Genetic factors of age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of blindness in the United States and developed countries. Although the etiology and pathogenesis of AMD remain unknown, a complex interaction of genetic and environmental factors is thought to exist. The incidence and progression of all of the features of AMD are known to increase significantly with age. The tendency for familial aggregation and the findings of gene variation association studies implicate a significant genetic component in the development of AMD. This review summarizes in detail the AMD-related genes identified by studies on genetically engineered and spontaneously gene-mutated (naturally mutated) animals, AMD chromosomal loci identified by linkage studies, AMD-related genes identified through studies of monogenic degenerative retinal diseases, and AMD-related gene variation identified by association studies.

[1]  A. Hutchinson,et al.  The ABCR gene in recessive and dominant Stargardt diseases: a genetic pathway in macular degeneration. , 1999, Genomics.

[2]  W. Willett,et al.  Dietary fat and risk for advanced age-related macular degeneration. , 2001, Archives of ophthalmology.

[3]  Frank Rn.  'Oxidative protector' enzymes in the macular retinal pigment epithelium of aging eyes and eyes with age-related macular degeneration , 1998 .

[4]  P. Demant,et al.  A new H-2-linked mutation, rds, causing retinal degeneration in the mouse. , 1978, Tissue Antigens.

[5]  J. Witte,et al.  Genetic dissection of complex traits. , 1994, Nature genetics.

[6]  E. Shooter,et al.  A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. , 1989, The Journal of clinical investigation.

[7]  A Hofman,et al.  Risk factors for age-related macular degeneration: Pooled findings from three continents. , 2001, Ophthalmology.

[8]  V. Sheffield,et al.  Allelic variation in the VMD2 gene in best disease and age-related macular degeneration. , 2000, Investigative ophthalmology & visual science.

[9]  A. Cideciyan,et al.  Dominant late-onset retinal degeneration with regional variation of sub-retinal pigment epithelium deposits, retinal function, and photoreceptor degeneration. , 2000, Ophthalmology.

[10]  T. Matise,et al.  Age-related Macular Degeneration: A Genome-wide Scan in Extended Families , 2003 .

[11]  A Hofman,et al.  Genetic risk of age-related maculopathy. Population-based familial aggregation study. , 1998, Archives of ophthalmology.

[12]  M. Müftüoğlu,et al.  The Cockayne Syndrome Group B Gene Product Is Involved in General Genome Base Excision Repair of 8-Hydroxyguanine in DNA* , 2001, The Journal of Biological Chemistry.

[13]  M. Tamai,et al.  Analysis of the metallothionein gene in age-related macular degeneration. , 2000, Japanese journal of ophthalmology.

[14]  M. Metzker,et al.  Identification of the gene responsible for Best macular dystrophy , 1998, Nature Genetics.

[15]  J L Haines,et al.  Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. , 2000, Molecular vision.

[16]  M. T. Davisson,et al.  Retinal degeneration mutants in the mouse , 2002, Vision Research.

[17]  C. Curcio,et al.  Ultrastructural changes in Bruch's membrane of apolipoprotein E-deficient mice. , 2000, Investigative ophthalmology & visual science.

[18]  R. Pruett,et al.  Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy , 1994, Nature Genetics.

[19]  V. Bohr,et al.  Functional crosstalk between hOgg1 and the helicase domain of Cockayne syndrome group B protein. , 2002, DNA repair.

[20]  D. Friedman,et al.  Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey. , 1999, Ophthalmology.

[21]  J. Naggert,et al.  Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6. , 2002, Human molecular genetics.

[22]  Masaru Miyagi,et al.  Drusen proteome analysis: An approach to the etiology of age-related macular degeneration , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Haines,et al.  Exclusion of TIMP3 as a candidate locus in age-related macular degeneration. , 1997, Investigative ophthalmology & visual science.

[24]  E. Stefánsson,et al.  Age related macular degeneration in monozygotic twins and their spouses in Iceland. , 1999, Acta ophthalmologica Scandinavica.

[25]  P. D. de Jong,et al.  Morphologic changes in age‐related maculopathy , 1997, Microscopy research and technique.

[26]  K. Csaky,et al.  Age as an independent risk factor for severity of experimental choroidal neovascularization. , 2002, Investigative ophthalmology & visual science.

[27]  V. Bohr,et al.  The Cockayne Syndrome Group B Gene Product Is Involved in Cellular Repair of 8-Hydroxyadenine in DNA* , 2002, The Journal of Biological Chemistry.

[28]  T. Yoshikawa,et al.  Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration. , 2001, American journal of ophthalmology.

[29]  S. Russell,et al.  Drusen associated with aging and age‐related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[30]  J. Haines,et al.  Linkage analysis for age-related macular degeneration supports a gene on chromosome 10q26. , 2004, Molecular vision.

[31]  C. Grimm,et al.  The genetic modifier Rpe65Leu(450): effect on light damage susceptibility in c-Fos-deficient mice. , 2003, Investigative ophthalmology & visual science.

[32]  R. Lewis,et al.  Late-onset autosomal dominant macular dystrophy with choroidal neovascularization and nonexudative maculopathy associated with mutation in the RDS gene. , 2003, Investigative ophthalmology & visual science.

[33]  D. Easty,et al.  Sorsby's fundus dystrophy mutant tissue inhibitors of metalloproteinase‐3 induce apoptosis of retinal pigment epithelial and MCF‐7 cells , 2002, FEBS letters.

[34]  M. Akimoto,et al.  Lack of association of mutations of the bestrophin gene with age-related macular degeneration in non-familial Japanese patients , 2001, Graefe's Archive for Clinical and Experimental Ophthalmology.

[35]  F. Ferris,et al.  Who should receive oral supplement treatment for age‐related macular degeneration? , 2003, Current opinion in ophthalmology.

[36]  K. Gregory-Evans.  What is Sorsby's fundus dystrophy? , 2000, The British journal of ophthalmology.

[37]  H. Stöhr,et al.  A second independent Tyr168Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy. , 1996, Journal of medical genetics.

[38]  A. Cideciyan,et al.  Phenotypic marker for early disease detection in dominant late-onset retinal degeneration. , 2001, Investigative ophthalmology & visual science.

[39]  E. Zrenner,et al.  Evaluation of the gene encoding the tissue inhibitor of metalloproteinases-3 in various maculopathies. , 1997, Investigative ophthalmology & visual science.

[40]  I. Constable,et al.  Progressive age-related changes similar to age-related macular degeneration in a transgenic mouse model. , 2002, The American journal of pathology.

[41]  Jennifer I. Lim.  Photodynamic therapy for choroidal neovascular disease: photosensitizers and clinical trials. , 2002, Ophthalmology clinics of North America.

[42]  S. Goldstein,et al.  An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis , 1995, Molecular and cellular biology.

[43]  A. Bird,et al.  Clinical features of codon 172 RDS macular dystrophy: similar phenotype in 12 families. , 1999, Archives of ophthalmology.

[44]  V. Sheffield,et al.  A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy , 1999, Nature Genetics.

[45]  M. Margaglione,et al.  Apolipoprotein E Polymorphisms in Age-Related Macular Degeneration in an Italian Population , 2001, Ophthalmic Research.

[46]  R. Guymer.  The genetics of age‐related macular degeneration , 2001, Clinical & experimental optometry.

[47]  A. Bird,et al.  TIMP-3, collagen, and elastin immunohistochemistry and histopathology of Sorsby's fundus dystrophy. , 2000, Investigative ophthalmology & visual science.

[48]  J. Sutcliffe,et al.  The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein , 1991, Neuron.

[49]  V. Sheffield,et al.  Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. , 2002, Archives of ophthalmology.

[50]  P. D. de Jong,et al.  The APO*E3-Leiden mouse as an animal model for basal laminar deposit , 2000, The British journal of ophthalmology.

[51]  T. Roderick,et al.  New mouse primary retinal degeneration (rd-3). , 1993, Genomics.

[52]  A. Munnich,et al.  The γ e4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration , 1998 .

[53]  R. Sidman,et al.  RETINAL DEGENERATION IN THE MOUSE: LOCATION OF THE RD LOCUS IN LINKAGE GROUP XVII. , 1965, The Journal of heredity.

[54]  Robert F. Mullins,et al.  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 , 2001, Progress in Retinal and Eye Research.

[55]  Jian-xing Ma,et al.  Correlation of regenerable opsin with rod ERG signal in Rpe65-/- mice during development and aging. , 2002, Investigative ophthalmology & visual science.

[56]  T. Roderick,et al.  Screening for mouse retinal degenerations , 1989, Documenta Ophthalmologica.

[57]  D. Weeks,et al.  Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. , 2001, American journal of ophthalmology.

[58]  A. Bird,et al.  Sorsby's fundus dystrophy. A light and electron microscopic study. , 1989, Ophthalmology.

[59]  M. Nissen,et al.  Age-Related Macular Degeneration , 2002, Drugs & aging.

[60]  A. Hofman,et al.  Genetic association of apolipoprotein E with age-related macular degeneration. , 1998, American journal of human genetics.

[61]  E. Hedgecock,et al.  Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions. , 2001, Development.

[62]  N. Copeland,et al.  The gene for the retinal pigment epithelium-specific protein RPE65 is localized to human 1p31 and mouse 3. , 1994, Genomics.

[63]  P. Durrington,et al.  Paraoxonase prevents accumulation of lipoperoxides in low‐density lipoprotein , 1991, FEBS letters.

[64]  L. Molday,et al.  The cGMP-gated Channel and Related Glutamic Acid-rich Proteins Interact with Peripherin-2 at the Rim Region of Rod Photoreceptor Disc Membranes* , 2001, The Journal of Biological Chemistry.

[65]  P. Brennan,et al.  Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? , 2002, Carcinogenesis.

[66]  B. Olsen,et al.  Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. , 1997, Investigative ophthalmology & visual science.

[67]  U. Kellner,et al.  Ten novel mutations in VMD2 associated with Best macular dystrophy (BMD) , 2003, Human mutation.

[68]  R. Frank,et al.  Antioxidant enzymes in the macular retinal pigment epithelium of eyes with neovascular age-related macular degeneration. , 1999, American journal of ophthalmology.

[69]  P. Sieving,et al.  Evaluation of the ELOVL4 gene in patients with age-related macular degeneration , 2001, Ophthalmic genetics.

[70]  H. Ohguro,et al.  Autosomal dominant central areolar choroidal dystrophy and a novel Arg195Leu mutation in the peripherin/RDS gene. , 2003, Archives of ophthalmology.

[71]  S M Meyers,et al.  A twin study of age-related macular degeneration. , 1995, American journal of ophthalmology.

[72]  S. Santangelo,et al.  A genomewide scan for age-related macular degeneration provides evidence for linkage to several chromosomal regions. , 2003, American journal of human genetics.

[73]  A. Munnich,et al.  ABCR gene analysis in familial exudative age-related macular degeneration. , 2000, Investigative ophthalmology & visual science.

[74]  V. Sheffield,et al.  A 2 base pair deletion in the RDS gene associated with butterfly-shaped pigment dystrophy of the fovea. , 1993, Human molecular genetics.

[75]  A. Harris,et al.  An update on photodynamic therapy in age-related macular degeneration , 2002, Expert opinion on pharmacotherapy.

[76]  T. Matise,et al.  Age-related macular degeneration--a genome scan in extended families. , 2003, American journal of human genetics.

[77]  T. Dawber,et al.  Prevalence of senile cataract, diabetic retinopathy, senile macular degeneration, and open-angle glaucoma in the Framingham eye study. , 1978, American journal of ophthalmology.

[78]  Simon M Laws,et al.  Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription , 2003, Journal of neurochemistry.

[79]  V. Sheffield,et al.  Allelic variation in ABCR associated with Stargardt disease but not age-related macular degeneration , 1998, Nature Genetics.

[80]  V. Sheffield,et al.  Full characterization of the maculopathy associated with an Arg-172-Trp mutation in the RDS/peripherin gene. , 1996, Ophthalmic genetics.

[81]  A. Marquardt,et al.  VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies , 2000, Human mutation.

[82]  N. Shen,et al.  Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis , 1999, Nature Genetics.

[83]  W. Huttner,et al.  A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. , 2000, Human molecular genetics.

[84]  J. Lupski,et al.  Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. , 2001, Human molecular genetics.

[85]  P. Froguel,et al.  Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. , 1997, The Journal of clinical investigation.

[86]  O. Sandgren,et al.  A Swedish family with a mutation in the peripherin/RDS gene (Arg-172-Trp) associated with a progressive retinal degeneration. , 1998, Ophthalmic genetics.

[87]  V. Bohr,et al.  Primary fibroblasts of Cockayne syndrome patients are defective in cellular repair of 8‐hydroxyguanine and 8‐hydroxyadenine resulting from oxidative stress , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[88]  B. Lorenz,et al.  A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. , 2000, American journal of human genetics.

[89]  R. Klein,et al.  A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. , 2003, American journal of human genetics.

[90]  S. Sonoda,et al.  Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration. , 2000, American journal of ophthalmology.

[91]  J. O’Connell,et al.  A new locus for dominant drusen and macular degeneration maps to chromosome 6q14. , 2000, American journal of ophthalmology.

[92]  A. Deutman,et al.  A peculiar autosomal dominant macular dystrophy caused by an asparagine deletion at codon 169 in the peripherin/RDS gene. , 2003, Archives of ophthalmology.

[93]  H. Stöhr,et al.  High-resolution meiotic and physical mapping of the best vitelliform macular dystrophy (VMD2) locus to pericentromeric chromosome 11. , 1994, American journal of human genetics.

[94]  S. Borrego,et al.  Evaluation of the ELOVL4 gene in families with retinitis pigmentosa linked to theRP25 locus , 2001, Journal of medical genetics.

[95]  A. Nesburn,et al.  Alu DNA polymorphism in ACE gene is protective for age-related macular degeneration. , 2002, Biochemical and biophysical research communications.

[96]  R. Williams,et al.  Decreased retinal ganglion cell number and misdirected axon growth associated with fissure defects in Bst/+ mutant mice. , 1997, Investigative Ophthalmology and Visual Science.

[97]  A. Hofman,et al.  Familial aggregation of age-related maculopathy. , 1997, American journal of ophthalmology.

[98]  Paul S. Bernstein,et al.  Mutation of the Stargardt Disease Gene (ABCR) in Age-Related Macular Degeneration , 1997 .

[99]  J. Ott,et al.  Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. , 2003, Archives of ophthalmology.

[100]  I. Constable,et al.  Distribution of cathepsin D in human eyes with or without age-related maculopathy. , 1999, Experimental eye research.

[101]  H. Schrewe,et al.  Sorsby fundus dystrophy mutation Timp3S156C affects the morphological and biochemical phenotype but not metalloproteinase homeostasis , 2003, Journal of cellular physiology.

[102]  A. Kong,et al.  The genealogic approach to human genetics of disease. , 2001, Cancer journal.

[103]  A. Munnich,et al.  A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1 , 1993, Nature Genetics.

[104]  A. Hutchinson,et al.  Evaluation of the G protein coupled receptor-75 (GPR75) in age related macular degeneration , 2001, The British journal of ophthalmology.

[105]  M. Kamei,et al.  TIMP-3 in Bruch's membrane: changes during aging and in age-related macular degeneration. , 1999, Investigative ophthalmology & visual science.

[106]  R. Allikmets,et al.  Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. , 2000, American journal of human genetics.

[107]  T. Matise,et al.  Age-related macular degeneration. Clinical features in a large family and linkage to chromosome 1q. , 1998, Archives of ophthalmology.

[108]  A. Bird,et al.  Founder effect, seen in the British population, of the 172 peripherin/RDS mutation-and further refinement of genetic positioning of the peripherin/RDS gene. , 1998, American journal of human genetics.

[109]  Yan Shen,et al.  DSPP mutation in dentinogenesis imperfecta Shields type II , 2001, Nature Genetics.

[110]  Alan Bird,et al.  Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy , 1993, Nature Genetics.

[111]  A. Deutman,et al.  Genetic heterogeneity of butterfly-shaped pigment dystrophy of the fovea. , 2003, Molecular vision.

[112]  C. Grimm,et al.  A mouse model for Sorsby fundus dystrophy. , 2002, Investigative ophthalmology & visual science.

[113]  B. Lorenz,et al.  Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration , 2000, European Journal of Human Genetics.

[114]  B. Godley,et al.  Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. , 2003, Experimental eye research.

[115]  M. Metzker,et al.  Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies , 1999, Human Genetics.

[116]  V. Sheffield,et al.  Butterfly–shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene , 1993, Nature Genetics.

[117]  M. Tamai,et al.  Macular dystrophy associated with monogenic Arg172Trp mutation of the peripherin/RDS gene in a Japanese family. , 1995 .

[118]  A. Cideciyan,et al.  Mutation in a short-chain collagen gene, CTRP5, results in extracellular deposit formation in late-onset retinal degeneration: a genetic model for age-related macular degeneration. , 2003, Human molecular genetics.

[119]  P. Gouras,et al.  Retinal degeneration and RPE transplantation in Rpe65(-/-) mice. , 2002, Investigative ophthalmology & visual science.

[120]  C. Delcourt,et al.  Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study , 2001, Ophthalmic epidemiology.

[121]  T Michael Redmond,et al.  Effect of Rpe65 knockout on accumulation of lipofuscin fluorophores in the retinal pigment epithelium. , 2001, Investigative ophthalmology & visual science.

[122]  S. Marklund,et al.  Superoxide dismutase isoenzymes in the human eye. , 1998, Investigative ophthalmology & visual science.

[123]  J. Lupski,et al.  A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Starqardt macular dystrophy , 1997, Nature Genetics.

[124]  Sonia H Yoo,et al.  Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. , 2003, Survey of ophthalmology.

[125]  E. Chew,et al.  The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age‐related macular degeneration , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[126]  M. Boulton,et al.  The role of oxidative stress in the pathogenesis of age-related macular degeneration. , 2000, Survey of ophthalmology.

[127]  P. Campochiaro,et al.  Role of hypoxia and extracellular matrix‐integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells , 1999 .

[128]  P. Allen,et al.  Analysis of the Arg345Trp disease‐associated allele of the EFEMP1 gene in individuals with early onset drusen or familial age‐related macular degeneration , 2002, Clinical & experimental ophthalmology.

[129]  G. Travis,et al.  The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR) , 1997, FEBS letters.

[130]  G. Silvestri.  Age-related macular degeneration: genetics and implications for detection and treatment. , 1997, Molecular medicine today.

[131]  Ian J Constable,et al.  Lipofuscin of the retinal pigment epithelium: A review , 1995, Eye.

[132]  M. Klein,et al.  Sorsby fundus dystrophy. A family with the Ser181Cys mutation of the tissue inhibitor of metalloproteinases 3. , 1996, Archives of ophthalmology.

[133]  Limited macular translocation for the management of subfoveal choroidal neovascularization after photodynamic therapy. , 2003, American journal of ophthalmology.

[134]  P. Demant,et al.  The map position of the rds gene on the 17th chromosome of the mouse. , 2008, Tissue antigens.

[135]  A. Milam,et al.  Histopathology and immunocytochemistry of the neurosensory retina in fundus flavimaculatus. , 1994, Ophthalmology.

[136]  Eiji Sakurai,et al.  An animal model of age-related macular degeneration in senescent Ccl-2- or Ccr-2-deficient mice , 2003, Nature Medicine.

[137]  T. Roderick,et al.  Retinal degeneration 6 (rd6): a new mouse model for human retinitis punctata albescens. , 2000, Investigative ophthalmology & visual science.

[138]  E. Lander,et al.  Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results , 1995, Nature Genetics.

[139]  S. Yoshida,et al.  Familial cases with age-related macular degeneration. , 2000, Japanese journal of ophthalmology.

[140]  R. D'Agostino,et al.  Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. , 2003, The Journal of clinical investigation.

[141]  M. Klein,et al.  Analysis of the ARMD1 locus: evidence that a mutation in HEMICENTIN-1 is associated with age-related macular degeneration in a large family. , 2003, Human molecular genetics.

[142]  S. Fine,et al.  A histopathologic study of Best's macular dystrophy. , 1982, Archives of ophthalmology.

[143]  A. Milam,et al.  Amyloid-beta is found in drusen from some age-related macular degeneration retinas, but not in drusen from normal retinas. , 2003, Molecular vision.

[144]  L. Hyman,et al.  Risk factors for age-related macular degeneration: an update , 2002, Current opinion in ophthalmology.

[145]  T. Roderick,et al.  Retinal degeneration in motor neuron degeneration: a mouse model of ceroid lipofuscinosis. , 1994, Investigative ophthalmology & visual science.

[146]  J. Gilbert,et al.  Analysis of the Stargardt disease gene (ABCR) in age-related macular degeneration. , 1999, Ophthalmology.

[147]  E. Zrenner,et al.  The Role of the Peripherin/RDS Gene in Retinal Dystrophies , 1998, Cells Tissues Organs.

[148]  A. Kornzweig.  The eye in old age. V. Diseases of the macula: a clinicopathologic study. , 1965, American journal of ophthalmology.

[149]  A. Hofman,et al.  Is age-related maculopathy associated with Alzheimer's Disease? The Rotterdam Study. , 1999, American journal of epidemiology.

[150]  Dissection of genomewide-scan data in extended families reveals a major locus and oligogenic susceptibility for age-related macular degeneration. , 2004, American journal of human genetics.

[151]  C. Hamel,et al.  Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. , 1993, The Journal of biological chemistry.

[152]  S. Gauthier,et al.  Cholesterol synthesis and lipoprotein reuptake during synaptic remodelling in hippocampus in adult rats , 1993, Neuroscience.

[153]  H. Stöhr,et al.  Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease). , 1998, Human molecular genetics.

[154]  I. Constable,et al.  Correlation between autofluorescent debris accumulation and the presence of partially processed forms of cathepsin D in cultured retinal pigment epithelial cells challenged with rod outer segments. , 1996, Experimental eye research.

[155]  Jennifer I. Lim,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. , 2001, Archives of ophthalmology.

[156]  D M Hunt,et al.  The genetics of inherited macular dystrophies , 2003, Journal of medical genetics.

[157]  D. Birch,et al.  Delayed dark-adaptation and lipofuscin accumulation in abcr+/- mice: implications for involvement of ABCR in age-related macular degeneration. , 2001, Investigative ophthalmology & visual science.

[158]  D. Birch,et al.  Insights into the Function of Rim Protein in Photoreceptors and Etiology of Stargardt's Disease from the Phenotype in abcr Knockout Mice , 1999, Cell.

[159]  J. Gilbert,et al.  Detailed analysis of allelic variation in the ABCA4 gene in age-related maculopathy. , 2003, Investigative ophthalmology & visual science.

[160]  F. Oesch,et al.  Microsomal epoxide hydrolase. , 1981, Methods in enzymology.

[161]  J. Grunwald,et al.  Changes in Choriocapillaris and Retinal Pigment Epithelium ( RPE ) in Age-Related Macular Degeneration , 1999 .

[162]  J. Seddon,et al.  Do age-related macular degeneration and cardiovascular disease share common antecedents? , 1999, Ophthalmic epidemiology.

[163]  G. Chader,et al.  Animal models in research on retinal degenerations: past progress and future hope , 2002, Vision Research.

[164]  A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study. , 2003, American journal of human genetics.

[165]  E. Zrenner,et al.  Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene. , 1995, The British journal of ophthalmology.

[166]  Linkage of autosomal dominant radial drusen (malattia leventinese) to chromosome 2p16-21. , 1996 .

[167]  V. Sheffield,et al.  An analysis of allelic variation in the ABCA4 gene. , 2001, Investigative ophthalmology & visual science.

[168]  Y. Arsenijévic,et al.  Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[169]  D. Hunt,et al.  Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy , 2000, Nature Genetics.

[170]  M. Mattei,et al.  Human fibulin-1D: molecular cloning, expression and similarity with S1-5 protein, a new member of the fibulin gene family. , 1997, Matrix biology : journal of the International Society for Matrix Biology.

[171]  M. Davisson,et al.  The bst locus on mouse chromosome 16 is associated with age-related subretinal neovascularization. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[172]  D F Schorderet,et al.  Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration. , 2001, Archives of ophthalmology.

[173]  C. Inglehearn,et al.  Mutations and polymorphisms in the human peripherin‐RDS gene and their involvement in inherited retinal degeneration , 1996, Human mutation.

[174]  M. Metzker,et al.  A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy , 2001, Nature Genetics.

[175]  A. Cideciyan,et al.  Sub-retinal pigment epithelial deposits in a dominant late-onset retinal degeneration. , 1996, Investigative ophthalmology & visual science.

[176]  Joan W. Miller,et al.  Mechanism of age related macular degeneration , 2002 .