Macular Degeneration: Dryja TP

Glazer LC, Dryja TP. · Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA. · Ophthalmol Clin North Am. · Pubmed #12064087 No free full text.

Abstract: Stargardt's disease is a form of juvenille macular degeneration. Patients with Stargardt's disease typically present in the first or second decade of life, complaining of decreased visual acuity. Recent research allows for a three-step explanation of the pathophysiology of Stargardt's disease: 1) Defective Rim Protein, a protein encoded by the ABCA4 gene, causes an accumulation of protonated N-retinylidene-PE in the rod outer segments; 2) A2-E, a byproduct of N-retinylidene-PE, then accumulates in the RPE cells and is toxic to them; 3) Photoreceptors eventually die secondary to loss of the RPE support function. With our new knowledge of the etiology of Stargardt's disease, we can devise future studies directed at treating affected patients.

Dryja TP. · Massachusetts Eye and Ear Infirmary, Boston 02114-3096, USA. · Arch Ophthalmol. · Pubmed #9930170 No free full text.

This publication has no abstract.

Kim IK, Ji F, Morrison MA, Adams S, Zhang Q, Lane AM, Capone A, Dryja TP, Ott J, Miller JW, DeAngelis MM. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA. · Mol Vis. · Pubmed #18704199 links to  free full text

Abstract: PURPOSE: To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort. METHODS: We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified. RESULTS: Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified. CONCLUSIONS: We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.

Deangelis MM, Ji F, Adams S, Morrison MA, Harring AJ, Sweeney MO, Capone A, Miller JW, Dryja TP, Ott J, Kim IK. · Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. · Ophthalmology. · Pubmed #18164066 No free full text.

Abstract: OBJECTIVE: To examine if the genes encoding the pleckstrin homology domain-containing protein gene (PLEKHA1), hypothetical LOC387715/ARMS2 gene, and HtrA serine peptidase 1 gene (HTRA1) located on the long arm of chromosome 10 (10q26 region) confer risk for neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for complement factor H gene (CFH) genotype and smoking exposure. DESIGN: Retrospective matched-pair case-control study. PARTICIPANTS: Hospital clinic-based sample of 134 unrelated patients with neovascular AMD who have a sibling with normal maculae (268 subjects). METHODS: Disease status was ascertained by at least 2 investigators by review of fundus photographs and/or fluorescein angiography according to the Age-Related Eye Disease Study grading scale. If necessary, a home retinal examination was performed (n = 6). A combination of direct sequencing and analysis of 8 highly polymorphic microsatellite markers was used to genotype 33 megabases of the 10q26 region on leukocyte DNA. Smoking history was obtained via a standardized questionnaire and measured in pack-years. The family-based association test, haplotype analysis, multiple conditional logistic regression, and linkage analysis were used to determine significant associations. MAIN OUTCOME MEASURE: Neovascular AMD status. RESULTS: Of the 23 variants we identified in the 10q26 region, 6 were significant. Four of the 6 were novel and included 2 genotypes that reduced risk of AMD. Many single-nucleotide polymorphisms (SNPs), including the previously reported variants rs10490924 (hypothetical LOC387715/ARMS2) and rs11200638 (HTRA1), defined 2 significant haplotypes associated with increased risk of neovascular AMD. The coding HTRA1 SNP rs2293870, not part of the significant haplotypes containing rs10490924 and rs11200638, showed as strong an association with increased susceptibility to neovascular AMD. Linkage analysis supported our findings of SNP association (P<10(-15)). No significant interactions were found between any of the SNPs in the 10q26 and smoking or between these SNPs and CFH genotype. CONCLUSIONS: Independent of CFH genotype or smoking history, an individual's risk of AMD could be increased or decreased, depending on their genotype or haplotype in the 10q26 region.

DeAngelis MM, Ji F, Kim IK, Adams S, Capone A, Ott J, Miller JW, Dryja TP. · Department of Ophthalmology, Harvard Medical School, and Massachusetts Eye and Ear Infirmary, Boston, USA. · Arch Ophthalmol. · Pubmed #17210851 links to  free full text

Abstract: OBJECTIVE: To examine if the genes encoding complement factor H (CFH), apolipoprotein E (APOE), and elongation of very-long-chain fatty acids-like 4 (ELOVL4) confer risk of neovascular age-related macular degeneration (AMD) in an independent or interactive manner when controlling for smoking exposure. METHODS: We studied 103 unrelated patients with neovascular AMD who each had at least 1 sibling with normal maculae. Smoking histories were obtained. Genotyping was performed by analyzing amplified genomic fragments from CFH, APOE, and ELOVL4 by direct sequencing or by restriction endonuclease digests. Conditional logistic regression analysis was used to build a multifactor model. RESULTS: For CFH, only the CC genotype carried a statistically significant elevation of disease risk (odds ratio, 49.37; 95% confidence interval, 6.20-393.22; P<.001). No significant association was observed between neovascular AMD and APOE or ELOVL4. No significant interactions were found between smoking and having the CFH or APOE genotype nor were significant interactions found between the CFH, ELOVL4, and APOE genotypes. CONCLUSIONS: Smoking and having the CFH CC genotype independently increase risk of neovascular AMD. APOE and ELOVL4 genotypes do not seem to modify risk. CLINICAL RELEVANCE: Smoking 10 pack-years or more and having the CFH CC genotype increase one's risk of neovascular AMD 144-fold compared with smoking less than 10 pack-years and having the CT or TT genotype.

Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. · Ocular Molecular Genetics Institute and the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. · Hum Mutat. · Pubmed #15712225 No free full text.

Abstract: Unrelated patients with achromatopsia, macular degeneration with onset under age 50 years, cone degeneration or dysfunction, cone-rod degeneration, or macular malfunction were screened for mutations in the three genes known to be associated with achromatopsia: the GNAT2 gene encoding the alpha subunit of cone transducin and the CNGA3 and CNGB3 genes encoding the alpha and beta subunits of the cone cGMP-gated cation channel. We found no examples of patients with GNAT2 mutations. Out of 36 achromats, 12 (33%) had mutations in CNGA3 (13 different mutations including five novel mutations) and 12 (33%) had mutations in CNGB3 (six different mutations including four novel mutations). All achromats with CNG mutations had residual, presumably cone function as determined by computer-averaged 30-Hz electroretinograms (ERGs). There was considerable variability in acuity and color vision, with most patients having acuities of 20/200-20/400 and complete absence of color perception, and others having acuities of 20/25-20/40 and some color vision. Two pseudodominant achromatopsia cases were uncovered, both with CNGA3 mutations, including one family in which some compound heterozygotes with achromatopsia mutations were clinically unaffected. We found two novel CNGB3 changes in three patients with juvenile macular degeneration, a phenotype not previously associated with mutations in the cone channel subunits. These patients had subnormal acuity (20/30-20/60), normal to subnormal color vision, and normal to subnormal full-field cone ERG amplitudes. Our results indicate that some patients with channel protein mutations retain residual foveal cone function. Based on our findings, CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration.

DeAngelis MM, Lane AM, Shah CP, Ott J, Dryja TP, Miller JW. · Ocular Molecular Genetics Institute, Harvard Medical School, Boston, MA 02114, USA. · Arch Ophthalmol. · Pubmed #15078676 No free full text.

Abstract: OBJECTIVE: To search for factors that contribute to the development of neovascular age-related macular degeneration (AMD). METHODS: In a matched-pair case-control study, we studied sib pairs in which the index sibling had neovascular AMD in at least 1 eye and the unaffected sibling had normal maculae (or at most only a few small drusen) and was past the age at which the index case was diagnosed. Factors studied included sex, iris color, education, alcohol consumption, body mass index, vitamin use, smoking history, hypercholesterolemia, aspirin use, hypertension, other cardiovascular disease, any autoimmune disease, and non-insulin-dependent diabetes mellitus. Conditional logistic regression was performed to identify predictors of neovascular AMD. RESULTS: On the basis of 73 sib pairs, multivariate regression analysis revealed a statistically significant 2% increase in risk of neovascular AMD with each pack-year of smoking (odds ratio, 1.02; 95% confidence interval, 1.01-1.04; P =.007). Suggestive but nonsignificant associations were also observed for mean lifetime alcohol consumption, adult lifetime body mass index, and hypertension in multivariate regression analyses. CONCLUSION: Using extremely discordant sib pairs to study risk factors for AMD, a novel approach in epidemiological design, we found evidence that smoking is a risk factor for neovascular AMD.

Briggs CE, Rucinski D, Rosenfeld PJ, Hirose T, Berson EL, Dryja TP. · Ocular Molecular Genetics Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA. · Invest Ophthalmol Vis Sci. · Pubmed #11527935 links to  free full text

Abstract: PURPOSE: To determine the spectrum of ABCR mutations associated with Stargardt macular degeneration and cone-rod degeneration (CRD). METHODS: One hundred eighteen unrelated patients with recessive Stargardt macular degeneration and eight with recessive CRD were screened for mutations in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Variants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more likely pathogenic sequence changes were identified. RESULTS: The authors found 77 sequence changes likely to be pathogenic: 21 null mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with Stargardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segregation analyses in the families of 19 of these patients were informative and revealed that the index cases and all available affected siblings were compound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one likely pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes. CONCLUSIONS: This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR to approximately 250.

To K, Adamian M, Dryja TP, Berson EL. · Berman-Gund Laboratory for the Study of Retinal Degenerations and the Ocular Molecular Genetics Institute, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA. · Am J Ophthalmol. · Pubmed #11124299 No free full text.

Abstract: PURPOSE: To compare histologic findings in an autopsy eye of an 84-year-old man with advanced retinitis pigmentosa and rhodopsin, Glu181Lys, with two cases of autosomal dominant retinitis pigmentosa (one with rhodopsin, Pro23His, and one with rhodopsin, Cys110Arg) and with a normal control, all of comparable age. METHODS: All eyes were prepared for light and electron microscopy within 6 hours after death. RESULTS: Extensive photoreceptor degeneration was revealed in the eyes with retinitis pigmentosa. Some macular cones showed membranous swirls only in the eye with rhodopsin, Glu181Lys. CONCLUSION: The retinal degeneration caused by rhodopsin, Glu181Lys, can feature membranous swirls in the inner segments of cones in the macula. These swirls have not been reported in other cases of dominant retinitis pigmentosa studied so far, and their pathogenesis remains to be defined.