A decade in search of myopia genes.

Nearly half of visual impairment in the world is caused by uncorrected refractive errors, and myopia constitutes a significant proportion of this problem. Moreover, the prevalence of myopia is increasing, especially in Asian countries. Linkage studies have identified at least 18 possible loci (MYP) in 15 different chromosomes associated with myopia, although some of these remain to be confirmed. However, when studies have been carried out to identify specific candidate genes, it is apparent that these genes are often not part of MYP loci. In studying the expression of specific genes that might be responsible for myopia, we are learning that the involvement of various small leucine-rich repeat proteoglycans and growth factors is not a simple one. The emerging picture is one of complex interaction, in which mutations in several genes likely act in concert. The majority of myopia cases are not likely caused by defects in structural proteins, but in defects involving the control of structural proteins. The future of genetic research in this area will likely rely increasingly on microchip array technology.

Refinement of the MYP3 locus on human chromosome 12 in a German family with Mendelian autosomal dominant high-grade myopia by SNP array mapping.

Myopia, or short-sightedness, is the most common form of vision disorder worldwide. Higher levels of myopia, usually defined as an axial eye length of >26 mm or a refractive error of < -5.00 diopters are often designated as 'pathologic' myopia, because of the predisposition to develop further eye disorders such as retinal detachment, macular degeneration, cataract, or glaucoma. Many distinct forms of autosomal dominant non-syndromic high-grade myopia are described in humans. While the underlying chromosomal locations and critical disease intervals have been identified and located to physical map positions, the gene defects and causative mutations responsible for autosomal dominant myopia remain elusive to date. Examination of a German six-generation kindred by 10K whole genome chips led to the identification of a 19-cM map segment as being the most likely familial myopia candidate region spanning from chromosomal band 12q14.3 to 12q21.31 (MYP3). In our family, a maximum multi-point LOD score of 3.9 was obtained between rs1373877 and rs717996. The recombination breakpoints in this family and the interval of the originally reported German/Italian family defining the MYP3 locus on chromosome 12 (OMIM 603221, two-point LOD score 3.85 for markers D12S1706 and D12S327 at 12q21-23) allowed us to significantly refine a minimum consensus region. This new composite region is located between microsatellite marker D12S1684 at 75.8 K and SNP_A-1509586 (alias rs717996) at position 82,636,288 bp, and narrows the original 30.1 cM of the MYP3 interval to 6.8 cM. The refined MYP3 interval allowed us to restrict the list of database-indexed genes to 25, several of which are promising MYP3 candidates based on similarities with genes and proteins involved in vision physiology and eye disease. While autosomal dominant high-grade myopia is recognized to be genetically heterogeneous, our results suggest genetic homogeneity of the MYP3-based condition in families that share the same ethnic and geographical background. The future identification of this MYP3 gene may provide insights into the pathophysiology of myopia and eye development.

Population haplotypes of exon ORF15 of the retinitis pigmentosa GTPase regulator gene in Germany : implications for screening for inherited retinal disorders.

BACKGROUND: Mutations in exon ORF15 of the retinitis pigmentosa GTPase regulator gene (RPGR) within chromosomal region Xp21.1 are a significant cause of a number of retinal disorders. The high mutation rate is ascribed to the highly repetitive, purine-rich tracts within the exon ORF15 sequence. Importantly, all exon ORF15 mutations observed to date represent protein-truncating mutations (nonsense and frameshift mutations). Because of its repetitive motifs, mutation screening of the hot-spot region by direct DNA sequencing is a technically challenging task. METHODS: We devised a screening strategy for exon ORF15 mutations that reserves DNA sequencing for precise sizing and base-order assessment of detected mutations. The screening strategy is based on a PCR/restriction fragment length polymorphism (RFLP) analysis of exon ORF15 and comparison with population-specific RFLP haplotypes. The latter were constructed from PCR/RFLP analysis of DNA samples from 100 healthy German male individuals. Mutational alterations of normal RFLP haplotype patterns were predicted. RESULTS: Six distinct RFLP haplotypes (founder alleles H1-H6) were observed with frequencies ranging from 2% to 63%. All natural variations of exon ORF15 were in-frame alterations ranging in size between 3bp and 36bp. Prediction of mutation-specific RFLP patterns indicated a high detection rate of mutations. CONCLUSION: A new strategy has been developed using routine protocols for mutation screening of difficult-to-sequence, highly repetitive exon ORF15 of the RPGR gene in a German population.

Mutational risk in highly repetitive exon ORF15 of the RPGR multidisease gene is not associated with haplotype background.

Exon ORF15 is an alternative exon in the retinitis pigmentosa GTPase regulator (RPGR) gene containing a highly repetitive, purine-rich internal region. It constitutes a mutational hot spot giving rise to a group of heterogeneous X-linked retinal disorders. We sought to determine whether non-pathogenic substitutions and sequence length variations in the repetitive sequence have an influence on the risk of pathogenic exon ORF15 mutations. The type and distribution of exon ORF15 polymorphisms were assessed by genotyping 107 healthy German males using standard procedures. Polymorphisms were grouped into haplotypes and their frequencies determined in normal controls and previously analyzed patients with X-linked retinitis pigmentosa (XLRP). In the control group we identified 6 complex variants of the most common, ancestral exon ORF15 allele corresponding to the GenBank reference sequence (accession no. AF286472). Exon ORF15 mutations in XLRP patients were associated with the ancestral allele in 75% of affected cases. Four of the most recent founder haplotypes termed H3, H4, H6 and H7 were not identified in the patient samples. Our analysis and review of polymorphism data from the published literature suggests the presence of common exon ORF15 haplotypes in the European population. While the mutational risk in the RPGR gene appears not to be altered by the haplotype background, exon ORF15 haplotype analysis may be useful for tracing the evolutionary history of RP3-associated diseases.

Multifocal intraocular lens implantation in patients with traumatic cataract.

OBJECTIVE: To evaluate the postoperative outcome and complication rate of cataract extraction with implantation of a zonal-progressive multifocal intraocular lens (IOL) for traumatic cataract. DESIGN: Prospective, nonrandomized, comparative trial. PARTICIPANTS: Fifty-one eyes of 51 subjects with traumatic cataract caused by nonpenetrating, penetrating, and perforating ocular trauma at two university institutions with more than 12 months follow-up. INTERVENTIONS: Temporal clear corneal phacoemulsification with foldable IOL implantation was performed in all eyes. In 29 subjects, a zonal-progressive optic multifocal IOL (Array SA40-N Allergan, Irvine, CA) was implanted, whereas 22 subjects received a monofocal IOL and served as controls. RESULTS: Preoperative subjects demographics, mean postoperative spherical equivalent, astigmatism, and uncorrected and best-corrected distance visual acuity were similar in the two groups. Subjects with a multifocal IOL achieved a significantly better uncorrected near visual acuity than subjects with monofocal IOL (0.24 vs. 0.40; P = 0.0001). With distance correction only, mean near visual acuity was 0.21 vs. 0.43 (P = 0.0001). Best-corrected near visual acuity was 0.17 for both groups (P = 0.91), with +1.24 diopters (D) for the multifocal group and +2.45 D for the monofocal group (P = 0.0001). Spectacle dependency differed significantly between the two groups, with 18 (81%) subjects of the monofocal group commonly requiring an additional plus add for near tasks compared with 5 (17%) subjects in the multifocal group (P = 0.001). Stereopsis was superior in the multifocal group (P < 0.001), with 20 (69%) and 16 (55%) patients with a multifocal IOL responding positively to the Lang and Titmus tests, respectively. In the monofocal group, only eight (36%) and five (22%) subjects gave correct answers. CONCLUSIONS: Multifocal IOL implantation is a viable alternative to monofocal pseudophakia in subjects with traumatic cataract.

Scleral fixation of secondary foldable multifocal intraocular lens implants in children and young adults.

OBJECTIVE: To assess the feasibility of transscleral fixation of a foldable, multifocal intraocular lens (IOL) as an alternative form of optical correction to monofocal IOL implantation in aphakic children and young adults intolerant of contact lenses in the absence of sufficient capsular support. STUDY DESIGN: Prospective, nonrandomized, comparative trial. PARTICIPANTS: Twenty-six eyes of 26 unilateral aphakic patients in the age group 6 to 29 years (mean, 13.2 years) at two university institutions with more than 6 months of follow-up. INTERVENTIONS: Anterior vitrectomy and secondary scleral-fixated foldable IOL implantation were performed in all cases. In 12 patients, a zonal-progressive optic multifocal IOL (Array SA40-N; Allergan, Irvine, CA) was implanted, whereas 14 patients received a monofocal IOL (SI40NB; Allergan). The follow-up ranged from 6 to 20 months (mean, 13.4 months). RESULTS: Preoperative patient demographics, mean postoperative spherical equivalent, astigmatism, and uncorrected and best-corrected distance visual acuity (BCDVA) were similar in the two groups. After surgery, BCDVA within one Snellen line of the preoperative BCDVA was achieved by 83% of the multifocal group and by 85% of the monofocal group. Patients with a multifocal IOL achieved a significantly better uncorrected near visual acuity than patients with monofocal IOL (019 versus 0.34; P = 0.02). With distance correction only, mean near visual acuity was 0.25 versus 0.44 (P = 0.01). Best-corrected near visual acuity was approximately 0.18 for both groups (P = 0.77), with +1.32 diopters (D) for the multifocal group and +2.54 D for the monofocal group (P = 0.001). Spectacle dependency differed significantly between the two groups, with 10 patients (71%) of the monofocal group commonly requiring an additional plus add for near tasks compared with two patients (16%) in the multifocal group (P = 0.001). The Lang test showed stereopsis to be superior in the multifocal group (P = 0.04). Complications encountered were: pressure increase in three eyes (11.5%), which was permanent in one case (3.8%); marked postoperative anterior chamber reaction in four eyes (15.4%); IOL decentration in five eyes (19.2%), one (3.8%) requiring surgical reintervention; and suture erosion through the conjunctiva in two eyes (7.4%). There was no statistically significant difference between the two groups. CONCLUSIONS: Secondary scleral-fixated multifocal IOL implantation was as successful as monofocal IOL implantation in achieving BCDVA comparable with preoperative BCDVA. Moreover, stereopsis, uncorrected and distance-corrected near visual acuities were better in the multifocal patients than in the monofocal eyes. Multifocal IOL seems a viable alternative to monofocal scleral fixation in children and young patients with contact lens-intolerant aphakia.

Phenotypic expression of the complete type of X-linked congenital stationary night blindness in patients with different mutations in the NYX gene.

PURPOSE: To describe the clinical phenotype of the complete type of X-linked congenital stationary night blindness (CSNB1) with different types of mutations in the NYX gene. METHODS: The clinical and genetic data from 18 male patients with eight different mutations from two ophthalmological institutes were reviewed. The variability in refractive error, reduced visual acuity and full-field electroretinogram (ERG) recordings was examined. RESULTS: Parameters were quantitatively analyzed based on the classification of mutations according to their predicted effect on protein structure and function. CSNB1 patients with mutations changing structurally conserved residues ( n=12) tended to have a lower degree of myopia than patients with mutations of non-conserved residues ( n=6). Visual acuity loss and the 30 Hz flicker ERG recordings were similar in the two groups. Values for the b/a amplitude ratio tended to be clustered in patients carrying the same mutation. Refractive error and the b/a amplitude ratio were highly correlated between the two eyes of an individual. CONCLUSIONS: These data suggest correlations between phenotypic expression in CSNB1 and individual genotypes as well as class types of mutations based on the extent of structural amino acid conservation. A high inter-eye correlation suggests that other genetic or environmental factors, rather than chance, play a part in determining the phenotypic diversity in CSNB1.

Ten novel ORF15 mutations confirm mutational hot spot in the RPGR gene in European patients with X-linked retinitis pigmentosa.

RGPR was the first gene found to be mutated in XLRP, the subtype of RP displaying the most severe form of retinal degeneration with partial or complete blindness in the third or fourth decade of life. Despite the RP3 locus on Xp21.1 accounting for 60-90% of XLRP, only 10-20% of identified RPGR mutations were reported in earlier analyses. This discrepancy appeared to be resolved when Vervoort et al. identified a mutational hot spot in a new purine-rich 3' exon (ORF15) that accounted for 60% of their XLRP patients [Vervoort et al., 2000]. In our mutation screening of 37 unrelated European XLRP patients we identified two recently described deletions and 10 novel mutations in exon ORF15 of RPGR, 4 of which were nonsense and 6 frameshift mutations. The latter included one duplication and 5 deletion mutations, all of which lead to a downstream premature termination. No mutations were detected in the additionally screened new exon ORF14. The data reported here, together with previous findings, document a significant clustering of mutations as well as polymorphisms in ORF15 of RPGR. In our unselected XLRP patient population, ORF15 mutations constitute 32% of cases, a finding that contradicts the results of Vervoort and coworkers [Vervoort et al., 2000] but is in agreement with a more recent study on North American XLRP patients [Breuer et al., 2002]. The observed prevalence is sufficient to justify an initial mutation screening of ORF15 in the genetically heterogeneous group of XLRP.

Multifocal intraocular lens implantation in prepresbyopic patients with unilateral cataract.

OBJECTIVE: To evaluate the benefits of implantation of a zonal-progressive multifocal intraocular lens (IOL) in prepresbyopic patients with unilateral cataract. STUDY DESIGN: Prospective, nonrandomized, comparative trial. PARTICIPANTS: Ninety-five eyes of 95 prepresbyopic patients aged between 14 and 40 years with either multifocal or monofocal IOL implantation at two institutions and with more than 6 months follow-up. INTERVENTIONS: Temporal clear corneal phacoemulsification and foldable IOL implantation was performed in all eyes. In 54 patients, a zonal-progressive optic multifocal IOL (Array SA40-N, Allergan, Irvine, CA) was implanted, whereas 41 patients received a monofocal IOL and served as controls. RESULTS: Preoperative patient demographics, mean postoperative spherical equivalent, astigmatism, and uncorrected and best-corrected distance visual acuities were similar in the two groups. Patients with a multifocal IOL achieved a significantly better uncorrected near visual acuity than patients with monofocal IOL (0.18 versus 0.37; P = 0.0001). With distance correction only, mean near visual acuity was 0.17 versus 0.43 (P = 0.0001). Best-corrected near visual acuity was 0.11 for both groups (P = 0.91), with +1.43 diopters (D) for the multifocal group and +2.35 D for the monofocal group (P = 0.0001). Spectacle dependency differed significantly between the two groups, with 21 patients (51%) of the monofocal group commonly requiring an additional plus add for near tasks compared with 5 patients (9%) in the multifocal group (P = 0.001). Stereopsis was superior in the multifocal group (P < 0.001), with 42 (77%) and 33 (61%) patients with a multifocal IOL responding positively to the Lang and Titmus tests, respectively. In the monofocal group; only 20 (48%) and 9 (22%) patients gave correct answers. CONCLUSIONS: Multifocal IOL implantation is a viable alternative to monofocal pseudophakia in prepresbyopic patients with unilateral cataract.