transport [7]. As previously described, our patient had a less severe phenotype than is usually associated with ABCA3 mutations [4].…”

Section: To the Editormentioning

confidence: 99%

Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations

Epaud

Delestrain

Louha

et al. 2013

European Respiratory Journal

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“…34 , 35 The direct impact of an individual mutation on ABCA3 structure and function in relation to the clinical course has been determined for a small number of defi ned ABCA3 mutations. 36 When mutations associated with mild disease were expressed in vitro , the mutant ABCA3 protein was found to retain residual transport activity and acquire a subcellular localization similar to wild-type ABCA3. These results were interpreted to indicate retention of partial catalytic and transport function accounts for the mild disease.…”

Section: Neuroendocrine Cells and Diffuse Lung Diseasementioning

confidence: 99%

Pathogenesis of Interstitial Lung Disease in Children and Adults

Glasser¹,

Hardie²,

Hagood³

2010

Pediatric Allergy, Immunology, and Pulmonology

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Interstitial lung diseases (ILDs) occur across the lifespan, from birth to advanced age. However, the causes, clinical manifestations, histopathology, and management of ILD differ greatly among infants, older children, and adults. The historical approach of classifying childhood ILD (chILD) using adult classifi cation schemes may therefore have done more harm than good. Nevertheless, identifi cation of novel forms of chILD in the past decade, such as surfactant metabolism dysfunction disorders and neuroendocrine cell hyperplasia of infancy (NEHI), as well as genomic analysis of adult ILDs, has taught us that identical genotypes may result in distinct phenotypes at different ages and developmental stages, and that lung developmental pathways and cellular phenotypes are often recapitulated in adult ILDs. Thus comparison of the pathophysiology of ILD in children and adults in the context of lung development is useful in understanding the pathogenesis of these disorders, and may lead to novel therapeutic interventions for ILDs at all ages.

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Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease

Cited by 72 publications

References 39 publications

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome

Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations

Pathogenesis of Interstitial Lung Disease in Children and Adults

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