Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies

Journal Article · Fri Aug 10 04:00:00 EDT 2007 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/j.bbrc.2007.05.219· OSTI ID:20991482

Hammel, Markus ^[1]; Michel, Geert ^[2]; Hoefer, Christina ^[2]; Klaften, Matthias ^[2]; Mueller-Hoecker, Josef ^[3]; Angelis, Martin Hrabe de ^[2]; Holzinger, Andreas ^[1]

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1. Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Lindwurmstrasse 4, 80337 Munich (Germany)
2. GSF-National Research Center for Environment and Health, Institute of Experimental Genetics, Ingolstaedter Landstrasse 1, 85764 Neuherberg (Germany)
3. Institute of Pathology, Ludwig-Maximilians-University Munich, Thalkirchner Strasse 36, 80337 Munich (Germany)

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.

• OSTI ID: 20991482
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 4 Vol. 359; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DISEASES
ELECTRON MICROSCOPY
FAILURES
GENES
INFANTS
LIPIDS
LUNGS
MUTATIONS
PEDIATRICS
STEM CELLS
TRANSGENIC MICE