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 mutation in CRYBB2 responsible for inherited coronary cataract.

PURPOSE: To study the molecular pathogenesis of a Chinese family with coronary form of cataract. METHODS: One Chinese three-generation family with inherited coronary cataract phenotype was recruited. Five affected and seven unaffected family members attended our study. Genome-wide linkage analysis was applied to map the disease loci, and two candidate genes from a locus on chromosome 1 and a locus on chromosome 22 were sequenced for mutation identification. Software at the Expasy proteomics server was utilized to predict the mutation effect on proteins. RESULTS: Whole genome linkage analysis indicated some regions on chromosome 1, 10, and 22, with LOD score values greater than 1. Within these loci, the GJA8 and CRYBB2 genes, located in the two loci with the highest LOD score of 1.51 on chromosomes 1 and 22, respectively, were sequenced. A novel mutation c.92C>G in exon 2 of CRYBB2 causing S31W was identified in all five patients. It was not found in 95 unrelated controls. This missense sequence alteration likely enhanced the local solubility. Around the mutation site, a lipocalin signature motif was predicted by ScanProsite. CONCLUSIONS: A novel disease-causing mutation S31W in CRYBB2 was identified in a Chinese cataract family. It is the first reported mutation for coronary cataract. Functional characterization should be carried out to evaluate the biological effects of this mutant.

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.