Novel RP1L1 Variants and Genotype-Photoreceptor Microstructural Phenotype Associations in Cohort of Japanese Patients With Occult Macular Dystrophy.

PURPOSE: To determine the clinical and genetic characteristics of Japanese patients with occult macular dystrophy (OMD) in a nationwide multicenter study. METHODS: Twenty-three patients from 21 families with clinically diagnosed OMD were studied at 10 institutions throughout Japan. Ophthalmologic examinations including spectral-domain optic coherence tomography were performed. Patients were classified into two phenotype groups: a classical group having both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors, and a nonclassical group lacking at least one of these two features. Whole-exome sequencing, direct sequencing, and in silico molecular analysis were performed to detect the pathogenic RP1L1 variants. Statistical associations between the phenotype and genotypes based on the presence of pathogenic RP1L1 variants were investigated. RESULTS: There were 12 families with the classical findings and 9 families with the nonclassical findings. Nine pathogenic RP1L1 missense variants were identified in 12 families (57%) including three reported variants, namely, p.R45W, p.S1199C, and p.G1200A, and six novel variants, p.G221R, p.T1194M, p.T1196I, p.G1200D, p.G1200V, and p.V1201G. The pathogenic missense variants in seven families (33%) were located between amino acid numbers 1196 and 1201. A significant association was found between the photoreceptor microstructural phenotypes and molecular genotypes. CONCLUSIONS: The spectrum of the morphologic phenotypes and pathogenic RP1L1 variants was documented in a well-characterized Japanese cohort with OMD. A unique motif including six amino acids (1196-1201) downstream of the doublecortin domain could be a hot spot for RP1L1 pathogenic variants. The significant association of the morphologic phenotypes and genotypes indicates that there are two types of pathophysiology underlying the occult macular dysfunction syndrome: a hereditary OMD with the classical phenotype (Miyake's disease), and a nonhereditary OMD-like syndrome with progressive occult maculopathy.

RPE65 Mutations in Two Japanese Families with Leber Congenital Amaurosis.

PURPOSE: To investigate genetic and clinical features of patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations. METHODS: Five Japanese families with LCA were recruited. We performed complete ophthalmic examinations, with optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Genetic analysis was performed with whole-exome sequencing analysis and Sanger sequencing. RESULTS: We identified RPE65 mutations in two unrelated LCA patients from two families. Case 1: A 5-month-old girl was diagnosed with LCA because of nystagmus, loss of vision and non-recordable ERG. She was the only one affected in her non-consanguineous family, and exhibited novel compound heterozygous RPE65 mutations (c.177C>G, p.H59Q and c.183_184insT, p.D62X). Case 2: A 30-year-old woman, who had night blindness and poor ocular pursuit during the first year of life, exhibited severe retinal degeneration and non-recordable ERG. She was the only affected in her non-consanguineous family, and showed a homozygous RPE65 mutation (c.1543C>T, p.R515W). CONCLUSIONS: By using whole-exome sequencing analysis, three RPE65 mutations were identified in two Japanese patients with LCA. This approach would be useful for identification of disease-causing mutations of LCA.

Novel C8orf37 Mutations in Patients with Early-onset Retinal Dystrophy, Macular Atrophy, Cataracts, and High Myopia.

PURPOSE: More than 50 genes are reported as causative genes of autosomal recessive (ar) retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). It is challenging to identify causative mutations for arRP and arCRD. The purpose of the present study was to investigate clinical and genetic features of two siblings with early-onset retinal dystrophy. METHODS: Whole-exome sequencing was conducted for the two affected siblings and their unaffected brother and mother from a Japanese family. We performed complete ophthalmic examinations, including visual acuity, funduscopy, visual-field testing, electroretinography and optical coherence tomography. RESULTS: Whole-exome sequencing analysis identified novel compound heterozygous mutations, a splice site mutation (c.374 + 2T > C in intron 4) and a deletion mutation (c.575delC [p.T192MfsX28] in exon 6) of chromosome 8 open reading frame 37 (C8orf37) gene, which encodes a ciliary protein, in both patients. The mother carried the truncating mutation, and the brother carried neither mutation. Ophthalmic examinations revealed diffuse retinal degeneration, macular atrophy, non-recordable electroretinography responses, cataracts, and high myopia in both patients, who could not be diagnosed with either RP or CRD because of the severe retinal degeneration and early onset disease. Longitudinal follow-up of the patients revealed highly progressive retinal degeneration, macular atrophy, and visual field loss. CONCLUSIONS: Recessive C8orf37 mutations have been identified in early to adolescent-onset arRP and arCRD with macular involvement. Our study identified two novel truncating mutations of the C8orf37 gene in siblings with early-onset retinal dystrophy, macular atrophy, cataracts, and high myopia.

Congenital Achromatopsia and Macular Atrophy Caused by a Novel Recessive PDE6C Mutation (p.E591K).

PURPOSE: We have previously reported clinical features of two siblings, a sister with complete achromatopsia (ACHM) and a brother with incomplete ACHM, in a consanguineous Japanese family. With the current study, we intended to identify a disease-causing mutation in the siblings and to investigate why the phenotypes of the siblings differed. METHODS: We performed a comprehensive ophthalmic examination for each sibling and parent. Whole-exome and Sanger sequencing were performed on genomic DNA. Molecular modeling was analyzed in an in silico study. RESULTS: The ophthalmic examination revealed severe macular atrophy in the older female sibling at 30 years of age and mild macular atrophy in the brother at 26 years of age. The genetic analysis identified a novel homozygous PDE6C mutation (p.E591K) as the disease-causing allele in the siblings. Each parent was heterozygous for the mutation. Molecular modeling showed that the mutation could cause a conformational change in the PDE6C protein and result in reduced phosphodiesterase activity. We also identified an OPN1SW mutation (p.G79R), which is associated with congenital tritan deficiencies, in the sister and the father but not in the brother. CONCLUSIONS: A novel homozygous PDE6C mutation was identified as the cause of ACHM. In addition, we identified an OPN1SW mutation in the sibling with complete ACHM, which might explain the difference in phenotype (complete versus incomplete ACHM) between the siblings.

Lack of association of LOXL1 gene variants in Japanese patients with central retinal vein occlusion without clinically detectable pseudoexfoliation material deposits.

PURPOSE: A possible association has been reported between exfoliation syndrome (EX) and various ocular and systemic vascular disorders; however, it is unclear if there is an association between EX and central retinal vein occlusion (CRVO). Because latent deposits of exfoliation materials might not be recognized during slit-lamp examination, an ocular biopsy is required to establish a precise diagnosis. We evaluated a possible association between EX and CRVO using lysyl oxidase-like 1 (LOXL1) gene variants as alternative markers for EX. METHODS: The allelic and genotypic frequencies of three LOXL1 variants (rs1048661, rs3825942, and rs2165241) were determined in 68 consecutive Japanese patients with CRVO [15 with exfoliation syndrome (EX+) and 53 without exfoliation syndrome (EX-)] and 90 control patients with cataract without EX (CT). RESULTS: The frequencies of the rs1048661 and rs3825942 variants showed borderline difference between the CRVO and CT groups (p = 0.04085 and p = 0.06088, respectively, for allelic frequencies, and p = 0.06838 and p = 0.03482, respectively, for genotypic frequencies). Compared with the CT group, subgroup analysis showed that the CRVO EX+ group had significant differences in the allelic and genotypic frequencies of rs1048661 (p = 0.0006447 and p = 0.0001392, respectively) and had borderline differences in the allelic and genotypic frequencies of rs3825942 (p = 0.03403 and p = 0.07341, respectively), while the CRVO EX- group did not (p = 0.1324-0.6306). Subgroup analysis showed that the frequencies of rs2165241 did not differ between the CRVO and CT groups. CONCLUSIONS: When the LOXL1 variants were used as disease markers for clinically undetectable EX, there was no association between CRVO and EX. The results suggested that the LOXL1 variants, which are well-established markers for EX, are not likely genetic markers for CRVO in Japanese subjects.

RHO Mutations (p.W126L and p.A346P) in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa.

Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO) mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP). Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L) and c.1036G>C (p.A346P)), one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L) might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L) may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling.

Whole exome analysis identifies frequent CNGA1 mutations in Japanese population with autosomal recessive retinitis pigmentosa.

OBJECTIVE: The purpose of this study was to investigate frequent disease-causing gene mutations in autosomal recessive retinitis pigmentosa (arRP) in the Japanese population. METHODS: In total, 99 Japanese patients with non-syndromic and unrelated arRP or sporadic RP (spRP) were recruited in this study and ophthalmic examinations were conducted for the diagnosis of RP. Among these patients, whole exome sequencing analysis of 30 RP patients and direct sequencing screening of all CNGA1 exons of the other 69 RP patients were performed. RESULTS: Whole exome sequencing of 30 arRP/spRP patients identified disease-causing gene mutations of CNGA1 (four patients), EYS (three patients) and SAG (one patient) in eight patients and potential disease-causing gene variants of USH2A (two patients), EYS (one patient), TULP1 (one patient) and C2orf71 (one patient) in five patients. Screening of an additional 69 arRP/spRP patients for the CNGA1 gene mutation revealed one patient with a homozygous mutation. CONCLUSIONS: This is the first identification of CNGA1 mutations in arRP Japanese patients. The frequency of CNGA1 gene mutation was 5.1% (5/99 patients). CNGA1 mutations are one of the most frequent arRP-causing mutations in Japanese patients.

Overexpression of HtrA1 and exposure to mainstream cigarette smoke leads to choroidal neovascularization and subretinal deposits in aged mice.

PURPOSE: We determined the function of ARMS2 and HtrA1 in the choroid and retina using transgenic (Tg) mice and evaluated the effects of mainstream cigarette smoke on these mice. METHODS: The chicken actin promoter (CAG) was used to drive mouse HtrA1, human ARMS2, and ARMS2 (A69S) expression in the entire body of a mouse for one year. Fundus observations were performed with a Spectralis HRA+ optical coherence tomograph (OCT). Eyes were sectioned, stained with hematoxylin and eosin (H&E), and analyzed with immunohistochemistry. Mice were exposed to cigarette smoke for 30 min/d, 5 d/wk for 12 weeks using a mainstream smoking chamber (INH06-CIGR02A, MIPS). After 12 weeks, fundus observations and pathological analyses were performed. RESULTS: Approximately 18.2% of 12-month-old HtrA1 Tg mice exhibited choroidal neovascularization (CNV) by OCT and positive immunostaining with anti-CD31 and anti-fibronectin antibodies. Furthermore, elastic van Gieson (EVG) staining showed Bruch's membrane damage in HtrA1 Tg mice. No retinal changes were observed in ARMS2 and ARMS2 (A69S) Tg mice. A total of 12 weeks of exposure to mainstream cigarette smoke led to CNV rates of 7.7% for wild type (Wt) mice and 20% for HtrA1 Tg mice, but had no effect on ARMS2 Tg mice. In addition, abnormal deposits were observed between photoreceptor cells and the RPE in an HtrA1 Tg mouse exposed to mainstream cigarette smoke. CONCLUSIONS: The HtrA1 overexpression and mainstream cigarette smoke can independently lead to CNV. The HtrA1 gene is a strong risk factor for wet AMD, but not all of the HtrA1 Tg mice developed CNV, suggesting that CNV development depends on multiple risk factors.

Autosomal recessive cone-rod dystrophy associated with compound heterozygous mutations in the EYS gene.

BACKGROUND: EYS mutations have been identified only in patients with autosomal recessive retinitis pigmentosa (arRP). This study was conducted to describe clinical and genetic features of a Japanese patient with autosomal recessive cone-rod dystrophy (arCRD) and EYS mutations. METHODS: We performed complete ophthalmic examinations including full-field electroretinography (ERG). Genetic analysis using whole-exome sequencing and Sanger sequencing was performed to identify the disease-causing mutation in a 31-year-old male patient. RESULTS: At the initial visit, the patient's decimal best-corrected visual acuity (BCVA) was 0.9 and 0.6 in his right and left eyes, respectively. Funduscopy indicated retinal degenerations were predominantly affected within the vascular arcades and preserved retinal vessels in the mid-periphery in both eyes. Visual field testing showed there were relative central scotomas and preserved peripheral visual fields in both eyes. ERG indicated there was a decreased pattern for both the rod and cone responses. At the age of 36 years, his BCVA decreased to 0.2 in both eyes. Optical coherence tomography showed marked retinal thinning of the macular regions in both eyes. Genetic analysis identified compound heterozygous truncating mutations (p.Y2935X and p.S1653KfsX2) in the EYS gene. His unaffected parents were heterozygous for each mutation. CONCLUSIONS: Our results demonstrated that EYS mutations can be the cause of not only arRP but also arCRD. Our findings extend the phenotypic spectrum of patients with EYS mutations.

Retinal angiomatous proliferation associated with risk alleles of ARMS2/HTRA1 gene polymorphisms in Japanese patients.

BACKGROUND: The purpose of this study was to investigate the association between ARMS2/HTRA1, CFH, and C3 gene polymorphisms and retinal angiomatous proliferation (RAP), an infrequent and severe form of exudative age-related macular degeneration, which is characterized by intraretinal neovascularization. METHODS: Diagnosis of RAP was based on fundus photographs, images of fluorescein and indocyanine green angiographies, and optical coherence tomography findings. Six single nucleotide polymorphisms (SNPs), A69S (rs10490924) in ARMS2, rs11200638 in HTRA1, I62V (rs800292) in CFH, Y402H (rs1061170) in CFH, R80G (rs2230199) in C3, and rs2241394 in C3, were genotyped in eight Japanese patients with RAP. RESULTS: The two SNPs in the ARMS2/HTRA1 were in complete linkage disequilibrium. The frequency of the risk T allele in ARMS2 (the risk A allele in HTRA1) was 93.8% in the RAP patients. The frequency of homozygosity for the risk genotype TT of ARMS2 (the risk genotype AA of HTRA1) was 87.5%. The frequency of the non-risk allele (A) of I62V was 100%. The frequencies of risk alleles of Y402H, R80G, and rs2241394 were 12.5%, 0%, and 18.8%, respectively. CONCLUSION: Our results suggest that the risk alleles of the ARMS2/HTRA1 SNPs may be associated with development of RAP and play a major role in the pathogenesis of intraretinal angiogenesis.

Whole-exome sequencing identifies a novel ALMS1 mutation (p.Q2051X) in two Japanese brothers with Alström syndrome.

PURPOSE: No mutations associated with Alström syndrome (AS), a rare autosomal recessive disease, have been reported in the Japanese population. The purpose of this study was to investigate the genetic and clinical features of two brothers with AS in a consanguineous Japanese family. METHODS: Whole-exome sequencing analysis was performed on two brothers with AS and their unaffected parents. We performed a complete ophthalmic examination, including decimal best-corrected visual acuity, slit-lamp and funduscopic examination, visual-field and color-vision testing, full-field electroretinography, and optical coherence tomography. Fasting blood tests and systemic examinations were also performed. RESULTS: A novel mutation (c.6151C>T in exon 8) in the Alström syndrome 1 (ALMS1) gene that causes a premature termination codon at amino acid 2051 (p.Q2051X), was identified in the homozygous state in the affected brothers and in the heterozygous state in the parents. The ophthalmologic findings for both brothers revealed infantile-onset severe retinal degeneration and visual impairment, marked macular thinning, and severe cataracts. Systemic findings showed hepatic dysfunction, hyperlipidemia, hypogonadism, short stature, and wide feet in both brothers, whereas hearing loss, renal failure, abnormal digits, history of developmental delay, scoliosis, hypertension, and alopecia were not observed in either brother. The older brother exhibited type 2 diabetic mellitus and obesity, whereas the younger brother had hyperinsulinemia and subclinical hypothyroidism. CONCLUSIONS: A novel ALMS1 mutation was identified by using whole-exome sequencing analysis, which is useful not only to identify a disease causing mutation but also to exclude other gene mutations. Although characteristic ophthalmologic findings and most systemic findings were similar between the brothers, the brothers differed slightly in terms of glucose tolerance and thyroid function.

Two siblings with late-onset cone-rod dystrophy and no visible macular degeneration.

BACKGROUND: We report our findings in two siblings with late-onset cone-rod dystrophy (CRD) with no visible macular degeneration. CASES AND METHODS: Case 1 was an 82-year-old man who first noticed a decrease in vision and color blindness in his early seventies. His mother and younger sister also had visual disturbances. His decimal visual acuity was 0.3 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed normal fundi, and fluorescein angiography was also normal in both eyes. The photopic single flash and flicker eletroretinograms (ERGs) were severely attenuated and the scotopic ERGs were slightly reduced in both eyes. Case 2 was the 80-year-old younger sister of Case 1. She first noticed a decline in vision and photophobia in both eyes in her early seventies. Her decimal visual acuity was 0.4 in the right eye and 0.2 in the left eye. Ophthalmoscopy showed mottling of the retinal pigment epithelium in the midperiphery with no visible macular degeneration. The photopic single flash and flicker ERGs were severely attenuated, and the scotopic ERGs were slightly reduced in both eyes. CONCLUSION: These siblings are the oldest reported cases of CRD with no visible macular degeneration. Thus, CRD should be considered in patients with reduced visual acuity, color blindness, and photophobia even if they are older than 70 years.

[Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram].

BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression.

Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants.

PURPOSE: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). METHODS: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. RESULTS: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. CONCLUSIONS: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population.

The association between complement component 2/complement factor B polymorphisms and age-related macular degeneration: a HuGE review and meta-analysis.

The authors performed a systematic review of the association of complement component 2(C2)/complement factor B (CFB) gene polymorphisms with age-related macular degeneration (AMD). In total, data from 19 studies published between 2006 and 2011 were pooled for 4 polymorphisms: rs9332739 and rs547154 in the C2 gene and rs4151667 and rs641153 in the CFB gene. Data extraction and assessments for risk of bias were independently performed by 2 reviewers. Allele frequencies and allele and genotypic effects were pooled. Heterogeneity and publication bias were explored. Pooled minor allele frequencies for all 4 SNPs were between 4.7% and 9.6% for all polymorphisms, except for an Indian population in which the C allele at rs9332739 was the major allele. For the C2 polymorphisms, the minor C allele at rs9332739 and the minor T allele at rs547154 carried estimated relative risks (odds ratios) of 0.55 (95% confidence interval (CI): 0.46, 0.65) and 0.47 (95% CI: 0.39, 0.57), respectively. For the CFB polymorphisms, the minor A alleles at rs4151667 and rs614153 carried estimated risks of 0.54 (95% CI: 0.45, 0.64) and 0.41 (95% CI: 0.34, 0.51), respectively. These allele effects contributed to an absolute lowering of the risk of all AMD in Caucasian populations by 2.0%-6.0%. This meta-analysis provides a robust estimate of the protective association of C2/CFB with AMD.

A new mutation in the RP1L1 gene in a patient with occult macular dystrophy associated with a depolarizing pattern of focal macular electroretinograms.

PURPOSE: To determine whether a mutation in the RP1-like protein 1 (RP1L1) gene is present in a Japanese patient with sporadic occult macular dystrophy (OMD) and to examine the characteristics of focal macular electroretinograms (ERGs) of the patient with genetically identified OMD. METHODS: An individual with OMD underwent detailed ophthalmic clinical evaluations including focal macular ERGs. Mutation screening of all coding regions and flanking intron sequences of the RP1L1 gene were performed with DNA sequencing analysis in this case with OMD. RESULTS: A new RP1L1 mutation (c.3596 C>G in exon 4) was identified. The variant c.3596 C>G in exon 4 resulted in the substitution of cysteine for serine at amino acid position 1199. The serine at position 1199 is well conserved among the RP1L1 family in other species. Four out of five computational assessment tools predicted that this mutation is damaging to the protein function. This mutation was not present in 294 control alleles. The waveform of focal macular ERGs recorded from the patient with OMD had a depolarizing pattern, simulating the ERG waveforms observed after the hyperpolarizing bipolar cell activity is blocked. CONCLUSIONS: We have demonstrated in a Japanese patient the possibility that sporadic OMD may also be caused by an RP1L1 mutation. The waveform of focal macular ERGs elicited from the OMD patient with the RP1L1 mutation showed a depolarizing pattern. This characteristic is the same as reported for the focal macular ERGs of OMD.

Clinical characteristics of occult macular dystrophy in family with mutation of RP1l1 gene.

PURPOSE: To report the clinical characteristics of occult macular dystrophy (OMD) in members of one family with a mutation of the RP1L1 gene. METHODS: Fourteen members with a p.Arg45Trp mutation in the RP1L1 gene were examined. The visual acuity, visual fields, fundus photographs, fluorescein angiograms, full-field electroretinograms, multifocal electroretinograms, and optical coherence tomographic images were examined. The clinical symptoms and signs and course of the disease were documented. RESULTS: All the members with the RP1L1 mutation except one woman had ocular symptoms and signs of OMD. The fundus was normal in all the patients during the entire follow-up period except in one patient with diabetic retinopathy. Optical coherence tomography detected the early morphologic abnormalities both in the photoreceptor inner/outer segment line and cone outer segment tip line. However, the multifocal electroretinograms were more reliable in detecting minimal macular dysfunction at an early stage of OMD. CONCLUSION: The abnormalities in the multifocal electroretinograms and optical coherence tomography observed in the OMD patients of different durations strongly support the contribution of RP1L1 mutation to the presence of this disease.

Analysis of LOXL1 gene variants in Japanese patients with branch retinal vein occlusion.

PURPOSE: Previous studies have described a possible association between exfoliation syndrome (EX) and various ocular and systemic vascular disorders; however, the association between EX and branch retinal vein occlusion (BRVO) remains unclear. Because slit-lamp examination may overlook latent deposits of exfoliation materials, an ocular biopsy is usually needed for a precise diagnosis. We evaluated a possible association between EX and BRVO using lysyl oxidase-like 1 (LOXL1) gene variants as alternative markers for EX. METHODS: Allelic and genotypic frequencies of three LOXL1 variants (rs1048661, rs3825942, and rs2165241) were determined for 78 consecutive Japanese patients with BRVO (11 patients with exfoliation syndrome [EX+], 67 patients without exfoliation syndrome [EX-]), and 158 patients with cataract without EX (CT) as controls. RESULTS: The rs1048661 variant differed between the BRVO and CT groups in allelic and genotypic frequencies (p=0.0137 and p=0.0203, respectively). Subgroup analysis, compared to the CT group, showed that BRVO EX+ had significantly different allelic and genotypic frequencies of rs1048661 (p=0.00011 and p=0.000189, respectively), while BRVO EX- did not (p=0.175 and p=0.288, respectively). The frequencies of rs3825942 and rs2165241 did not differ between the BRVO and CT groups. CONCLUSIONS: No association was found between BRVO and EX if LOXL1 variants were used as disease markers for clinically undetectable EX. The results suggested that LOXL1 variants, well established markers for EX, are not likely genetic markers for BRVO in Japanese subjects.

Dominant mutations in RP1L1 are responsible for occult macular dystrophy.

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.