title: Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies.
abstract: Mutations in the human ABCA3 gene, encoding an ABC-transporter, are associated with respiratory failure in newborns and pediatric interstitial lung disease. In order to study disease mechanisms, a transgenic mouse model with a disrupted Abca3 gene was generated by targeting embryonic stem cells. While heterozygous animals developed normally and were fertile, individuals homozygous for the altered allele (Abca3-/-) died within one hour after birth from respiratory failure, ABCA3 protein being undetectable. Abca3-/- newborns showed atelectasis of the lung in comparison to a normal gas content in unaffected or heterozygous littermates. Electron microscopy demonstrated the absence of normal lamellar bodies in type II pneumocytes. Instead, condensed structures with apparent absence of lipid content were found. We conclude that ABCA3 is required for the formation of lamellar bodies and lung surfactant function. The phenotype of respiratory failure immediately after birth corresponds to the clinical course of severe ABCA3 mutations in human newborns.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstrasse 4, 80337 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hammel
authors.forename: Geert
authors.initials: G
authors.lastname: Michel
authors.forename: Christina
authors.initials: C
authors.lastname: Hoefer
authors.forename: Matthias
authors.initials: M
authors.lastname: Klaften
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Andreas
authors.initials: A
authors.lastname: Holzinger
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn / Q000235:genetics*; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods*; D008168:Lung / Q000002:abnormalities* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012131:Respiratory Insufficiency / Q000151:congenital* / Q000473:pathology*
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse