Genetics of Retinal Disease

Abstract

The retina forms the inner lining of the posterior segment of the eye. Vision is dependent on intact retinal photoreceptors to transduce incident light to an electrical signal for relay to the brain. The function of these cells is in turn reliant upon their intimate relationship with the adjacent retinal pigment epithelium (RPE). Indeed, if RPE cells become degenerate or are lost, PR degeneration ensues and vice versa. These events form the basis of vision loss in many retinal degenerative diseases and are key features of such conditions as age‐related macular degeneration (AMD), retinitis pigmentosa and other genetically inherited retinal diseases such as Stargardt macular dystrophy. Cumulatively, these conditions now comprise the foremost causes of untreatable visual loss in developed countries. The diverse phenotypes observed reflect the remarkable genetic heterogeneity of retinal disease. Furthermore, different mutations within the same gene can cause different phenotypes. AMD is now known to be a complex genetic disorder with a number of genetic variants (single nucleotide polymorphisms, SNPs) now known to confer susceptibility to vision loss from the condition.

Key Concepts:

  • The retina is a multilayered neural tissue that comprises a variety of highly specialised cells that receive and process visual stimuli.

  • The majority of genetic diseases of the retina affect the photoreceptor cell.

  • Although many diseases affect the whole retina, certain conditions affect predominantly or exclusively the macula of the eye, that region of the retina specialised for central vision.

  • More than 200 genes have been identified that cause monogenic retinal degeneration in humans.

  • Hundreds of mutations have been described that can be inherited as autosomal dominant, recessive, X‐linked, mitochondrial, oligogenic and digenic traits.

  • Monogenic retinal diseases are slowly progressive and in many instances lead to blindness.

  • Age‐related macular degeneration is the most frequent cause of blindness in older individuals. It is a complex disease, one that arises due to the interplay of both multiple genetic and environmental factors.

  • Although major advances are being made in treating these with gene and stem cell therapies, there is no currently approved treatment.

Keywords: retina; genes; mutations; age‐related macular degeneration; retinitis pigmentosa; macular; complex disease; photoreceptor; retinal pigment epithelium

Figure 1.

Retinitis pigmentosa showing bone spicule pigmentary change, optic disc palor and vascular attenuation.

Figure 2.

Stargardt macular dystrophy: Right eye of affected individual with central macular atrophy and yellow flecks in the retina.

Figure 3.

Advanced choroideraemia showing extensive loss of retinal pigmentation due to atrophy of the choroid and retinal pigment epithelium.

Figure 4.

Age‐related macular degeneration. Left eye (macula) showing extensive drusen (yellow deposits) and focal areas of haemorrhaging due to ‘wet’ AMD.

close

References

Aaberg TM and Han DP (1987) Evaluation of phenotypic similarities between Stargardt flavimaculatus and retinal pigment epithelial pattern dystrophies. Transactions of the American Ophthalmological Society 85: 101–119.

Allikmets R (1997) A photoreceptor cell‐specific ATP‐binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nature Genetics 17(1): 122.

Allikmets R (2000) Further evidence for an association of ABCR alleles with age‐related macular degeneration. The International ABCR Screening Consortium. American Journal of Human Genetics 67(2): 487–491.

Allikmets R, Shroyer NF, Singh N et al. (1997) Mutation of the Stargardt disease gene (ABCR) in age‐related macular degeneration. Science 277(5333): 1805–1807.

Anderson DH, Mullins RF, Hageman GS and Johnson LV (2002) A role for local inflammation in the formation of drusen in the aging eye. American Journal of Ophthalmology 134(3): 411–431.

Baird PN, Chu D, Guida E, Vu HT and Guymer R (2004) Association of the M55L and Q192R paraoxonase gene polymorphisms with age‐related macular degeneration. American Journal of Ophthalmology 138(4): 665–666.

Baird PN, Guida E, Chu DT, Vu HT and Guymer RH (2004) The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age‐related macular degeneration. Investigative Ophthalmology & Visual Science 45(5): 1311–1315.

Baird PN, Richardson AJ, Robman LD et al. (2006) Apolipoprotein (APOE) gene is associated with progression of age‐related macular degeneration (AMD). Human Mutation 27(4): 337–342.

Barbazetto I, Burdan A, Bressler NM et al. (2003) Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin: fluorescein angiographic guidelines for evaluation and treatment – TAP and VIP report No. 2. Archives of Ophthalmology 121(9): 1253–1268.

Barral S, Francis PJ, Shultz DW et al. (2006) Expanded genome scan in extended families with age‐related macular degeneration. Investigative Ophthalmology & Visual Science 47(12): 5453–5459.

Bird AC, Bressler NM, Bressler SB et al. (1995) An international classification and grading system for age‐related maculopathy and age‐related macular degeneration. The International ARM Epidemiological Study Group. Survey of Ophthalmology 39(5): 367–374.

Boulton M and Dayhaw‐Barker P (2001) The role of the retinal pigment epithelium: topographical variation and ageing changes. Eye 15(part 3): 384–389.

Chen W, Stambolian D, Edwards AD et al. (2010) Genetic variants near TIMP3 and high‐density lipoprotein‐associated loci influence susceptibility to age‐related macular degeneration. Proceedings of the National Academy of Sciences of the USA 107(16): 7401–7406.

Churchill AJ, Carter JG, Lovell HC et al. (2006) VEGF polymorphisms are associated with neovascular age‐related macular degeneration. Human Molecular Genetics 15(19): 2955–2961.

Cideciyan AV, Hauswirth WW, Aleman TS et al. (2009) Human RPE65 gene therapy for Leber congenital amaurosis: persistence of early visual improvements and safety at 1 year. Human Gene Therapy 20(9): 999–1004.

Clemons TE, Milton RC, Klein R, Seddon JM and Ferris FL 3rd (2005) Risk factors for the incidence of advanced age‐related macular degeneration in the Age‐Related Eye Disease Study (AREDS) AREDS report no. 19. Ophthalmology 112(4): 533–539.

Combadiere C, Feumi C, Raoul W et al. (2007) CX3CR1‐dependent subretinal microglia cell accumulation is associated with cardinal features of age‐related macular degeneration. Journal of Clinical Investigation 117(10): 2920–2928.

Conley YP, Jakobsdottir J, Mah T et al. (2006) CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age‐related maculopathy: AREDS and CHS cohorts and meta‐analyses. Human Molecular Genetics 15(21): 3206–3218.

Conley YP, Thalamuthu A, Jakobsdottir J et al. (2005) Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age‐related maculopathy. Human Molecular Genetics 14(14): 1991–2002.

Cottet S and Schorderet DF (2009) Mechanisms of apoptosis in retinitis pigmentosa. Current Molecular Medicine 9(3): 375–383.

Dewan A, Liu M, Hartman S et al. (2006) HTRA1 promoter polymorphism in wet age‐related macular degeneration. Science 314(5801): 989–992.

Edwards AO, Ritter R 3rd, Abel KJ et al. (2005) Complement factor H polymorphism and age‐related macular degeneration. Science 308(5720): 421–424.

Ennis S, Jomary C, Mullins R et al. (2008) Association between the SERPING1 gene and age‐related macular degeneration: a two‐stage case‐control study. Lancet 372(9652): 1828–1834.

Fagerness JA, Maller JB, Neale BM et al. (2009) Variation near complement factor I is associated with risk of advanced AMD. European Journal of Human Genetics 17(1): 100–104.

Ferrara N, Damico L, Shams L, Lowman H and Kim R (2006) Development of ranibizumab, an anti‐vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age‐related macular degeneration. Retina 26(8): 859–870.

Fisher SA, Abecasis GR, Yashar BM et al. (2005) Meta‐analysis of genome scans of age‐related macular degeneration. Human Molecular Genetics 14(15): 2257–2264.

Fleischhauer J, Njoh WA and Niemeyer G (2005) Syndromic retinitis pigmentosa: ERG and phenotypic changes. Klinische Monatsblätter für Augenheilkunde 222(3): 186–190.

Francis PJ, George S, Schultz DW et al. (2007) The LOC387715 gene, smoking, body mass index, environmental associations with advanced age‐related macular degeneration. Human Heredity 63(3–4): 212–218.

Francis PJ, Schultz DW, Hamon S et al. (2007) Haplotypes in the complement factor H (CFH) gene: associations with drusen and advanced age‐related macular degeneration. PLoS ONE 2(11): e1197.

Francis PJ, Zhang H, Dewan A et al. (2008) Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population. Molecular Vision 14: 1395–1400.

Friedman DS, O'Colmain BJ, Munoz B et al. (2004) Prevalence of age‐related macular degeneration in the United States. Archives of Ophthalmology 122(4): 564–572.

Friedman E (2004) Update of the vascular model of AMD. British Journal of Ophthalmology 88(2): 161–163.

Fritsche LG, Loenhardt T, Janssen A et al. (2008) Age‐related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nature Genetics 40(7): 892–896.

Gold B, Merriam JE, Zernant J et al. (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age‐related macular degeneration. Nature Genetics 38(4): 458–462.

Grover S, Fishman GA and Stone EM (2002) Atypical presentation of pattern dystrophy in two families with peripherin/RDS mutations. Ophthalmology 109(6): 1110–1117.

Guymer R, Luthert P and Bird A (1999) Changes in Bruch's membrane and related structures with age. Progress in Retinal and Eye Research 18(1): 59–90.

Guymer RH and Chong EW (2006) Modifiable risk factors for age‐related macular degeneration. Medical Journal of Australia 184(9): 455–458.

Hageman GS, Anderson DH, Johnson LV et al. (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age‐related macular degeneration. Proceedings of the National Academy of Sciences of the USA 102(20): 7227–7232.

Hageman GS, Hancox LS, Taiber AJ et al. (2006) Extended haplotypes in the complement factor H (CFH) and CFH‐related (CFHR) family of genes protect against age‐related macular degeneration: characterization, ethnic distribution and evolutionary implications. Annals of Medicine 38(8): 592–604.

Hageman GS, Luthert PJ, Victor Chong NH et al. (2001) An integrated hypothesis that considers drusen as biomarkers of immune‐mediated processes at the RPE‐Bruch's membrane interface in aging and age‐related macular degeneration. Progress in Retinal and Eye Research 20(6): 705–732.

Haines JL, Hauser MA, Schmidt S et al. (2005) Complement factor H variant increases the risk of age‐related macular degeneration. Science 308(5720): 419–421.

Haines JL, Schnetz‐Boutaud N, Schmidt S et al. (2006) Functional candidate genes in age‐related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Investigative Ophthalmology & Visual Science 47(1): 329–335.

Hamel CP (2007) Cone rod dystrophies. Orphanet Journal of Rare Diseases 2: 7.

Hartong DT, Berson EL and Dryja TP (2006) Retinitis pigmentosa. Lancet 368(9549): 1795–1809.

Hughes AE, Orr N, Esfandiary H et al. (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age‐related macular degeneration. Nature Genetics 38(10): 1173–1177.

Jakobsdottir J, Conley YP, Weeks DE et al. (2005) Susceptibility genes for age‐related maculopathy on chromosome 10q26. American Journal of Human Genetics 77(3): 389–407.

Johnson LV, Leitner WP, Staples MK and Anderson DH (2001) Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Experimental Eye Research 73(6): 887–896.

Kanda A, Chen W, Othman M et al. (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age‐related macular degeneration. Proceedings of the National Academy of Sciences of the USA 104(41): 16227–16232.

Kenealy SJ, Schmidt S, Agarwal A et al. (2004) Linkage analysis for age‐related macular degeneration supports a gene on chromosome 10q26. Molecular Vision 10: 57–61.

Klaver CC, Kliffen M, van Duijn CM et al. (1998) Genetic association of apolipoprotein E with age‐related macular degeneration. American Journal of Human Genetics 63(1): 200–206.

Klein ML and Francis PJ (2003) Genetics of age‐related macular degeneration. Ophthalmology Clinics of North America 16(4): 567–574.

Klein ML, Mauldin WM and Stoumbos VD (1994) Heredity and age‐related macular degeneration. Observations in monozygotic twins. Archives of Ophthalmology 112(7): 932–937.

Klein R, Deng Y, Klein BE et al. (2007) Cardiovascular disease, its risk factors and treatment, and age‐related macular degeneration: women's health initiative sight exam ancillary study. American Journal of Ophthalmology 143(3): 473–483.

Klein R, Klein BE, Knudtson MD et al. (2006) Prevalence of age‐related macular degeneration in 4 racial/ethnic groups in the multi‐ethnic study of atherosclerosis. Ophthalmology 113(3): 373–380.

Klein RJ, Zeiss C, Chew EY et al. (2005) Complement factor H polymorphism in age‐related macular degeneration. Science 308(5720): 385–389.

Koenekoop RK (2004) An overview of Leber congenital amaurosis: a model to understand human retinal development. Survey of Ophthalmology 49(4): 379–398.

Lim J, Enger C and Fine S (1994) Foveomacular dystrophy. American Journal of Ophthalmology 117(1): 1–5.

Magnusson KP, Duan S, Sigurdsson H et al. (2006) CFH Y402H confers similar risk of soft drusen and both forms of advanced AMD. PLoS Medicine 3(1): e5.

Maguire AM, High KA, Auricchio A et al. (2009) Age‐dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose‐escalation trial. Lancet 374(9701): 1597–1605.

Majewski J, Schultz DW, Weleber RG et al. (2003) Age‐related macular degeneration – a genome scan in extended families. American Journal of Human Genetics 73(3): 540–550.

Maller JB, Fagerness JA, Reynolds RC et al. (2007) Variation in complement factor 3 is associated with risk of age‐related macular degeneration. Nature Genetics 39(10): 1200–1201.

Marmor MF and McNamara JA (1996) Pattern dystrophy of the retinal pigment epithelium and geographic atrophy of the macula. American Journal of Ophthalmology 122(3): 382–392.

McTaggart KE, Tran M, Mah DY et al. (2002) Mutational analysis of patients with the diagnosis of choroideremia. Human Mutation 20(3): 189–196.

Michaelides M, Holder GE, Bradshaw K, Hunt DM and Moore AT (2005) Cone‐rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene. Ophthalmology 112(9): 1592–1598.

Miller DM, Espinosa‐Heidmann DG, Legra J et al. (2004) The association of prior cytomegalovirus infection with neovascular age‐related macular degeneration. American Journal of Ophthalmology 138(3): 323–328.

Neale BM, Fagerness J, Reynolds R et al. (2010) Genome‐wide association study of advanced age‐related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proceedings of the National Academy of Sciences of the USA 107(16): 7395–7400.

Rivera A, Fisher SA, Fritsche LG et al. (2005) Hypothetical LOC387715 is a second major susceptibility gene for age‐related macular degeneration, contributing independently of complement factor H to disease risk. Human Molecular Genetics 14(21): 3227–3236.

Robman L, Mahdi O, McCarty C et al. (2005) Exposure to Chlamydia pneumoniae infection and progression of age‐related macular degeneration. American Journal of Epidemiology 161(11): 1013–1019.

Santangelo SL, Yen CH, Haddad S et al. (2005) A discordant sib‐pair linkage analysis of age‐related macular degeneration. Ophthalmic Genetics 26(2): 61–67.

Schmidt S, Scott WK, Postel EA et al. (2004) Ordered subset linkage analysis supports a susceptibility locus for age‐related macular degeneration on chromosome 16p12. BMC Genetics 5: 18.

Schultz DW, Klein ML, Humpert AJ et al. (2003) Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN‐1 is associated with age‐related macular degeneration in a large family. Human Molecular Genetics 12(24): 3315–3323.

Schultz DW, Weleber RG, Lawrence G et al. (2005) HEMICENTIN‐1 (FIBULIN‐6) and the 1q31 AMD locus in the context of complex disease: review and perspective. Ophthalmic Genetics 26(2): 101–105.

Seabra MC (1996) New insights into the pathogenesis of choroideremia: a tale of two REPs. Ophthalmic Genetics 17(2): 43–46.

Seabra MC, Mules EH and Hume AN (2002) Rab GTPases, intracellular traffic and disease. Trends in Molecular Medicine 8(1): 23–30.

Seddon JM, Ajani UA and Mitchell BD (1997) Familial aggregation of age‐related maculopathy. American Journal of Ophthalmology 123(2): 199–206.

Seddon JM, George S, Rosner B and Klein ML (2006) CFH gene variant, Y402H, and smoking, body mass index, environmental associations with advanced age‐related macular degeneration. Human Heredity 61(3): 157–165.

Sieving PA, Niffenegger JH and Berson EL (1986) Electroretinographic findings in selected pedigrees with choroideremia. American Journal of Ophthalmology 101(3): 361–367.

Souied EH, Rozet JM, Gerber S et al. (1998) Two novel missense mutations in the peripherin/RDS gene in two unrelated French patients with autosomal dominant retinitis pigmentosa. European Journal of Ophthalmology 8(2): 98–101.

Spencer KL, Hauser MA, Olson LM et al. (2007) Protective effect of complement factor B and complement component 2 variants in age‐related macular degeneration. Human Molecular Genetics 16(16): 1986–1992.

Stone EM, Braun TA, Russel SR et al. (2004) Missense variations in the fibulin 5 gene and age‐related macular degeneration. New England Journal of Medicine 351(4): 346–353.

Swaroop A, Branham KE, Chen W and Abecasis G (2007) Genetic susceptibility to age‐related macular degeneration: a paradigm for dissecting complex disease traits. Human Molecular Genetics 16(Spec. No. 2): R174–R182.

Tuo J, Ning B, Bojanowski CM et al. (2006) Synergic effect of polymorphisms in ERCC6 5′ flanking region and complement factor H on age‐related macular degeneration predisposition. Proceedings of the National Academy of Sciences of the USA 103(24): 9256–9261.

Tuo J, Smith BC, Bojanowski CM et al. (2004) The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age‐related macular degeneration. Faseb Journal 18(11): 1297–1299.

Wang G, Spencer KL, Scott WK et al. (2010) Analysis of the indel at the ARMS2 3′UTR in age‐related macular degeneration. Human Genetics 127(5): 595–602.

Watzke RC, Folk JC and Lang RM (1982) Pattern dystrophy of the retinal pigment epithelium. Ophthalmology 89(12): 1400–1406.

Westerfeld C and Mukai S (2008) Stargardt's disease and the ABCR gene. Seminar in Ophthalmology 23(1): 59–65.

Yang Z, Camp NJ, Sun H et al. (2006) A variant of the HTRA1 gene increases susceptibility to age‐related macular degeneration. Science 314(5801): 992–993.

Yang Z, Lin W, Moshfeghi D et al. (2003) A novel mutation in the RDS/peripherin gene causes adult‐onset foveomacular dystrophy. American Journal of Ophthalmology 135: 213–218.

Yang Z, Stratton C, Francis PJ et al. (2008) Toll‐like receptor 3 and geographic atrophy in age‐related macular degeneration. New England Journal of Medicine 359(14): 1456–1463.

Yates JR, Sepp T, Matharu BK et al. (2007) Complement C3 variant and the risk of age‐related macular degeneration. New England Journal of Medicine 357(6): 553–561.

Zareparsi S, Buraczynska M, Branham KE et al. (2005) Toll‐like receptor 4 variant D299G is associated with susceptibility to age‐related macular degeneration. Human Molecular Genetics 14(11): 1449–1455.

Zhang K, Garibaldi DC, Li Y, Green WR and Zack DJ (2002) Butterfly‐shaped pattern dystrophy: a genetic, clinical, and histopathological report. Archives of Ophthalmology 120(4): 485–490.

Further Reading

Daiger SP, Rossiter BJF, Greenberg J, Christoffels A and Hide W (1998) Data services and software for identifying genes and mutations causing retinal degeneration. Investigative Ophthalmology & Visual Science 39: S295. RetNet, http://www.sph.uth.tmc.edu/RetNet/

Genetests http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests

Heckenlively JR and Arden GB (eds) (2006) Principles and Practice of Clinical Electrophysiology of Vision, 2nd edn. Boston: MIT Press.

Klintworth G and Garner A (eds) (2008) Garner and Klintworth's Pathobiology of Ocular Disease, 3rd edn. Informa Healthcare USA.

Ryan SJ (ed.) (2005) Retina, 4th edn. Philadelphia: Mosby and Elsevier.

Taylor D and Hoyt CS (eds) (2004) Pediatric Ophthalmology and Strabismus, 3rd edn. Oxford: Blackwell Science.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Francis, Peter J(Sep 2010) Genetics of Retinal Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0023109]