Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration
Open accessAbstract
Stargardt disease is a common inherited macular degeneration characterized by a significant loss in central vision in the first or second decade of life, bilateral atrophic changes in the central retina associated with degeneration of photoreceptors and underlying retinal pigment epithelial cells, and the presence of yellow flecks extending from the macula. Autosomal recessive Stargardt disease, the most common macular dystrophy, is caused by mutations in the gene encoding ABCA4, a photoreceptor ATP binding cassette (ABC) transporter. Biochemical studies together with analysis of abca4 knockout mice and Stargardt patients have implicated ABCA4 as a lipid transporter that facilitates the removal of potentially toxic retinal compounds from photoreceptors following photoexcitation. An autosomal dominant form of Stargardt disease also known as Stargardt-like dystrophy is caused by mutations in a gene encoding ELOVL4, an enzyme that catalyzes the elongation of very long-chain fatty acids in photoreceptors and other tissues. This review focuses on the molecular characterization of ABCA4 and ELOVL4 and their role in photoreceptor cell biology and the pathogenesis of Stargardt disease.
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ATP-dependent transporters such as ABCA4 or the channel-like property of STRA6 could facilitate retinoid transport.
“But this process could be facilitated by ATP-dependent transporters such as ABCA476,485−487 or the channel-like property of STRA6.488−492”
From Chemistry of the Retinoid (Visual) Cycle (2014) · cites this paper as [486]
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BackgroundInfluentialHistopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus.
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BackgroundRad50/SMC proteins and ABC transporters: unifying concepts from high-resolution structures
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BackgroundLipids of ocular tissues. 6. Phospholipids of bovine rod outer segments
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BackgroundBiochemical defects in ABCR protein variants associated with human retinopathies
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“In recent years, significant progress has been made in identifying genetic variants that increase one's risk for developing AMD.”
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Self-citationA gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1
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“Extensive clinical and genetic analyses have shown that autosomal recessive Stargardt disease and fundus flavimaculatus are variations of the same disease, typically caused by different mutations in the same gene [28,45,46].”
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“The ATPase activity of ABCA4 cannot be directly measured in isolated photoreceptor outer segment membranes due to the low enzymatic activity of ABCA4 and the high activity of other ATPases in these preparations [23,116].”
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“The rim region of the discs in rod and cone outer segments contains a distinct set of membrane proteins [95].”
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“Addition of ATP (or GTP) to ABCA4 containing bound N-ret-PE resulted in the dissociation of substrate from the protein [113,122].”
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“Of the twelve members in the human ABCA subfamily, three ABCA transporters (ABCA1, ABCA3, ABCA12) in addition to ABCA4 have been linked to inherited diseases associated with defective transport of lipids [76].”
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“Genetically distinct autosomal dominant forms of Stargardt-like disease have been mapped to chromosome 6q (STGD3; MIM #600110) and chromosome 4q (STGD4) [157,161].”
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“This may be due an increase in the formation of A2E epoxides or oxiranes [131,132] in the absence of pigmentation.”
BackgroundThe lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells
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“This is consistent with the proposed role of ELOVL4 in the elongation of very long chain fatty acids [180,181].”
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Stargardt's Disease and Fundus Flavimaculatus
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Diverse macular dystrophy phenotype caused by a novel complex mutation in the ELOVL4 gene.
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“Earlier studies have indicated that C28–C36 containing phospholipids bind tightly to rhodopsin [202].”
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“They comprise as much as 10 mol % of the fatty acids of rod and cone outer segment membranes [191,193,201].”
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“They comprise as much as 10 mol % of the fatty acids of rod and cone outer segment membranes [191,193,201].”
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“This is consistent with the proposed role of ELOVL4 in the elongation of very long chain fatty acids [180,181].”
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Complement Activation by Bisretinoid Constituents of RPE Lipofuscin
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“A2E has also been shown to activate the complement system possibly contributing to the pathogenesis of Stargardt disease as well as age-related macular degeneration [151].”
BackgroundVisual Acuity Loss in Patents with Stargardt's Macular Dystrophy
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ABCR unites what ophthalmologists divide(s)
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“To get around this problem, detergent solubilized ABCA4 was purified from either rod outer segment membranes or transfected cells by immunoaffinity chromatography and reconstituted into lipid vesicles for analysis of ATP hydrolysis activity [23,113,114,117].”
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“Homologues of mammalian ABCA proteins have been identified in eukaryotic and prokaryotic organisms suggesting that ABCA genes have evolved from a common primordial gene [79].”
BackgroundSimple and Complex ABCR: Genetic Predisposition to Retinal Disease
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“In recent years, significant progress has been made in identifying genetic variants that increase one's risk for developing AMD.”
BackgroundInfluentialMutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration.
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A Ligand Channel through the G Protein Coupled Receptor Opsin
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BackgroundMammalian fatty acid elongases
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BackgroundSelf-citationLipid to Protein Chromophore Transfer in the Photolysis of Visual Pigments
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“However, it is known that a fraction of all-trans retinal released from rhodopsin reversibly reacts with PE in the disc membrane to form N-ret-PE [142,143].”
BackgroundMechanisms of Opsin Activation
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“Extensive clinical and genetic analyses have shown that autosomal recessive Stargardt disease and fundus flavimaculatus are variations of the same disease, typically caused by different mutations in the same gene [28,45,46].”
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“Progressive decrease in visual acuity generally occurs throughout life with values reaching 20/200 or worse in the final stages of the disease [29].”
BackgroundIntrafamilial variation of phenotype in Stargardt macular dystrophy-Fundus flavimaculatus.
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“The topological organization of ABCA4 within the membrane has been predicted using computer algorithms in conjunction with biochemical studies [25,50,78].”
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BackgroundA New Locus for Autosomal Dominant Stargardt-Like Disease Maps to Chromosome 4
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“Genetically distinct autosomal dominant forms of Stargardt-like disease have been mapped to chromosome 6q (STGD3; MIM #600110) and chromosome 4q (STGD4) [157,161].”
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A Novel Mutation in the ELOVL4 Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy
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“During fluorescein angiography, lipofuscin absorbs blue excitatory light producing the characteristic “dark choroid” appearance in many Stargardt patients [40].”
BackgroundDelayed Rod Dark Adaptation in Patients with Stargardt's Disease
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Age related macular degeneration
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Histopathology of Incipient Fundus Flavimaculatus
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Self-citationMutations in ABC1 in Tangier disease and familial high-density lipoprotein
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“Immunoelectron microscopic studies have shown that ABCA4 is confined to the rim region and incisures of rod and cone photoreceptor disc membranes (Figure 3B,C) [48, 50, 94].”
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“These mice with a retinal pathology similar to patients with Stargardt-like disease have a significant deficiency in C32– C36 acyl phosphatidylcholines [186,199].”
BackgroundZhong, M., Molday, L. L., & Molday, R. S. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m806580200 · Cited by 66 · cited 7× · see citing works
“To get around this problem, detergent solubilized ABCA4 was purified from either rod outer segment membranes or transfected cells by immunoaffinity chromatography and reconstituted into lipid vesicles for analysis of ATP hydrolysis activity [23,113,114,117].”
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“These include an A-loop with a conserved aromatic amino acid (phenylalanine in NBD1 and tyrosine in NBD2) involved in stacking interactions with the adenine ring of ATP [106,107], flexible Q-loop containing a conserved glutamine and involved in the transmission of conformational changes between the NBDs and the TMD [1…”
BackgroundGenetics of age-related macular degeneration
Ting, A., Lee, T. K. M., & MacDonald, I. M. (2009) · Current Opinion in Ophthalmology · doi:10.1097/icu.0b013e32832f8016 · Cited by 56 · see citing works
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“In contrast, the ABCA4D24 mutant lacking the C-terminal 24 amino acids and associated with a mild form of Stargardt disease [155] displayed essentially normal N-retPE binding, a small reduction in retinal stimulated ATPase activity and intracellular vesicular localization characteristic of wild-type ABCA4 implying rel…”
BackgroundEdwards, A. O., Miedziak, A. I., Vrabec, T. R., Verhoeven, J., Acott, T. S., Weleber, R. G., & Donoso, L. A. (1999) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(98)00331-6 · Cited by 54 · see citing works
The Natural History of Stargardt Disease with Specific Sequence Mutation in the ABCA4 Gene
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“Sparrow JR, Kim SR, Cuervo AM, Bandhyopadhyayand U. A2E, a pigment of RPE lipofuscin, is generated from the precursor, A2PE by a lysosomal enzyme activity.”
BackgroundInfluentialAutosomal Dominant Stargardt-Like Macular Dystrophy
Donoso, L. A., Edwards, A. O., Frost, A. T., Vrabec, T. R., Stone, E. M., Hageman, G. S., & Perski, T. (2001) · Survey of Ophthalmology · doi:10.1016/s0039-6257(01)00251-x · Cited by 50 · see citing works
Retinal Function in Stargardt's Disease and Fundus Flavimaculatus
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“Of the twelve members in the human ABCA subfamily, three ABCA transporters (ABCA1, ABCA3, ABCA12) in addition to ABCA4 have been linked to inherited diseases associated with defective transport of lipids [76].”
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A2E, a Fluorophore of RPE Lipofuscin: Can It Cause RPE Degeneration?
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“In contrast mice heterozygous for Elovl4 deletion showed reduced Elovl4 RNA expression, but developed normally and had relatively normal ERGs and only minimal morphological abnormalities in their photoreceptors [182,183].”
BackgroundEvolutionarily Conserved ELOVL4 Gene Expression in the Vertebrate Retina
Lagali, P. S., Liu, J., Ambasudhan, R., Kakuk, L. E., Bernstein, S. L., Seigel, G. M., WONG, P. W. K., & Ayyagari, R. (2003) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.02-0991 · Cited by 43 · cited 1× · see citing works
“ELOVL4 proteins are highly conserved with the human protein being over 90% identical to mouse and bovine orthologues and 66% identical to the zebrafish protein [176].”
BackgroundPolyunsaturated very-long-chain C28-C36 fatty acids and retinal physiology
McMahon, A., & Kędzierski, W. (2009) · British Journal of Ophthalmology · doi:10.1136/bjo.2008.149286 · Cited by 43 · see citing works
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Stargardt's Disease and the ABCR Gene
Westerfeld, C. B., & Mukai, S. (2008) · Seminars in Ophthalmology · doi:10.1080/08820530701745249 · Cited by 39 · cited 1× · see citing works
“Fundus flavimaculatus is generally used to describe a late onset, more mild form of Stargardt disease [30,47].”
BackgroundDHA does not protect ELOVL4 transgenic mice from retinal degeneration.
Li, F., Marchette, L. D., Brush, R. S., Elliott, M. H., Le, Y.-Z., Henry, K., Anderson, A. G., Zhao, C., Sun, X., Zhang, K., et al. (2009) · PubMed Central · Cited by 37 · see citing works
Self-citationSynthesis of very long chain (up to 36 carbon) tetra, penta and hexaenoic fatty acids in retina
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Elovl4 haploinsufficiency does not induce early onset retinal degeneration in mice
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“ABCA4 protein and mRNA expression has also been found in the choroid plexus of rats, although the role of ABCA4 in this tissue remains to be determined [90,91].”
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“coli and shown to display ATP hydrolysis activity [110,111].”
BackgroundEnhancement of Opsin Activity by all-trans-retinal
Surya, A., & Knox, B. E. (1998) · Experimental Eye Research · doi:10.1006/exer.1997.0453 · Cited by 26 · cited 1× · see citing works
“All-trans retinal can reassociate with opsin to form a complex that activates the visual cascade, although less efficiently than the photoactivated rhodopsin [152,153].”
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“coli and shown to display ATP hydrolysis activity [110,111].”
BackgroundRecovery of Rod Photoresponses in ABCR-Deficient Mice
Pawar, A. S., Qtaishat, N. M., Little, D. M., & Pepperberg, D. R. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1499 · Cited by 19 · see citing works
Genetics of Macular Dystrophies and Implications for Age-Related Macular Degeneration
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“Early onset or juvenile MD is a set of disorders caused by a mutation in a given gene and therefore they are referred to as monogenic diseases [9,10].”
BackgroundBiswas, E. E. (2006) · Biochemistry · doi:10.1021/bi052059u · Cited by 16 · see citing works
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Chemistry of the Retinoid (Visual) Cycle
Kiser, P. D., Golczak, M., & Palczewski, K. (2014) · Chemical Reviews · doi:10.1021/cr400107q · Cited by 353 · see citing works
Effective delivery of large genes to the retina by dual AAV vectors
Trapani, I., Colella, P., Sommella, A., Iodice, C., Cesi, G., de Simone, S., Marrocco, E., Rossi, S., Giunti, M., Palfi, A., et al. (2014) · EMBO Molecular Medicine · doi:10.1002/emmm.201302948 · Cited by 269 · see citing works
Molday, R. S., & Moritz, O. L. (2015) · Journal of Cell Science · doi:10.1242/jcs.175687 · Cited by 235 · see citing works
“High levels of bisretinoids within lipofuscin deposits are found in individuals with Stargardt macular degeneration linked to mutations in the gene encoding ABCA4 as well as in Abca4-knockout mice (Allikmets et al., 1997; Mata et al., 2000; Molday and Zhang, 2010; Sparrow et al., 2012).”
BackgroundSelf-citationRecessive Mutations in ELOVL4 Cause Ichthyosis, Intellectual Disability, and Spastic Quadriplegia
Aldahmesh, M. A., Mohamed, J. Y., Alkuraya, H., Verma, I. C., Puri, R. D., Alaiya, A. A., Rizzo, W. B., & Alkuraya, F. S. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.10.011 · Cited by 186 · see citing works
“The identification of ELOVL4mutations in patients with the atypical juvenile form of macular degeneration (SGDT3) sparked interest in the role of VLCFAs in the physiology of the retina.(22,23) Using several mouse models in which the heterozygous-dominant SGDT3 mutation was introduced by genetic knockin made it possibl…”
BackgroundKohno, H., Chen, Y., Kevany, B. M., Pearlman, E. M., Miyagi, M., Maeda, T., Palczewski, K., & Maeda, A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.448712 · Cited by 175 · see citing works
“AMD is the leading cause of legal blindness in industrialized countries (1), and Stargardt disease is the most common form of juvenile macular degeneration (2).”
BackgroundMammalian P4-ATPases and ABC transporters and their role in phospholipid transport
Coleman, J. A., Quazi, F., & Molday, R. S. (2012) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2012.10.006 · Cited by 154 · see citing works
Self-citationEndoplasmic Reticulum Stress and the Unfolded Protein Responses in Retinal Degeneration
Zhang, S. X., Sanders, E., Fliesler, S., & Wang, J. (2014) · Experimental Eye Research · doi:10.1016/j.exer.2014.04.015 · Cited by 151 · see citing works
“A rare form of autosomal dominant Stargardt disease is linked to the mutant ELOVL4 gene, which encodes an enzyme thought to be involved in the generation of very long-chain fatty acids (reviewed in Agbaga et al., 2010; Molday and Zhang, 2010).”
BackgroundPrimary amines protect against retinal degeneration in mouse models of retinopathies
Maeda, A., Golczak, M., Chen, Y., Okano, K., Kohno, H., Shiose, S., Ishikawa, K., Harte, W., Palczewska, G., Maeda, T., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.759 · Cited by 135 · see citing works
“However, a pool of atRAL that is trapped within the inner leaflet of rod photoreceptor outer segment disc membranes in the form of N -retinylidenephosphatidyletanolamine ( N -ret-PE) is not accessible for reductio”
Cadieux-Dion, M., Turcotte-Gauthier, M., Noreau, A., Martin, C., Meloche, C., Gravel, M., Drouin, C. A., Rouleau, G. A., Nguyen, D. K., & Cossette, P. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6337 · Cited by 124 · see citing works
Constitutive phospholipid scramblase activity of a G protein-coupled receptor
Goren, M. A., Morizumi, T., Menon, I. A., Joseph, J. S., Dittman, J. S., Cherezov, V., Stevens, R. C., Ernst, O. P., & Menon, A. K. (2014) · Nature Communications · doi:10.1038/ncomms6115 · Cited by 122 · see citing works
Monroig, Ó., Webb, K. A., Ibarra‐Castro, L., Holt, G. J., & Tocher, D. R. (2010) · Aquaculture · doi:10.1016/j.aquaculture.2010.12.024 · Cited by 120 · see citing works
Novel Cellular Functions of Very Long Chain-Fatty Acids: Insight From ELOVL4 Mutations
Deák, F., Anderson, R. E., Fessler, J. L., & Sherry, D. M. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00428 · Cited by 110 · see citing works
Lipid transport by mammalian ABC proteins
Quazi, F., & Molday, R. S. (2011) · Essays in Biochemistry · doi:10.1042/bse0500265 · Cited by 107 · see citing works
“Stargardt macular degeneration [10], defects in ABCG5/ABCG8, transport‐ ers of nutritional plant sterols, are linked to sitosterolaemia [11], and defects in ABCB4 are involved in the transport of PC on to bile micelles cause PFIC (progressive familial intrahepatic cholestasis) [12].”
BackgroundSelf-citationDynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life
Lewandowski, D., Sander, C. L., Tworak, A., Gao, F., Xu, Q., & Skowronska‐Krawczyk, D. (2021) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2021.101037 · Cited by 104 · see citing works
Trapani, I., Toriello, E., de Simone, S., Colella, P., Iodice, C., Polishchuk, E. V., Sommella, A., Colecchi, L., Rossi, S., Simonelli, F., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv386 · Cited by 94 · see citing works
“Consequently, abnormally high levels of lipofuscin pigments, such as A2E and all-transretinal dimer-phosphatidylethanolamine, accumulate in the RPE, triggering RPE-cell death and causing secondary PR degeneration (2).”
Berry, K. A. Z., Gordon, W. C., Murphy, R. C., & Bazan, N. G. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m044990 · Cited by 95 · see citing works
Role of membrane integrity on G protein-coupled receptors: Rhodopsin stability and function
Jastrzębska, B., Dębiński, A., Filipek, S., & Palczewski, K. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2011.03.002 · Cited by 74 · see citing works
An Overview of the Genetics of ABCA4 Retinopathies, an Evolving Story
Al‐Khuzaei, S., Broadgate, S., Foster, C. R., Shah, M., Yu, J., Downes, S. M., & Halford, S. (2021) · Genes · doi:10.3390/genes12081241 · Cited by 73 · see citing works
“As a result, the A2E accumulates within the RPE and forms a major component of lipofuscin, which is toxic to the RPE, thus leading to degeneration of the RPE and subsequently loss of the photoreceptor cells [33,35,46,50,51] (Figure 3B).”
BackgroundSTRA6: role in cellular retinol uptake and efflux.
Kelly, M., & Lintig, J. V. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2304-3881.2015.01.12 · Cited by 67 · see citing works
“Previously, the existence of a second RBP receptor expressed in tissues lacking STRA6 was postulated (53), and in 2013, RBPR2 was molecularly identified (14,54).”
BackgroundParker, M. A., Erker, L. R., Audo, I. S., Choi, D., Mohand‐Saïd, S., Šeštakauskas, K., Benoit, P., Appelqvist, T., Krahmer, M. R., Ségaut-Prévost, C., et al. (2022) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2022.02.013 · Cited by 61 · see citing works
Fatty acid transport proteins in disease: New insights from invertebrate models
Dourlen, P., Sujkowski, A. L., Wessells, R. J., & Mollereau, B. (2015) · Progress in Lipid Research · doi:10.1016/j.plipres.2015.08.001 · Cited by 60 · see citing works
“3: Role of FATP in mouse and Drosophila retina In mouse (A), the visual cycle recycles the chromophore, 11-cis retinal, of Rh, the lightsensitive protein of PRs [for a review, see [123][124]].”
BackgroundBarabás, P., Liu, A., Xing, W., Chen, C.-K., Tong, Z., Watt, C. B., Jones, B. W., Bernstein, P. S., & Križaj, D. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1214707110 · Cited by 57 · see citing works
Therapy Approaches for Stargardt Disease
Piotter, E., McClements, M. E., & MacLaren, R. E. (2021) · Biomolecules · doi:10.3390/biom11081179 · Cited by 49 · see citing works
“tails on the function of ABCA4 to be found elsewhere [10].”
BackgroundGarcía‐Cazorla, À., Mochel, F., Lamari, F., & Saudubray, J. (2014) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-014-9776-6 · Cited by 50 · see citing works
“Two genes associated with inherited macular degenerative diseases encode proteins whose function is to process lipids in photoreceptor cells: ABCA4 mutations cause the autosomal recessive Stargardt macular degeneration and ELOVL4 mutations lead to the autosomal dominant Stargardt-like disease (Molday and Zhang 2010).”
BackgroundChen, C., Yang, K., He, D., Yang, B., Tao, L., Chen, J., & Wu, Y. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.12.008 · Cited by 49 · see citing works
Zaneveld, J. E., Siddiqui, S. N., Li, H., Wang, X., Wang, H., Wang, K., Li, H., Ren, H., López, I., Dorfman, A. L., et al. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.174 · Cited by 46 · see citing works
Quantifying the Rate of Ellipsoid Zone Loss in Stargardt Disease
Cai, C. X., Light, J. G., & Handa, J. T. (2017) · American Journal of Ophthalmology · doi:10.1016/j.ajo.2017.10.032 · Cited by 47 · see citing works
Tanna, P., Georgiou, M., Strauss, R. W., Ali, N., Kumaran, N., Kalitzeos, A. A., Fujinami, K., & Michaelides, M. (2019) · Translational Vision Science & Technology · doi:10.1167/tvst.8.2.1 · Cited by 46 · see citing works
Retinal cone and rod photoreceptor cells exhibit differential susceptibility to light‐induced damage
Okano, K., Maeda, A., Chen, Y., Chauhan, V., Tang, J. C. O., Palczewska, G., Sakai, T., Tsuneoka, H., Palczewski, K., & Maeda, T. (2012) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2012.07647.x · Cited by 44 · see citing works
Gene Therapy of ABCA4-Associated DiseasesPreprint
Auricchio, A., Trapani, I., & Allikmets, R. L. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a017301 · Cited by 41 · see citing works
“After demonstrating safety and acceptable biodistribution of EIAV vectors carrying the human ABCA4 gene under the constitutive CMV promoter, phase I/II clinical trials for patients with STGD1 were started in 2012 by Oxford BioMedica (NCT01367444; see http:// www.clinicaltrials.gov).”
BackgroundInfluentialCell-autonomous lipid-handling defects in Stargardt iPSC-derived retinal pigment epithelium cells
Farnoodian, M., Bose, D., Khristov, V., Susaimanickam, P. J., Maddileti, S., Mariappan, I., Abu-Asab, M. S., Campos, M. M., Villasmil, R., Wan, Q., et al. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.10.001 · Cited by 38 · see citing works
Barbet, R., Peiffer, I., Hutchins, J. R. A., Hatzfeld, A., Garrido, E., & Hatzfeld, J. (2012) · Cell Cycle · doi:10.4161/cc.20023 · Cited by 36 · see citing works
ABCA4 Gene Screening in a Chinese Cohort With Stargardt Disease: Identification of 37 Novel Variants
Hu, F., Li, J., Gao, F., Qi, Y.-H., Xu, P., Zhang, Y.-J., Wang, D., Wang, L.-S., Li, W. S., Wang, M., et al. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00773 · Cited by 36 · see citing works
Nano-scale resolution of native retinal rod disk membranes reveals differences in lipid composition
Sander, C. L., Sears, A. E., Pinto, A. F. M., Choi, E. H., Kahremany, S., Gao, F., Salom, D., Jin, H., Pardon, E., Suh, S., et al. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202101063 · Cited by 36 · see citing works
Dual AAV Vectors for Stargardt Disease
Trapani, I. (2017) · Methods in molecular biology · doi:10.1007/978-1-4939-7522-8_11 · Cited by 30 · see citing works
Liu, Q., Sabirzhanova, I. B., Bergbower, E. A. S., Yanda, M. K., Guggino, W. G., & Cebotaru, L. (2019) · Cellular Physiology and Biochemistry · doi:10.33594/000000146 · Cited by 27 · see citing works
Julien, S., Illing, B., Tschulakow, A., Taubitz, T., Guezguez, J., Burnet, M. W. M., & Schraermeyer, U. (2020) · Pharmacology Research & Perspectives · doi:10.1002/prp2.683 · Cited by 25 · see citing works
Battu, R., Verma, A., Hariharan, R., Krishna, S., Kiran, R. P., Jacob, J., Ganapathy, A., Ramprasad, V. L., Kumaramanickavel, G., Jeyabalan, N., et al. (2015) · BioMed Research International · doi:10.1155/2015/940864 · Cited by 25 · see citing works
“Identification of Novel Mutations in ABCA4 Gene: Clinical and”
BackgroundThe lipid translocase, ABCA4: seeing is believing
Pollock, N. L., & Callaghan, R. (2011) · The FEBS Journal · doi:10.1111/j.1742-4658.2011.08169.x · Cited by 22 · see citing works
Evaluation of the ELOVL4, PRPH2 and ABCA4 genes in patients with Stargardt macular degeneration
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Clinical and genetic analyses reveal novel pathogenic ABCA4 mutations in Stargardt disease families
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Split AAV8 Mediated ABCA4 Expression for Gene Therapy of Mouse Stargardt Disease (STGD1)
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Identification of novel pathogenic ABCA4 variants in a Han Chinese family with Stargardt disease
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Role of Lipids in Retinal Vascular and Macular Disorders
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Cell therapy for retinal degenerative disorders: a systematic review and three-level meta-analysis
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“RDD can manifest in various forms, such as AMD, retinitis pigmentosa (RP), and less well-known inherited retinal dystrophies like Stargardt macular degeneration (SMD) [5, 6].”
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Regulatory Mechanisms of Retinal Photoreceptors Development at Single Cell Resolution
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“As photoreceptor survival depends on the RPE cells, the photoreceptor cells undergo damage, and degeneration subsequent to the RPE, causing loss of central vision that progresses over time (Molday and Zhang, 2010).”
BackgroundElovl4b knockout zebrafish as a model for ocular very-long-chain PUFA deficiency
Nwagbo, U., Parvez, S., Maschek, J. A., & Bernstein, P. S. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100518 · Cited by 8 · see citing works
Energy Metabolism in the Vertebrate Retina
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“Several mutations in STGD3, the human gene encoding ELOVL4, are linked to autosomal dominant Stargardt type 3 disease, a heritable form of blindness (Molday and Zhang 2010).”
BackgroundLin, Y., Gao, H., Chen, C., Zhu, Y., Li, T., Liu, B., Ma, C., Jiang, H., Li, Y., Huang, Y., et al. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3308 · Cited by 8 · see citing works
“The N and c halves are predicted to have a single membrane-spanning segment followed by a large exocytoplasmic domain, a transmembrane domain (TMd) and a nucleotide-binding domain (36,37).”
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Retinal Pigment Epithelial Detachment in ABCA4-Associated Stargardt’s Disease
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Stargardt Disease Caused by a Rare Combination of Double Homozygous Mutations
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“components derived from the incomplete degradation of phagocytized photoreceptor outer segments (4).”
BackgroundInfluentialAutosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication
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“ELOVL4 and ABCA4 are HMD subtypes involving lipid dysregulation that have been previously described (70).”
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“Pathogenic variants in ABCA4 results in a group of retinal phenotypes, collec - tively referred as ABCA4-associated retinal degenerations (ABCA4R) which are characterized by a notable clinical and allelic heterogeneity (Molday and Zhang 2010 ).”
BackgroundGene Therapy for Blinding Pediatric Eye Disorders
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“Another type of macular dystrophy is the autosomal dominant Stargardt-like macular dystrophy type 3 (STGD3), which is caused by 3 sets of mutations in the ELOVL4 gene (elongation of very long chain fatty acids protein 4) [67, 68].”
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“Dysfunction of this fl ippase activity leads to accumulation of NrPE and all-trans -retinal which condense to form A2PE [14, 15].”
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“Stargardt’s disease is a juvenile inherited form of macular degeneration, where defects in lipid biosynthesis and transport occur (reviewed in Molday and Zhang, 2010).”
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- Authors
- Molday, R. S., & Zhang, K.
- Affiliations
- University of British Columbia (CA)
- University of California San Diego (US)
- Corresponding author
- Molday, Robert S.
- Venue
- Progress in Lipid Research
- Publisher
- Elsevier BV
- Published
- 2010-10
- Volume
- 49
- Issue
- 4
- Pages
- 476-492
- ISSN
- 0163-7827 (ISSN-L)
- PMC
- PMC2946192
- OpenAlex
- W2168030414
- Cited by
- 82
- References
- 213
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 9 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 7 · 2014: 9 · 2013: 11 · 2012: 8
- FWCI
- 0.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Progress in Lipid Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research (MT5822)
- National Eye Institute (EY02422, R01EY002422)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- Stargardt disease, ABCA4, ELOVL4, photoreceptors, very long chain fatty acids, macular degeneration, retinal pigment epithelium, pathogenesis
- MeSH terms
- Stargardt Disease, Amino Acid Sequence, Animals, Chromosomes, Human, Pair 6, Eye Proteins, Humans, Macular Degeneration, Membrane Proteins, Models, Biological, Molecular Sequence Data, Phosphatidylethanolamines, Retina, Retinoids, Molecular Structure, ATP-Binding Cassette Transporters, Chromosome Disorders, Lipid Metabolism
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