The ABCA3 gene, of the ABCA subclass of ATP-binding cassette (ABC) transporters, is expressed exclusively in lung. We report here the cloning, molecular characterization, and distribution of human ABCA3 in the lung. Immunoblot analysis using the specific antibody reveals a 150-kDa protein in the crude membrane fraction of human lung. Immunohistochemical analyses of alveoli show that ABCA3 is expressed only in the type II cells expressing surfactant protein A. At the ultrastructural level, ABCA3 immunoreactivity was detected mostly at the limiting membrane of the lamellar bodies. Since members of the ABCA transporter family are known to be involved in transmembrane transport of endogenous lipids, our findings suggest that ABCA3 plays an important role in the formation of pulmonary surfactant in type II cells.
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"Abca3 is one of the lipid-transporting ABC transporters, and is predominantly expressed in the lung. In the lung, Abca3 is expressed only in alveolar type II epithelial cells, and is localized to the limiting membrane of the lamellar bodies . Abca3 transports surfactant phospholipids into lamellar bodies, and the deficiency of Abca3 function disrupts lamellar body biogenesis, resulting in lung diseases with fatal pulmonary surfactant deficiency and chronic interstitial lung disease [23e25]. "
"Phospholipids and the hydrophobic SP-B and -C are synthesized in AT II cells, stored in their lamellar bodies and secreted together into the alveolar lumen (Rooney 2001). The essential lipid transporter selecting surfactant-speciWc lipids for incorporation into the storing compartment of AT II cells (lamellar bodies) is ABCA3, a member of the ATPbinding cassette (ABC) family of trans-membrane transport proteins located predominantly at the limiting membrane of the lamellar bodies (Mulugeta et al. 2002; Yamano et al. 2001). DeWciency of ABCA3 in humans results in dysgenesis of lamellar bodies and decreases surfactant PL, symptoms also seen in ABCA3 ¡/¡ mice (Besnard et al. 2010; Brasch et al. 2006; Fitzgerald et al. 2007; Matsumura et al. 2008). "
[Show abstract][Hide abstract] ABSTRACT: Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl-PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85 % O(2) for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development.
"Mutations in the genes encoding SP-B (SFTPBSP-C (SFTPC), and ABCA3 (ABCA3), have been associated with surfactant dysfunction and respiratory disease in full-term infants with neonatal respiratory failure, and interstitial lung disease in older children and adults (6, 7, 8, 9). Although the precise incidences of these disorders are unknown, ABCA3 mutations appear to be the most common cause of inborn errors of surfactant metabolism (1, 2, 3). "
[Show abstract][Hide abstract] ABSTRACT: Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease.
ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF.
ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes.
These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.
Full-text · Article · Feb 2012 · Pediatric Research