Journal Article

Molecular and cellular characteristics of <i>ABCA3</i> mutations associated with diffuse parenchymal lung diseases in children

Florence Flamein, Laure Riffault, Céline Muselet-Charlier, Julie Pernelle, Delphine Feldmann, Laurence Jonard, Anne-Marie Durand-Schneider, Aurore Coulomb, Michèle Maurice, Lawrence M. Nogee, Nobuya Inagaki, Serge Amselem, Jean Christophe Dubus, Virginie Rigourd, François Brémont, Christophe Marguet, Jacques Brouard, Jacques de Blic, Annick Clement, Ralph Epaud and Loïc Guillot

in Human Molecular Genetics

Volume 21, issue 4, pages 765-775
Published in print February 2012 | ISSN: 0964-6906
Published online November 2011 | e-ISSN: 1460-2083 | DOI:
Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children

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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.

Journal Article.  5117 words.  Illustrated.

Subjects: Genetics and Genomics

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