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

作者：Flamein Florence; Riffault Laure; Muselet Charlier Celine; Pernelle Julie; Feldmann Delphine; Jonard Laurence; Durand Schneider Anne Marie; Coulomb Aurore; Maurice Michele; Nogee Lawrence M; Inagaki Nobuya; Amselem Serge; Dubus Jean Christophe; Rigourd Virginie; Bremont Francois; Marguet Christophe; Brouard Jacques; de Blic Jacques; Clement Annick; Epaud Ralph; Guillot Loic^*

来源：Human Molecular Genetics, 2012, 21(4): 765-775.

DOI：10.1093/hmg/ddr508

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.

• 出版日期2012-2-15