Alternative titles; symbols
HGNC Approved Gene Symbol: ABCA3
SNOMEDCT: 1222678003;
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:2,275,881-2,340,728 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Surfactant metabolism dysfunction, pulmonary, 3 | 610921 | Autosomal recessive | 3 |
ABCA3, which is expressed in alveolar type II pneumocytes and localizes predominantly to the limiting membrane of lamellar bodies, is critical for synthesis of surfactant (Ban et al., 2007).
Klugbauer and Hofmann (1996) isolated cDNA clones encoding the ABCA3 protein, which they designated ABCA3, from a human medullary thyroid cancer cell line. ABCA3 has typical structural features of the ABC transporter family (see 600046). They determined that the transporter consists of a 1,704-amino acid polypeptide with 2 homologous repeats, each harboring 6 putative transmembrane helices and an ATP-binding cassette motif. The ABCA3 protein showed approximately 50% homology with the MRP1 (158343) protein.
Connors et al. (1997) independently cloned the ABCA3 gene. By Northern blot analysis, they found that the 6.8-kb mRNA was present at highest levels in lung.
Using the 5-prime UTR of mouse Abca3 as probe, Yamano et al. (2001) cloned ABCA3 from a lung cDNA library. Western blot analysis of crude membrane fractions of human lung determined that ABCA3 migrated at an apparent molecular mass of 150 kD. Immunohistochemical analysis of alveoli showed ABCA3 expression only in alveolar type II (ATII) cells that also expressed surfactant protein A (see 178630). At the ultrastructural level, ABCA3 immunoreactivity was detected mostly at the limiting membrane of the lamellar bodies.
By homology analysis of partial sequences, Mulugeta et al. (2002) found that the ABCA3 protein is highly conserved among species. ABCA3 transcripts were found in cell lines of human lung origin, in ATII cells of human, rat, and mouse, and in various rat tissues. Highest expression of rat Abca3 was in ATII cells, and expression of Abca3 was at its maximum in rats prior to birth.
Yoshida et al. (2004) cloned and characterized the promoter region of the human ABCA3 gene and identified a potential glucocorticoid-responsive element (GRE) motif. Electrophoretic mobility shift assay using nuclear extracts from dexamethasone-treated cells from a human ATII cell line demonstrated specific binding of the glucocorticoid receptor to the GRE.
By Western blot analysis, Nagata et al. (2004) found that transfected HEK293 cells expressed ABCA3 as proteins with apparent molecular masses of approximately 190 and 150 kD. Glycosidase treatment reduced the apparent mass of the larger protein.
Klugbauer and Hofmann (1996) mapped the ABCA3 gene to chromosome 16p13.3 by comparison with an identical cDNA clone mapping to that chromosomal region. They noted that the ABCA3 gene and the gene encoding MRP1 map within the same chromosomal band.
Wu and Horvitz (1998) found that the C. elegans protein ced7 is homologous to human ABCA3. Ced-7 functions in the engulfment of cell corpses during programmed cell death, is broadly expressed during embryogenesis, and is localized to the plasma membrane. Mosaic analysis revealed that ced7 functions in both dying cells and engulfing cells during the engulfment process. Wu and Horvitz (1998) proposed that ced7 functions to translocate molecules that mediate homotypic adhesion between the cell surfaces of the dying and engulfing cells. They also suggested that ABCA3 may be functionally similar and that the molecular mechanism underlying cell corpse engulfment during programmed cell death may be conserved from nematodes to mammals.
By Northern blot analysis, Mulugeta et al. (2002) found the expression of ABCA3 increased more than 30-fold following stimulation of fetal lung explants with dexamethasone, cAMP, and isobutylmethylxanthine. Because ABCA3 is a member of a subfamily of ABC transporters involved in the regulation of lipid transport and membrane trafficking, Mulugeta et al. (2002) proposed that ABCA3 may play a role in lipid organization during the formation of lamellar bodies.
Shulenin et al. (2004) examined lung tissue from 4 patients with severe neonatal surfactant deficiency and different mutations of the ABCA3 gene. They found markedly abnormal lamellar bodies and concluded that ABCA3 is critical for the proper formation of lamellar bodies and surfactant function.
Yoshida et al. (2004) found that expression of ABCA3 in rat lung is dramatically increased after embryonic day (E) 20.5. Administration of dexamethasone to pregnant rats for 3 days starting on E15.5 markedly induced expression of ABCA3 by E18.5. Dexamethasone also increased ABCA3 mRNA expression levels in human ATII cells 4-fold and upregulated promoter activity of the ABCA3 5-prime flanking region containing the GRE about 2-fold. Upregulation by dexamethasone was not observed when the GRE-containing region was deleted or when a point mutation was introduced into the GRE. Yoshida et al. (2004) concluded that glucocorticoid-induced upregulation of ABCA3 expression in vivo is mediated by transcriptional activation through the GRE in the promoter, and suggested that ABCA3 plays an important role in the formation of pulmonary surfactant, probably by transporting lipids such as cholesterol.
Nagata et al. (2004) found that expression of human ABCA3 in HEK293 cells resulted in the appearance of 0.6- to 1.0-micrometer multivesicular lamellar body-like structures that were not found in untransfected cells. ABCA3-containing membranes hydrolyzed a photoaffinity analog of ATP in the presence of several divalent cations. The reaction did not proceed with addition of a cholesterol-depleting compound, suggesting that cholesterol is an endogenous substrate in the membrane fraction.
Ban et al. (2007) found that overexpression of ABCA3 in human lung adenocarcinoma A549 cells elevated choline phospholipid content in intracellular LAMP3 (605883)-positive vesicles.
In 16 of 21 racially and ethnically diverse infants with severe neonatal respiratory distress and surfactant deficiency (SMDP3; 610921), Shulenin et al. (2004) identified mutations in the ABCA3 gene (see 601615.0001-601615.0006). They detected nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the gene. In 5 consanguineous families with mutations, each pair of sibs was homozygous for the same mutation and each mutation was found in only 1 family. Most of the infants died within 1 month after birth, although 1 child who was heterozygous was still alive at 6 years of age.
In a male infant who died in the neonatal period from surfactant-related respiratory failure, Kunig et al. (2007) identified homozygosity for a missense mutation in the ABCA3 gene (601615.0007).
Kaltenborn et al. (2012) studied the effects of 2 clinically relevant ABCA3 mutations, E292V and Q215K, alone and in combination with respiratory syncytial virus (RSV) infection. The authors noted that E292V has a prevalence of 1:277 in the United States and thus is the most common ABCA3 mutation reported in children (Garmany et al., 2008); the Q215K mutation was reported in a neonate who died of respiratory distress (Brasch et al., 2006). After stable transfection into A549 lung epithelial cells, the ABCA3 mutations strongly impaired expression of the alveolar type II differentiation marker SPC (178620) and the epithelial cell adhesion proteins E-cadherin (192090) and zonula occludens-1 (601009). Concurrently, cells expressing the ABCA3 mutations acquired mesenchymal features as evidenced by increased expression of SNAI1 (604238), MMP2 (120360), and TGFB1 (190180), and elevated phosphorylation of SRC (190090). Infection with the most common viral respiratory pathogen in small children, RSV, potentiated the transition from epithelial to mesenchymal characteristics as well as a morphologic shift to a mesenchymal phenotype. Kaltenborn et al. (2012) suggested that impairment of epithelial function might be a mechanism by which ABCA3 mutations cause interstitial lung disease.
Ban et al. (2007) obtained Abca3 -/- mice at the expected mendelian ratio. Abca3 -/- pups were of normal size and body weight at birth, but all failed to inflate their lungs and died of acute respiratory failure. Abca3 -/- lungs were immature, lacked expression of surfactant C (SFTPC; 178620), and showed altered phospholipid profiles, predominantly of phosphatidylcholines and phosphatidylglycerols.
Independently, Hammel et al. (2007) reported findings similar to those of Ban et al. (2007). Electron microscopy showed absence of normal-appearing lamellar bodies in type II pneumocytes and lack of alveolar deposition of surfactant material in Abca3 -/- mice.
Herber-Jonat et al. (2013) found that Abca3 haploinsufficiency predisposed adult mice to lung injury induced by hyperoxia and mechanical ventilation. Unchallenged Abca3 +/- mice showed significantly reduced lung phosphatidylcholine and phosphatidylglycerol levels and decreased lung compliance, although other measures of lung mechanics appeared normal. Upon mechanical ventilation, bronchoalveolar lavage fluid of Abca3 +/- mice showed an inflammatory response not seen in wildtype animals. Abca3 +/- lungs were also more sensitive than wildtype to injury induced by hyperoxia.
In 2 white sisters from a consanguineous family with neonatal pulmonary surfactant metabolism dysfunction-3 (SMDP3; 610921), Shulenin et al. (2004) identified homozygosity for a 3426G-A transition in exon 23 of the ABCA3 gene, resulting in a trp1142-to-ter (W1142X) mutation. One infant died during the neonatal period and the other within 3 months after birth.
In 2 black brothers from a consanguineous family with surfactant metabolism dysfunction-3 (SMDP3; 610921), Shulenin et al. (2004) identified homozygosity for a 301T-C transition in exon 5 of the ABCA3 gene, resulting in a leu101-to-pro (L101P) mutation. Both infants died during the neonatal period.
In 2 Middle Eastern brothers from a consanguineous family with neonatal surfactant metabolism dysfunction-3 (SMDP3; 610921), Shulenin et al. (2004) identified homozygosity for a 4657T-C transition in exon 30 of the ABCA3 gene, resulting in a leu1553-to-pro (L1553P) mutation. Both infants died during the neonatal period.
In a white male from a nonconsanguineous family with neonatal surfactant metabolism dysfunction-3 (SMDP3; 610921) and with a history of a similarly affected sib, Shulenin et al. (2004) identified heterozygosity for a 4772A-C transversion in exon 31 of the ABCA3 gene, resulting in a gln1591-to-pro (Q1591P) mutation. The patient was still alive at 6 years of age with chronic lung disease, suggesting that some ABCA3 mutations are not fatal; however, a second mutation in the ABCA3 gene was not identified.
In a Hispanic male from a nonconsanguineous family with pulmonary surfactant metabolism dysfunction-3 (SMDP3; 610921), Shulenin et al. (2004) identified heterozygosity for a 1702G-A transition in exon 14 of the ABCA3 gene, resulting in an asn568-to-asp (N568D) mutation. The patient died after lung transplantation. The N568 residue is within the N-terminal ATP-binding domain and is conserved in the mammalian and fish ABCA3 genes as well as almost all other members of ABC subfamily A. The corresponding residue is mutated in the ABCA1 gene (600046) in patients with Tangier disease (205400) and in the ABCA4 gene (601691) in patients with Stargardt disease (248200).
In 2 Asian female cousins from consanguineous families with pulmonary surfactant metabolism dysfunction-3 (SMDP3; 610921), Shulenin et al. (2004) identified homozygosity for a 4909+1G-A splice mutation in exon 31 of the ABCA3 gene. Histologic findings in 1 infant included pulmonary alveolar proteinosis; both infants died during the neonatal period.
In a male infant who died in the neonatal period from surfactant-related respiratory failure (SMDP3; 610921), Kunig et al. (2007) identified homozygosity for a leu326-to-pro (L326P) mutation in the ABCA3 gene. The patient differed from previously reported cases in that his initial presentation was severe pulmonary hypertension that appeared to be out of proportion to the degree of lung disease.
Ban, N., Matsumura, Y., Sakai, H., Takanezawa, Y., Sasaki, M., Arai, H., Inagaki, N. ABCA3 as a lipid transporter in pulmonary surfactant biogenesis. J. Biol. Chem. 282: 9628-9634, 2007. [PubMed: 17267394] [Full Text: https://doi.org/10.1074/jbc.M611767200]
Brasch, F., Schimanski, S., Muhlfeld, C., Barlage, S., Langmann, T., Aslanidis, C., Boettcher, A., Dada, A., Schroten, H., Mildenbreger, E., Prueter, E., Ballmann, M., Ochs, M., Johnen, G., Griese, M., Schmitz, G. Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency. Am. J. Resp. Crit. Care Med. 174: 571-580, 2006. [PubMed: 16728712] [Full Text: https://doi.org/10.1164/rccm.200509-1535OC]
Connors, T. D., Van Raay, T. J., Petry, L. R., Klinger, K. W., Landes, G. M., Burn, T. C. The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3. Genomics 39: 231-234, 1997. [PubMed: 9027511] [Full Text: https://doi.org/10.1006/geno.1996.4500]
Garmany, T. H., Wambach, J. A., Heins, H. B., Watkins-Torry, J. M., Wegner, D. J., Bennet, K., An, P., Land, G., Saugstad, O. D., Henderson, H., Nogee, L. M., Cole, F. S., Hamvas, A. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediat. Res. 63: 645-649, 2008. [PubMed: 18317237] [Full Text: https://doi.org/10.1203/PDR.0b013e31816fdbeb]
Hammel, M., Michel, G., Hoefer, C., Klaften, M., Muller-Hocker, J., de Angelis, M. H., Holzinger, A. Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies. Biochem. Biophys. Res. Commun. 359: 947-951, 2007. [PubMed: 17577581] [Full Text: https://doi.org/10.1016/j.bbrc.2007.05.219]
Herber-Jonat, S., Mittal, R., Huppmann, M., Hammel, M., Liebisch, G., Yildirim, A. O., Eickelberg, O., Schmitz, G., de Angelis, M. H., Flemmer, A. W., Holzinger, A. Abca3 haploinsufficiency is a risk factor for lung injury induced by hyperoxia or mechanical ventilation in a murine model. Pediat. Res. 74: 384-392, 2013. [PubMed: 23881110] [Full Text: https://doi.org/10.1038/pr.2013.127]
Kaltenborn, E., Kern, S., Frixel, S., Fragnet, L., Conzelmann, K.-K., Zarbock, R., Griese, M. Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation. Hum. Molec. Genet. 21: 2793-2806, 2012. [PubMed: 22434821] [Full Text: https://doi.org/10.1093/hmg/dds107]
Klugbauer, N., Hofmann, F. Primary structure of a novel ABC transporter with a chromosomal localization on the band encoding the multidrug resistance-associated protein. FEBS Lett. 391: 61-65, 1996. [PubMed: 8706931] [Full Text: https://doi.org/10.1016/0014-5793(96)00700-4]
Kunig, A. M., Parker, T. A., Nogee, L. M., Abman, S. H., Kinsella, J. P. ABCA3 deficiency presenting as persistent pulmonary hypertension of the newborn. J. Pediat. 151: 322-324, 2007. [PubMed: 17719949] [Full Text: https://doi.org/10.1016/j.jpeds.2007.05.054]
Mulugeta, S., Gray, J. M., Notarfrancesco, K. L., Gonzales, L. W., Koval, M., Feinstein, S. I., Ballard, P. L., Fisher, A. B., Shuman, H. Identification of LBM180, a lamellar body limiting membrane protein of alveolar type II cells, as the ABC transporter protein ABCA3. J. Biol. Chem. 277: 22147-22155, 2002. [PubMed: 11940594] [Full Text: https://doi.org/10.1074/jbc.M201812200]
Nagata, K., Yamamoto, A., Ban, N., Tanaka, A. R., Matsuo, M., Kioka, N., Inagaki, N., Ueda, K. Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles. Biochem. Biophys. Res. Commun. 324: 262-268, 2004. [PubMed: 15465012] [Full Text: https://doi.org/10.1016/j.bbrc.2004.09.043]
Shulenin, S., Nogee, L. M., Annilo, T., Wert, S. E., Whitsett, J. A., Dean, M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. New Eng. J. Med. 350: 1296-1303, 2004. [PubMed: 15044640] [Full Text: https://doi.org/10.1056/NEJMoa032178]
Wu, Y.-C., Horvitz, H. R. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93: 951-960, 1998. [PubMed: 9635425] [Full Text: https://doi.org/10.1016/s0092-8674(00)81201-5]
Yamano, G., Funahashi, H., Kawanami, O., Zhao, L.-X., Ban, N., Uchida, Y., Morohoshi, T., Ogawa, J., Shioda, S., Inagaki, N. ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett. 508: 221-225, 2001. [PubMed: 11718719] [Full Text: https://doi.org/10.1016/s0014-5793(01)03056-3]
Yoshida, I., Ban, N., Inagaki, N. Expression of ABCA3, a causative gene for fatal surfactant deficiency, is up-regulated by glucocorticoids in lung alveolar type II cells. Biochem. Biophys. Res. Commun. 323: 547-555, 2004. [PubMed: 15369786] [Full Text: https://doi.org/10.1016/j.bbrc.2004.08.133]