title: 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.
authors: Inserm U938, UPMC, Univ Paris 6, France.
authors: Florence
authors: F
authors: Flamein
authors: Laure
authors: L
authors: Riffault
authors: Céline
authors: C
authors: Muselet-Charlier
authors: Julie
authors: J
authors: Pernelle
authors: Delphine
authors: D
authors: Feldmann
authors: Laurence
authors: L
authors: Jonard
authors: Anne-Marie
authors: AM
authors: Durand-Schneider
authors: Aurore
authors: A
authors: Coulomb
authors: Michèle
authors: M
authors: Maurice
authors: Lawrence M
authors: LM
authors: Nogee
authors: Nobuya
authors: N
authors: Inagaki
authors: Serge
authors: S
authors: Amselem
authors: Jean Christophe
authors: JC
authors: Dubus
authors: Virginie
authors: V
authors: Rigourd
authors: François
authors: F
authors: Brémont
authors: Christophe
authors: C
authors: Marguet
authors: Jacques
authors: J
authors: Brouard
authors: Jacques
authors: J
authors: de Blic
authors: Annick
authors: A
authors: Clement
authors: Ralph
authors: R
authors: Epaud
authors: Loïc
authors: L
authors: Guillot
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002648:Child; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D016207:Cytokines