ABCA4 gene

The ABCA4 gene (ABCA4 stands for: ATP Binding Cassette Subfamily A Member 4) is a protein-coding gene located on chromosome 1p22.1. An important paralog of this gene is ABCA1.

The ABCA4 gene encodes a membrane-associated protein that belongs to the ATP-binding cassette transporter (ABC) superfamily. ABC proteins transport various molecules through extra- and intracellular membranes.

ABC genes are divided into seven different subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. The members of the ABC1 subfamily form the only large ABC subfamily that occurs exclusively in multicellular eukaryotes.

The ABCA4 protein is a retina-specific ABC transporter with N-retinylidene-PE as substrate. It is expressed exclusively in photoreceptor cells of the retina. The gene product mediates the transport of an essential molecule, all-trans-retinal aldehyde (atRAL), across the photoreceptor cell membrane.

Mutations in this gene are diagnosed in patients with Stargardt's disease, a form of juvenile macular degeneration. Mutations in this gene are also associated with retinitis pigmentosa-19, cone-rod dystrophy type 3, early-onset severe retinal dystrophy, fundus flavimaculatus and age-related macular degeneration 2.

The encoded protein, a flippase (flippases are translocases that maintain the asymmetric distribution of phospholipids of the cell membrane), an enzyme that catalyzes the ATP-dependent transport of retinal-phosphatidylethanolamine conjugates such as the 11-cis and all-trans isomers of N-retinylidene-phosphatidylethanolamine from the lumen to the cytoplasmic leaflet of the outer photoreceptor segment membranes, where N-cis-retinylidene-phosphatidylethanolamine (N-cis-R-PE) is then isomerized to its all-trans isomer (N-trans-R-PE) and reduced by RDH8 to generate all-trans-retinol (all-trans-rol), thus preventing the accumulation of excess 11-cis-retinal and its Schiff base conjugate and the formation of toxic bisretinoid

The encoded enzyme can exhibit both ATPase and GTPase activity, which is strongly influenced by the lipid environment and the presence of retinoid compounds (Quazi F et al. 2013). Binds the unprotonated form of N-retinylidene phosphatidylethanolamine with high affinity in the absence of ATP, and ATP binding and hydrolysis induce a conformational change of the protein that causes dissociation of N-retinylidene phosphatidylethanolamine.

1. Garces FA et al. (2020) Functional Characterization of ABCA4 Missense Variants Linked to Stargardt Macular Degeneration. Int J Mol Sci 22:185.
2. Quazi F et al. (2013) Differential phospholipid substrates and directional transport by ATP-binding cassette proteins ABCA1, ABCA7, and ABCA4 and disease-causing mutants. J Biol Chem 288: 34414-34426.

3. Ścieżyńska A et al. (2020) Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles. Int J Mol Sci 21:3430.