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Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.

ABSTRACT: ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 mutations were identified in 10 out of 47 patients, including 2 homozygous, 5 compound heterozygous and 3 heterozygous patients. SP-B and SP-C expression patterns varied across patients. Among patients with ABCA3 mutations, five died shortly after birth and five developed ILD (including one without NRD). Functional studies of p.D253H and p.T1173R mutations revealed that p.D253H and p.T1173R induced abnormal lamellar bodies. Additionally, p.T1173R increased IL-8 secretion in vitro. In conclusion, we identified new ABCA3 mutations in patients with life-threatening NRD and/or ILD. Two mutations associated with ILD acted via different pathophysiological mechanisms despite similar clinical phenotypes.

SUBMITTER: Flamein F

PROVIDER: S-EPMC3263986 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.

Flamein Florence F Riffault Laure L Muselet-Charlier Céline C Pernelle Julie J Feldmann Delphine D Jonard Laurence L Durand-Schneider Anne-Marie AM Coulomb Aurore A Maurice Michèle M Nogee Lawrence M LM Inagaki Nobuya N Amselem Serge S Dubus Jean Christophe JC Rigourd Virginie V Brémont François F Marguet Christophe C Brouard Jacques J de Blic Jacques J Clement Annick A Epaud Ralph R Guillot Loïc L

Human molecular genetics 20111107 4

ABCA3 (ATP-binding cassette subfamily A, member 3) is expressed in the lamellar bodies of alveolar type II cells and is crucial to pulmonary surfactant storage and homeostasis. ABCA3 gene mutations have been associated with neonatal respiratory distress (NRD) and pediatric interstitial lung disease (ILD). The objective of this study was to look for ABCA3 gene mutations in patients with severe NRD and/or ILD. The 30 ABCA3 coding exons were screened in 47 patients with severe NRD and/or ILD. ABCA3 ...[more]

PMID: 22068586

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Project description:Diffuse cystic lung diseases are characterized by cysts in more than one lung lobe, the cysts originating from various mechanisms, including the expansion of the distal airspaces due to airway obstruction, necrosis of the airway walls, and parenchymal destruction. The progression of these diseases is variable. One essential tool in the evaluation of these diseases is HRCT, because it improves the characterization of pulmonary cysts (including their distribution, size, and length) and the evaluation of the regularity of the cyst wall, as well as the identification of associated pulmonary and extrapulmonary lesions. When combined with clinical and laboratory findings, HRCT is often sufficient for the etiological definition of diffuse lung cysts, avoiding the need for lung biopsy. The differential diagnoses of diffuse cystic lung diseases are myriad, including neoplastic, inflammatory, and infectious etiologies. Pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, lymphocytic interstitial pneumonia, and follicular bronchiolitis are the most common diseases that produce this CT pattern. However, new diseases have been included as potential determinants of this pattern. RESUMO As doenças pulmonares císticas difusas se caracterizam pela presença de cistos envolvendo mais de um lobo pulmonar, que se originam por diversos mecanismos, incluindo dilatação dos espaços aéreos distais por obstrução, necrose das paredes das vias aéreas e destruição do parênquima. Essas doenças apresentam evolução variável. A TCAR é fundamental na avaliação dessas doenças uma vez que permite uma melhor caracterização dos cistos pulmonares, incluindo sua distribuição, tamanho, extensão e regularidade das paredes, assim como a determinação de outras lesões pulmonares e extrapulmonares associadas. Frequentemente a TCAR é suficiente para a definição etiológica dos cistos pulmonares difusos, associada a achados clínicos e laboratoriais, sem a necessidade de realização de biópsia pulmonar. O diagnóstico diferencial das doenças pulmonares císticas difusas é extenso, incluindo etiologias neoplásicas, inflamatórias e infecciosas, sendo as mais frequentes determinantes desse padrão tomográfico a histiocitose pulmonar de células de Langerhans, a linfangioleiomiomatose, a pneumonia intersticial linfocitária e a bronquiolite folicular. Novas etiologias foram incluídas como potenciais determinantes desse padrão.

Dataset Information

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.

Publications

Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children.

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