ABCA4, a member of the ATP-binding cassette (ABC) transporter superfamily, is preferentially located along the rim region of rod and cone photoreceptor outer segment disc membranes. It uses ATP-binding and hydrolysis energy to transport N-retinylidene-phosphatidylethanolamine from the lumen to the cytoplasmic leaflet of disc membranes. This function is crucial for clearing all-trans-retinal and excess 11-cis-retinal from photoreceptor cells, preventing the accumulation of toxic retinoid compounds [2].

Mutations in ABCA4 are associated with a wide range of retinal diseases. It was first linked to autosomal recessive Stargardt disease (STGD1) in 1997, and since then, its variants have been found to cause phenotypes such as cone-rod dystrophy, retinitis pigmentosa-like phenotypes, and some late-onset cases sometimes confused with age-related macular degeneration. Genetic analysis has identified over 1200 disease-causing mutations of various types, including missense, nonsense, small deletions/insertions, and splicing-affecting variants, some of which are deep-intronic [1]. In different patient cohorts, like German, Chinese, and Spanish, researchers have established the mutational spectrum of ABCA4. For example, in a German cohort, 148 pathogenic or likely pathogenic mutations were identified, with 48 being previously unpublished [3]. In a Chinese cohort, 35 novel ABCA4 mutations were found, and the mutation spectrum was different from that of the Caucasian population [4].

In conclusion, ABCA4 is essential for maintaining normal retinal function by regulating retinoid metabolism in photoreceptor cells. Studies on ABCA4-related mutations across different populations have enhanced our understanding of the genetic complexity of ABCA4-associated retinopathies, which is crucial for disease diagnosis, prognosis, and the development of therapeutic strategies for these retinal diseases [1,3,4].

References:

1. Cremers, Frans P M, Lee, Winston, Collin, Rob W J, Allikmets, Rando. 2020. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. In Progress in retinal and eye research, 79, 100861. doi:10.1016/j.preteyeres.2020.100861. https://pubmed.ncbi.nlm.nih.gov/32278709/

2. Molday, Robert S, Garces, Fabian A, Scortecci, Jessica Fernandes, Molday, Laurie L. 2021. Structure and function of ABCA4 and its role in the visual cycle and Stargardt macular degeneration. In Progress in retinal and eye research, 89, 101036. doi:10.1016/j.preteyeres.2021.101036. https://pubmed.ncbi.nlm.nih.gov/34954332/

3. Schulz, Heidi L, Grassmann, Felix, Kellner, Ulrich, Weber, Bernhard H F, Stöhr, Heidi. . Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. In Investigative ophthalmology & visual science, 58, 394-403. doi:10.1167/iovs.16-19936. https://pubmed.ncbi.nlm.nih.gov/28118664/

4. Sun, Zixi, Yang, Lizhu, Li, Hui, Zhong, Yong, Sui, Ruifang. 2020. Clinical and genetic analysis of the ABCA4 gene associated retinal dystrophy in a large Chinese cohort. In Experimental eye research, 202, 108389. doi:10.1016/j.exer.2020.108389. https://pubmed.ncbi.nlm.nih.gov/33301772/