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Official Full Name
ATP-binding cassette, sub-family A (ABC1), member 3
ATP-binding cassette sub-family A member 3 is a protein that in humans is encoded by the ABCA3 gene.
ABCA3; ATP-binding cassette, sub-family A (ABC1), member 3; ABC3; ATP-binding cassette sub-family A member 3; ABC C; EST111653; LBM180; ABC transporter 3; ABC-C transporter; ATP-binding cassette transporter 3; ABC-C; SMDP3; MGC72201; MGC166979; ABC3, ABC-C, SMDP3, LBM180, EST111653

Pulmonary surfactant (PS) plays a vital role in regulating the surface tension of the alveoli, preventing alveolar collapse, and providing a spatial structure for gas exchange. Studies have found that there is a transporter of ATP-binding Cassette transporters A3 (ABCA3) on the outer membrane of lamellar bodies. Its function is to transport phospholipids and cholesterol in lamellar bodies out of the cell membrane and participate in the storage and secretion process of PS.

The post-transcriptional mRNA of the ABCA3 gene is approximately 6500 bp long and forms a primary translation product of approximately 190 kDa consisting of 1,704 amino acids after translation. At the N-terminus of the primary translation product, there is a signal sequence consisting of 5-6 amino acids, which has a guiding role in protein targeted delivery. Under targeted delivery, ABCA3 enters the rough endoplasmic reticulum for glycosylation folding. In vitro studies by Beers et al. found two glycosylation sites at positions 124 and 140 of the N-terminus. The study also showed that glycosylation folding plays a key role in protein folding, stabilization and cell localization. The primary translation product of the ABCA3 gene is glycosylated and folded in the endoplasmic reticulum, transported to the outer membrane of the lamellar body via vesicles or multivesicular bodies through the Golgi apparatus, and finally releases phospholipids and cholesterol into the alveolar space through exocytosis. . In immunoblotting, ABCA3 showed two protein bands with relative molecular masses of 190 000 and 170 000, respectively, demonstrating that ABCA3 was cleaved during transport.

Predicted topological model of the ABCA3 protein.Figure 1. Predicted topological model of the ABCA3 protein. (Beers, et al. 2013).

ABCA3 gene expression is regulated by a variety of factors and hormones. In lung tissue, thyroid transcription factor 1 (TTF1), signal transduction and transcriptional activator 3 (STAT3) are involved in the induction of ABCA3 gene expression, PS synthesis, and promotion of alveolar type II epithelial cell maturation. Hofmann et al. found that the transcription factor GATA-6, forkhead box protein A2 (FOXA2),  CCAAT/enhancer binding protein a (C/EBPa), and activated T cell nuclear transcription factor 3 (NFATC3) initiate the gene by binding between 2591 bp and 1102 bp of exon 1 of the ABCA3 gene. Glucocorticoid upregulates the transcription level of the ABCA3 gene through a glucocorticoid response element that binds to the promoter region. When the glucocorticoid response element is deleted or the promoter sequence is mutated, the effect of dexamethasone disappears. Houda et al. found that the miR-200 family regulates the expression of ABCA3 gene by increasing the transcriptional activity of TTF-1 to promote the differentiation of alveolar type II epithelial cells.

ABCA3 Protein Physiological Function

ABCA3 belongs to a member of the A subfamily of the ABC superfamily and is highly expressed in lung tissue. The ABC superfamily is a large family with similar structure and material transport functions. It is widely distributed in various organisms from bacteria to humans and belongs to a class of ATP-driven pumps. ABCA3 has a similar structure to other subclasses of class A and consists of four domains: two transmembrane domains (TMD1 and TMD2) and two nucleotide binding domains (NBD1 and NBD2) located in the intracellular cytoplasm. TMD consists of six α helices that recognize the structure of various transmembrane transport substrates and complete transmembrane transport of substrate molecules. NBD is a site of ATP binding, NBD protein structure is highly conserved, and TMD has a variety of sequence structures, which indirectly reflects the diversity of substrate chemical structure. NBD binds to ATP and hydrolyzes ATP, which uses the energy of hydrolyzing ATP to transport the substrate out of the cell membrane. The function of ABCA3 in lung tissue is to transport cholesterol and phospholipids into the alveolar space to form PS, including phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, and sphingomyelin.


Neonatal Respiratory Distress Syndrome (NRDS) is a respiratory distress and respiratory failure that occurs progressively after birth in neonates due to a lack of PS. NRDS is a multifactorial, multi-gene involved disease. In 2004, it was first discovered that mutations in the ABCA3 gene cause NRDS in term infants. Subsequent reports have also confirmed that ABCA3 gene mutation is one of the important causes of NRDS.

ABCA3 gene mutations are homozygous gene mutations and heterozygous gene mutations. The genetic phenotype and disease severity of different gene mutations are different. Farideh et al. reported that a NRDS full-term (38 weeks) male boy was found to have a homozygous mutation in the ABCA3 gene c. 604G> A (p.G 202R). Both parents were mutation carriers and close relatives were married. Mukhtar et al. reported that 3 children with NRDS were found to have homozygous mutations in c.4545delC, 2 patients had lung transplantation and 1 died. In addition, a study reported a male infant with NRDS after birth, but after a series of treatments without remission and died on the 72nd day after birth, ABCA3 gene detection found a composite mutation of c. 556C> A and c. 2632 delA.

The investigators performed ABCA3 gene testing in 11 children with NRDS and found c.2169 G>A (p.M723I), c.1010T>G (pV 337G), and c. 4972 A >G(p.S 1658G) exon variation, and ABCA3 gene Exon 30+2 T/G scissors site variation. Wambach et al. found that complex heterozygous mutations in mutations accounted for about 3/4 of all mutations, and the phenotypes were quite different. Homozygous mutations accounted for 1/4, and clinical manifestations were more serious. In a mouse model study, it was found that ABCA3 homozygous mutations usually die soon after birth, while ABCA3 heterozygous mutations can survive. This also confirms that the initial clinical manifestations of homozygous gene mutations are severe, and die in the first year after birth or in the first year of life; however, heterozygous mutations can survive to infancy or childhood, or even longer.


  1. Beers, M. F., Zhao, M., Tomer, Y., Russo, S. J., Zhang, P., & Gonzales, L. W., et al. (2013). Disruption of n-linked glycosylation promotes proteasomal degradation of the human atp-binding cassette transporter abca3. American Journal of Physiology Lung Cellular & Molecular Physiology, 305(12), L970-L980.
  2. Hofmann, N., Galetskiy, D., Rauch, D., Wittmann, T., Marquardt, A., & Griese, M., et al. (2016). Analysis of the proteolytic processing of abca3: identification of cleavage site and involved proteases. Plos One, 11(3), e0152594.
  3. Houda, B., Wei, G., Pierce, B. M., & Mendelson, C. R. (2015). The mir-200 family and its targets regulate type ii cell differentiation in human fetal lung. Journal of Biological Chemistry, 290(37), 22409.
  4. Farideh, R., Mohammad, S., Gholamreza, S., Ali, D., Maryam, M., & Hamid, G. (2016). Novel mutation in the atp-binding cassette transporter a3 (abca3) encoding gene causes respiratory distress syndrome in a term newborn in southwest iran:. Iranian Journal of Pediatrics, 26(2).
  5. Mukhtar, G. M. A., Otaibi, W. H. A., Almobaireek, K. F. A., & Alsaleh, S. (2016). Adenosine triphosphate-binding cassette member a3 gene mutation in children from one family from saudi arabia. Annals of Thoracic Medicine, 11(3), 227-229.
  6. Wambach, J. A., Casey, A. M., Fishman, M. P., Wegner, D. J., Wert, S. E., & Cole, F. S., et al. (2014). Genotype-phenotype correlations for infants and children with abca3 deficiency. Am J Respir Crit Care Med, 189(12), 1538-1543.

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