Inherited retinal degenerative diseases are a clinically and genetically heterogeneous group of disorders that constitute a major cause of vision loss in the world population. They are typically characterized by the progressive loss of rod and cone photoreceptor cells often leading to severe blindness [1
]. To date over 160 genes associated with various retinal diseases have been identified and partially characterized at a genetic and molecular level and the loci of another 42 genes have been mapped (http://www.sph.uth.tmc.edu/Retnet/
). The heterogeneity of retinal degenerative diseases is further highlighted by the finding that different mutations in a given gene can lead to different clinically defined disease phenotypes.
Retinal degenerative diseases are typically classified by their phenotypic characteristics. Two major classes are retinitis pigmentosa (RP) and macular degeneration (MD). RP affects 1 in 3,500 people and is typically characterized by night blindness, progressive loss in peripheral vision and subsequent loss in central vision, often leading to total loss in vision [1
]. Genetically, RP can be separated into three subtypes: autosomal dominant RP, autosomal recessive RP, and X-linked RP. Each subtype is caused by any of a number of different genetic defects. MD involves the loss in central vision with varying preservation of peripheral vision and can affect people of all ages [7
]. 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
]. These macular dystrophies are divided into subtypes based on their clinical presentation and include such diseases as Best disease, Stargardt macular degeneration, Doyne honeycomb retinal degeneration also known as Malattia Leventinese, Sorby fundus dystrophy, dominant macular dystrophies and others. Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly affecting as many as 30–50 million people world-wide [11
]. It is a complex disease involving both genetic and environmental factors. In recent years, significant progress has been made in identifying genetic variants that increase one's risk for developing AMD. Major contributors are genetic variants that encode immunoregulatory proteins including complement factor H [16
]. Genetic studies, however, also point to the involvement of other cellular pathways in AMD pathogenesis [20
Most monogenic forms of RP, MD and related inherited retinal degenerative diseases are associated with genes that are expressed in photoreceptor cells or retinal pigment epithelial (RPE) cells where they encode proteins that are critical for photoreceptor structure, function and survival. Specific cellular processes and biochemical pathways implicated in various retinopathies include: phototransduction, visual cycle, photoreceptor structure and morphogenesis, cell adhesion, cellular metabolism, vesicle and protein trafficking, synaptic function, cilium structure and transport, ion and small molecular transport, chaperones, RNA splicing, transcription factors associated with photoreceptor development, protein folding and subunit assembly, posttranslational protein modification, among others. In some instances the function of the protein encoded by disease-associated genes is not known.
Two genes associated with inherited macular degenerative diseases encode proteins that function in the processing of lipids in photoreceptor cells. Mutations in the gene encoding a photoreceptor ABC transporter known as ABCA4 cause autosomal recessive Stargardt macular degeneration and related retinal degenerative diseases [22
]. Biochemical studies have implicated ABCA4 in the transport of a retinal phospholipid compound, known as N-retinylidene-phosphatidylethanolamine, across photoreceptor outer segment disc membranes following photoexcitation, thereby facilitating the removal of potentially toxic retinal compounds from photoreceptor cells [23
]. Mutations in the gene encoding ELOVL4, an elongase enzyme involved in the elongation of very long chain fatty acids, have been linked to autosomal dominant Stargardt-like disease [26
]. In this chapter, we review the genetic and biochemical studies linking ABCA4 to lipid transport and ELOVL4 to lipid biosynthesis in photoreceptors and provide insight into molecular mechanisms underlying these forms of Stargardt diseases.