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Aims: To evaluate the complement factor H (CFH) p.402Y>H polymorphism as a risk factor in age related macular degeneration (AMD) in an Italian population. Methods: 104 unrelated Italian AMD patients and 131 unrelated controls were screened for the CFH polymorphism p.402Y>H (c.1277 T>C), which has been associated with AMD. Retinography was obtained for patients and controls; the AMD diagnosis was confirmed by fluorescein angiograms. The c.1277 T>C polymorphism was genotyped with the TaqMan real time polymerase chain reaction single nucleotide polymorphism assay. Results: The frequency of c.1277C allele was higher in AMD patients than in controls (57.2% v 39.3%; p<0.001). The odds ratio (OR; logistic regression analysis) for AMD was 3.9 (95% confidence interval (CI): 1.9 to 8.2) for CC homozygotes. The CC genotype conferred a higher risk for sporadic (OR 4.6; CI: 2.0 to 10.5) than for familial AMD (OR 2.9; CI: 1.0 to 8.4). Genotypes were not related to either age at AMD diagnosis or to AMD phenotype. However, geographic atrophy and choroidal neovascularisation were more frequent in sporadic than in familial AMD (p = 0.027). Overall, the percentage of population attributable risk for the CC genotype was 28% (95% CI:18% to 33%). Conclusion: The association between the p.402Y>H (c.1277T>C) polymorphism and AMD applies to the Italian population and the CC genotype is more frequent in sporadic than in familial AMD cases.

Aims: To describe the clinical phenotype of X linked juvenile retinoschisis in eight Italian families with six different mutations in the XLRS1 gene. Methods: Complete ophthalmic examinations, electroretinography and A and B-scan standardised echography were performed in 18 affected males. The coding sequences of the XLRS1 gene were amplified by polymerase chain reaction and directly sequenced on an automated sequencer. Results: Six different XLRS1 mutations were identified; two of these mutations Ile81Asn and the Trp122Cys, have not been previously described. The affected males showed an electronegative response to the standard white scotopic stimulus and a prolonged implicit time of the 30 Hz flicker. In the families with Trp112Cys and Trp122Cys mutations we observed a more severe retinoschisis (RS) clinical picture compared with the other genotypes. Conclusion: The severe RS phenotypes associated with Trp112Cys and to Trp122Cys mutations suggest that these mutations determine a notable alteration in the function of the retinoschisin protein.

Retinitis pigmentosa is the most common form of retinal degeneration and is heterogeneous both clinically and genetically. The autosomal dominant forms (ADRP) can be caused by mutations in 12 different genes. This report describes the first simultaneous mutation analysis of all the known ADRP genes in the same population, represented by 43 Italian families. This analysis allowed the identification of causative mutations in 12 of the families (28% of the total). Seven different mutations were identified, two of which are novel (458delC and 6901C→T (P2301S), in the CRX and PRPF8 genes, respectively). Several novel polymorphisms leading to amino acid changes in the FSCN2, NRL, IMPDH1, and RP1 genes were also identified. Analysis of gene prevalences indicates that the relative involvement of the RHO and the RDS genes in the pathogenesis of ADRP is less in Italy than in US and UK populations. As causative mutations were not found in over 70% of the families analysed, this study suggests the presence of further novel genes or sequence elements involved in the pathogenesis of ADRP.

Objective: Apolipoprotein E (apoE) is an important regulator of cholesterol and lipid transport during compensatory synaptogenesis. Our purpose was to investigate the role of apoE gene polymorphisms in Italian patients with age-related macular degeneration (AMD). Methods: We used the polymerase chain reaction technique to analyze apoE genotypes in 87 patients with AMD, in 47 age-matched controls and in 1,287 individuals from a general reference population. Results: The frequency of allele Ε4 carriers was significantly higher (p = 0.002) in the general population than in AMD patients, while the frequency of allele Ε2 was higher in the patients (p = 0.069) with an increased risk for AMD in the patients versus the population-based controls (odds ratio = 1.7; 95% confidence interval: 1.0–2.9). Allele Ε4 was associated with a decreased risk for AMD in the patients versus the population-based controls (odds ratio = 0.3; 95% confidence interval: 0.1–0.8). Clinical Relevance: These data suggest that apoE testing may represent a tool for the evaluation of the relative risk of AMD. Consequently, a preventive strategy can be initiated at an early stage of the disorder. Conclusion: The apoE gene polymorphism showed a significant association with the risk of AMD. The lower frequency of the Ε4 allele in AMD patients suggests that the apoE gene could play a protective role in the pathogenesis of the disease. In contrast, the Ε2 allele was found associated with a slightly increased risk of AMD, although we did not find a statistically significant effect.

Background: Mutations in the retina-specific ABC transporter (ABCA4) gene have been associated with several forms of macular degenerations. Because the high complexity of the molecular genotype makes scanning of the ABCA4 gene cumbersome, we describe here the first use of denaturing HPLC (DHPLC) to screen for ABCA4 mutations. Methods: Temperature conditions were designed for all 50 exons based on effective separation of 83 samples carrying 86 sequence variations and 19 mutagenized controls. For validation, samples from 23 previously characterized Stargardt patients were subjected to DHPLC profiling. Subsequently, samples from a cohort of 30 patients affected by various forms of macular degeneration were subjected to DHPLC scanning under the same conditions. Results: DHPLC profiling not only identified all 132 sequence alterations previously detected by double-gradient denaturing gradient gel electrophoresis but also identified 5 sequence alterations that this approach had missed. Moreover, DHPLC scanning of an additional panel of 30 previously untested patients led to the identification of 26 different mutations and 29 polymorphisms, accounting for 203 sequence variations on 29 of the 30 patients screened. In total, the DHPLC approach allowed us to identify 16 mutations that had never been reported before. Conclusions: These results provide strong support for the use of DHPLC for molecular characterization of the ABCA4 gene.