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The Significance of the ABCA3 Mutation

written by: Dr. Pharm Tao•edited by: Emma Lloyd•updated: 7/11/2010

The ABCA3 gene is a membrane transporter protein. ABCA3 gene mutation may cause many serious health problems. These problems include fatal respiratory distress syndrome in the neonatal period, and interstitial lung disease in older infants, children, and adults.

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    What is the ABCA3 gene?

    The full name of the ABCA3 gene is “ATP-binding cassette, sub-family A (ABC1), member 3." The protein encoded by this gene is a membrane transporter that belongs to the superfamily of ATP-binding cassette (ABC) transporters. Membrane transporters play important roles in moving various molecules across cellular membranes.

    In humans, ABCA3 is located on the chromosome 16. It is expressed abundantly at the membrane of the lamellar bodies in the type II cells of lung alveolar epithelium (Matsumura et al., 2006). It transports surfactant phospholipids.

    ABCA3 has been found to be involved in the development of drug resistance. It may be also related to the engulfment of dead cells during programmed cell death (Wu and Horvitz, 1998). It is crucial for the formation of lamellar bodies and surfactant function (Shulenin et al., 2004). Lamellar bodies are specialized secretary organelles. ABCA3 genes are needed for the normal transportation of surfactant phospholipids into lamellar bodies.

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    Mutations in ABCA3 and diseases

    Various types of mutations can occur in ABCA3, including nonsense and frameshift mutations (Shulenin et al., 2004). Mutations have also been found in its highly conserved residues and in its splice sites. Because of the gene’s important role in normal physiological functions, ABCA3 gene mutation may cause many serious health problems. In newborns, ABCA3 gene mutation may lead to fatal surfactant deficiency.

    Pulmonary surfactant is critical for keeping normal functions of the lung alveolar epithelium. Pulmonary surfactant is a mixture of lipids and proteins. The mixture reliefs the surface tension at the interface between the air and liquid, and prevents the lung from collapsing at the end of expiration (Wert et al., 2009).

    Surfactant deficiency is involved in the infant respiratory distress syndrome (IRDS). IRDS is a syndrome found in premature infants. Reduced surfactant levels have been associated with respiratory failure and death soon after birth (Bruder et al., 2007). For example, a study of three Norwegian term infants found that mutations in the ABCA3 gene were the factors for the fatal lung disease in the three patients (Saugstad et al., 2007). Two of the infants had respiratory symptoms right after birth.

    ABCA3 gene mutations have been connected to not only fatal respiratory distress syndrome in the neonatal period. They have also been associated with interstitial lung disease in older infants, children, and adults (Wert et al., 2009). It has been suggested that in infants with unexplained severe respiratory failure and interstitial lung disease, ABCA3 gene mutations need to be examined (Bruder et al., 2007).

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    Other relevant diseases

    Other than mutations, quantitative changes in ABCA3 have also been associated with diseases. For example, ABCA3 genes are abundant in normal mammary gland epithelium cells. Abnormal ABCA3 expression may be a risk factor for tumor recurrence. Reduced ABCA3 expression in breast cancer has been connected to poor prognosis (Schimanski et al., 2010).

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    Bruder, E., Hofmeister, J., Aslanidis, C., Hammer, J., Bubendorf, L., Schmitz, G., et al. (2007). Ultrastructural and molecular analysis in fatal neonatal interstitial pneumonia caused by a novel ABCA3 mutation. Mod Pathol, 20(10), 1009-1018.

    Matsumura, Y., Ban, N., Ueda, K., & Inagaki, N. (2006). Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. J Biol Chem, 281(45), 34503-34514.

    Saugstad, O. D., Hansen, T. W., Ronnestad, A., Nakstad, B., Tollofsrud, P. A., Reinholt, F., et al. (2007). Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease. Acta Paediatr, 96(2), 185-190.

    Schimanski, S., Wild, P. J., Treeck, O., Horn, F., Sigruener, A., Rudolph, C., et al. Expression of the lipid transporters ABCA3 and ABCA1 is diminished in human breast cancer tissue. Horm Metab Res, 42(2), 102-109.

    Shulenin, S., Nogee, L. M., Annilo, T., Wert, S. E., Whitsett, J. A., & Dean, M. (2004). ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med, 350(13), 1296-1303.

    Wert, S. E., Whitsett, J. A., & Nogee, L. M. (2009). Genetic disorders of surfactant dysfunction. Pediatr Dev Pathol, 12(4), 253-274.

    Wu, Y. C., & Horvitz, H. R. (1998). The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell, 93(6), 951-960.