FPR1 interacts with CFH, HTRA1 and smoking in exudative age-related macular degeneration and polypoidal choroidal vasculopathy.

PURPOSE: To determine the genetic association of an inflammation-related gene, formyl peptide receptor 1 (FPR1), in exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: The coding region of FPR1 gene was sequenced in 554 unrelated Chinese individuals: 155 exudative AMD patients, 179 PCV patients, and 220 controls. Interactions and combined effects of FPR1 with complement factor H (CFH), high temperature requirement factor A1 (HTRA1), and smoking were also investigated. RESULTS: A total of 28 polymorphisms in FPR1 were identified. Single nucleotide polymorphisms (SNP) rs78488639 increased the risk to exudative AMD (P=0.043) and PCV (P=0.016), whereas SNP rs867229 decreased the risk to exudative AMD (P=0.0026), but not PCV. Homozygous G allele of rs1042229 was associated with exudative AMD (P=0.0394, odds ratio (OR)=2.27, 95% confident interval: 1.08-4.74), but not with PCV. Exudative AMD, but not PCV, was associated with the heterozygous genotypes of rs2070746 (P=0.019, OR=0.57) and rs867229 (P=0.0082, OR=0.54). Significantly, interactions were identified among FPR1 rs78488639, CFH rs800292, and HTRA1 rs11200638 in both exudative AMD and PCV. Combined heterozygous risk alleles of CFH rs800292 GA and FPR1 rs78488639 CA were posed to PCV (P=2.22 × 10(-4), OR=10.47), but not exudative AMD. Furthermore, FPR1 rs78488639 CA combining with HTRA1 rs11200638 and smoking was also predisposed risks to exudative AMD and PCV. CONCLUSION: FPR1 is associated with exudative AMD and PCV in a Hong Kong Chinese cohort. FPR1 rs78488639 interacted with CFH rs800292, HTRA1 rs11200638, and smoking, enhancing risk to exudative AMD and PCV.

Contribution of SNRNP200 sequence variations to retinitis pigmentosa.

PURPOSE: Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients. METHODS: Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12-16, 22-32, and 38-45, which covered the two helicase ATP-binding domains in DEAD-box and two sec-63 domains. The targeted regions were amplified by polymerase chain reaction and analyzed by direct DNA sequencing, followed by in silico analyses. RESULTS: Totally 26 variants were identified, 18 of which were novel. Three non-synonymous variants (p.C502R, p.R1779H and p.I698V) were found exclusively in patients. Two of them, p.C502R and p.R1779H, were each identified in one simplex RP patient, whereas p.I698V occurred in one patient with unknown inheritance pattern. All three residues are highly conserved in SNRNP200 orthologs. Nevertheless, only p.C502R and p.R1779H were predicted to affect protein function by in silico analyses, suggesting these two variants are likely to be disease-causing mutations. Notably, all mutations previously identified in other study populations were not detected in this study. CONCLUSIONS: Our results reveal a distinct mutation profile of the SNRNP200 gene in a southern Chinese cohort of RP patients. The identification of two novel candidate mutations in two respective patients affirmed that SNRNP200 contributes to a proportion of overall RP.

A novel missense RP1 mutation in retinitis pigmentosa.

AIMS: More than 20 mutations associated with retinitis pigmentosa (RP) have been identified in the retinitis pigmentosa 1 (RP1) gene, all of them leading to the production of a truncated protein without 50-70% of the C-terminal of the RP1 protein. RP1 was recently found to be a microtubule-associated protein (MAP) and responsible for the organisation of the photoreceptor outer segment. The N-terminal doublecortin (DCX) domain of RP1 is essential for its function. But how the C-terminal of the protein affects its function is still not known. This study aims to get a better understanding of the RP1 gene by mutation screening on RP patients. METHODS: Peripheral blood was taken from 72 RP patients. Together with 101 RP patients and 190 control subjects previously reported, mutation screening was performed by polymerase chain reaction (PCR) and direct sequencing. Statistical analysis was performed using SPSS. RESULTS: Two novel missense sequence changes, D984G and C727W, and one novel variant, 6492T>G, at the 3' untranslated region were found. They were not found in 190 control subjects. D984G causes RP. It creates two possible N-myristoylation sites according to PROSITE. C727W does not segregate with RP in the family. It abolishes an N-myristoylation site. R872H, a previously reported polymorphism, was predominantly present in control subjects (P=0.001). CONCLUSIONS: Our results suggest that disruption of the C-terminal of RP1 may be associated with the development of RP, and the possible involvement of the RP1 polypeptide downstream of its DCX domain in normal RP1 function.

Genetic markers for retinitis pigmentosa.

OBJECTIVE: To review recent advances in the molecular genetics of retinitis pigmentosa with emphasis on the development of genetic markers that aids diagnosis and prognosis. DATA SOURCES AND EXTRACTION: Literature search of MEDLINE from 1988 to 2005 using the following key words: 'retinitis pigmentosa', 'rhodopsin', 'RP1', 'RPGR', and 'genetic counseling'. References of two genes--RHO and RP1--causing retinitis pigmentosa in the Chinese population were reviewed. STUDY SELECTION: Literature and data related to genetic markers for retinitis pigmentosa. DATA SYNTHESIS: The genetics of retinitis pigmentosa is complex. It can be sporadic or familial, with heterogeneous transmission modes. Retinitis pigmentosa is associated with nearly 40 chromosomal loci, where 32 candidate genes have been identified. A large number of mutations are known to cause retinitis pigmentosa. But no single mutation alone accounts for more than 10% of unrelated retinitis pigmentosa patients. Genetic tests for retinitis pigmentosa require screening for a consort of mutations in a large number of genes. High throughput screening technology such as denaturing high performance liquid chromatography and automated DNA sequencing should make such tests feasible. CONCLUSIONS: Rapid developments in the understanding of the genetics of retinitis pigmentosa have helped to establish genetic tests of clinical value. The complex mode of inheritance nonetheless makes genetic counselling difficult, even in the presence of positive genetic screening results.

Gene mutations in retinitis pigmentosa and their clinical implications.

Retinitis pigmentosa (RP) is a group of inherited progressive retinal diseases affecting about 1 in 3500 people worldwide. So far, there is no prevention or cure, with permanent visual loss or even blindness the ultimate consequence usually after midlife. The genetics of RP are complex. It can be sporadic, autosomal dominant, autosomal recessive, or X-linked. Thirty-two genes are known to be associated with RP, sometimes the same gene gets involved in different inheritance traits. Some RP cases have a digenic cause. About 60% RP cases still have no known genetic cause. A large number of mutations cause RP, and they can be deletions, insertions, or substitutions that cause missense mutations or truncations. The RHO, RP1, and RPGR genes contribute the greatest number of known mutations causative of RP. But there is no single mutation that alone accounts for more than 10% of unrelated patients. Genetic testing for RP therefore requires screening for a group of genes. High-throughput and automated sequence detection technologies are essential. Due to the complexity in phenotype and genetics, and the fact that RP is untreatable, genetic testing for presymptomatic diagnosis of RP is controversial. Meanwhile, new genes are still to be identified, mostly by family linkage and sib-pair analysis. Research on gene therapy for RP requires information on gene mutations causative of RP.