Genotypic and phenotypic diversity in X-linked retinoschisis: Findings from a South Indian patient cohort.

PURPOSE: Retinoschisis is a distinctive condition characterized by intraretinal layer clefts, primarily associated with X-linked recessive inheritance due to RS1 gene mutations. This study aims to uncover the RS1 mutation spectrum in a cohort of 22 X-linked retinoschisis cases from South India and emphasizes the genotypic and phenotypic associations within patients harboring only RS1 mutations. METHODS: A total of 22 probands were suspected of having X-linked retinoschisis. All study subjects underwent ophthalmic investigations, including assessments of visual acuity, fundus examination, optical coherence tomography (OCT), and electroretinogram (ERG). RS1 gene screening was conducted using Sanger sequencing, and the pathogenicity of the variants was assessed through Sorting Intolerant from Tolerant (SIFT) and PolyPhen-2 in silico tools. RESULTS: The study found that the probands had an average visual acuity of 0.79 ± 0.39 log of minimum angle of resolution (logMAR), ranging from 0.17 to 1.77. During fundus examination, the probands exhibited a characteristic spoke wheel-like pattern in the macular region. Furthermore, OCT analysis revealed distinct alterations in the inner retinal microstructure, and ERG results consistently showed a reduction in b-wave amplitude. Eventually, Sanger sequencing results showed hemizygous mutations in the RS1 gene in only 12 probands, including a novel missense mutation in the RS1 gene's signal sequence. CONCLUSION: This study provides valuable insights into the spectrum of RS1 mutations in X-linked retinoschisis probands from South India. It reveals distinct genotypic-phenotypic associations and highlights the clinical manifestations associated with the disease pathogenesis.

Myocilin Mutation N480K Leads to Early Onset Juvenile and Adult-onset Primary Open Angle Glaucoma in a Six Generation Family.

PRCIS: A pathogenic autosomal dominant MYOC mutation N480K detected in 6 generations of an Indian family is primarily responsible for juvenile open angle glaucoma (JOAG) and adult-onset primary open angle glaucoma (POAG), emphasizing the importance of screening this mutation at a younger age. PURPOSE: To screen myocilin mutations in a large South Indian family with early-onset JOAG and adult-onset POAG. METHODS: In a large South Indian family with 20 members, 8 members diagnosed as JOAG, 7 members as POAG, 4 members as JOAG suspect, and 1 member as POAG suspect were screened for myocilin ( MYOC) mutations using Sanger sequencing. Whole exome sequencing was performed on clinically suspected JOAG/POAG individuals. RESULTS: Myocilin gene mutation N480K (c.1440C>G) was detected in 20 family members, including proband, of whom 8 were JOAG and 7 were POAG patients, 3 were JOAG suspects, and 2 were unaffected. Among the unaffected carriers, 1 was less than 5 years old, and another was 25 years old. The earliest to develop the disease was a 10-year-old child. The penetrance of the mutation was 95% over 10 years of age. This family had JOAG/POAG suspects with no N480K MYOC mutation, and they were further screened for other mutations using whole-exome sequencing. Polymorphisms CYP1B1 L432V and MYOC R76K were detected in 3 JOAG/POAG suspects, and among these 3, one had another CYP1B1 polymorphic variant R368H. The presence of the CYP1B1 polymorphism along with an MYOC polymorphic variant among the JOAG/POAG suspects needs additional studies to explore their combined role in the onset of glaucoma. CONCLUSIONS: This study reveals that MYOC mutation is primarily responsible for JOAG and adult-onset POAG in a family, emphasizing the importance of screening for this mutation at a younger age for early treatment.

Exploring mito-nuclear genetic factors in Leber's hereditary optic neuropathy: insights from comprehensive profiling of unique cases.

Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing. Interestingly, whole mtDNA sequencing revealed primary mtDNA mutations in 30 % of the probands (n=9), secondary mtDNA mutations in 40 % of the probands (n=12) and no mitochondrial changes in 30 % of individuals (n=9). Further, WES analysis determined pathogenic mutations in 11 different nuclear genes, especially in cases with secondary mtDNA mutations (n=6) or no mtDNA mutations (n=6). These findings provide valuable insight into LHON genetic predisposition, particularly in cases lacking primary mtDNA mutations. See also Figure 1(Fig. 1).

Mutation profile of neurodegenerative mitochondriopathy - LHON in Southern India.

BACKGROUND: Leber's Hereditary Optic Neuropathy (LHON) is a rare mitochondriopathy causing retinal ganglion cell degeneration resulting in central vision loss. It is caused by mitochondrial DNA (mtDNA) mutations and thus follows maternal inheritance pattern. METHODS: We analysed the whole mitochondrial genome in 100 South Indian LHON patients by utilizing Sanger and Next Generation Sequencing approaches. Haplogroup analysis was performed using HaploGrep2 to predict the risk group. Methylation changes in the mtDNA D-loop region were investigated by performing methylation-specific polymerase chain reaction (MSP). RESULTS: LHON associated mutations were detected in 55% of the patients of which 42% harboured the primary mutations and 13% harboured potentially pathogenic variants that were previously reported to cause LHON. The candidate mutations identified with confirmed pathogenicity are: m.11778G > A (38%), m.14484 T > C (3%), m.4171C > A (1%) and m.11696G > A (1%). MSP results demonstrated that the D-loop region was unmethylated in all the study subjects including mutation-positive patients, mutation-negative patients, asymptomatic carriers, and controls. Haplogroup-M was prevalent (69%) in the study cohort followed by R (14%), U (9%), N (3%), HV (2%), G (2%), and W (1%). The frequency of the predominant mutation m.11778G > A was found lower (Ì´ 11%) in haplogroup-U. CONCLUSIONS: South Indian LHON cohort shows a unique profile of mtDNA mutations and haplogroup association presumably with no role of D-loop methylation. MT-ND4, MT-ND5, and MT-ND1 serve as the hotspot genes in this cohort. The presence of LHON associated mutations in patients lacking the common primary mutations insists on the necessity of mitochondrial genome sequencing in individuals suspected with LHON.

Clinical reassessments and whole-exome sequencing uncover novel BEST1 mutation associated with bestrophinopathy phenotype.

BACKGROUND: The diagnosis of retinal dystrophies can be challenging due to the spectrum of protean phenotypic manifestations. This study employed trio-whole-exome sequencing (trio-WES) to unveil the genetic cause of an inherited retinal disorder in a south Indian family. MATERIALS AND METHODS: Proband's initial ophthalmic examinations was performed in the year 2016. WES was performed on a proband-parent trio to identify causative mutation followed by Sanger validation, segregation analysis, sequence and structure-based computational analysis to assess its pathogenicity. Based on the genetic findings, detailed clinical reassessments were performed in year 2020 for the proband and available family members. RESULTS: WES revealed a novel homozygous BEST1 mutation c.G310A (p.D104N) in the proband and heterozygous for the parents, indicating autosomal recessive inheritance. Segregation analysis showed heterozygous mutation in maternal grandfather and normal genotype for younger brother and maternal grandmother. Moreover, the structure-based analysis revealed the mutation p.D104N in the cytoplasmic domain, causing structural hindrance by altering hydrogen bonds and destabilizing the BEST1 protein structure. Proband's clinical assessments were consistent with autosomal recessive bestrophinopathy (ARB) phenotype. Additionally, characteristic absent light rise and decreased light peak-to-dark trough ratio (LP:DT) was observed bilaterally in EOG. CONCLUSIONS: Our study demonstrates the utility of WES and clinical re-evaluations in establishing the precise diagnosis of autosomal recessive bestrophinopathy associated with a novel mutation, thus expanding the BEST1-related mutation spectrum.

Whole-exome sequencing identifies multiple pathogenic variants in a large South Indian family with primary open-angle glaucoma.

PURPOSE: To identify the pathogenic variants associated with primary open-angle glaucoma (POAG) using whole-exome sequencing (WES) data of a large South Indian family. METHODS: We recruited a large five-generation South Indian family (n = 84) with a positive family history of POAG (n = 19). All study participants had a comprehensive ocular evaluation. We performed WES for 16 samples (nine POAG and seven unaffected controls) since Sanger sequencing of the POAG candidate genes (MYOC, OPTN, and TBK1) showed no genetic variation. We used an in-house pipeline for prioritizing the pathogenic variants based on their segregation among the POAG individual. RESULTS: We identified one novel and five low-frequency pathogenic variants with consistent co-segregation in all affected individuals. The variant c.G3719A in RPGR-interacting domain of RPGRIP1 that segregated heterozygously with the six POAG cases is distinct from variants causing photoreceptor dystrophies, reported affecting the RPGR protein complex signaling in primary cilia. The cilia in trabecular meshwork (TM) cells has been reported to mediate the intraocular pressure (IOP) sensation. Furthermore, we identified a novel c.A1295G variant in Rho guanine nucleotide exchange factors Gene 40 (ARHGEF40) and a likely pathogenic variant in the RPGR gene, suggesting that they may alter the RhoA activity essential for IOP regulation. CONCLUSION: Our study supports that low-frequency pathogenic variants in multiple genes and pathways probably affect Primary Open Angle Glaucoma's pathogenesis in the large South Indian family. Furthermore, it requires larger case-controls to perform family-based association tests and to strengthen our analysis.

Whole-Exome Sequencing Reveals Novel TSPAN12 Variants in Autosomal Dominant Familial Exudative Vitreoretinopathy.

Background: Familial exudative vitreoretinopathy (FEVR), a group of rare inherited retinal vascular disorders, is the major cause of vision loss in juveniles. At present, the diagnosis of FEVR remains difficult due to its clinical and genetic heterogeneities. Aims: To identify the causative genetic variants in two unrelated FEVR-affected families: one Indian family and one Chinese Han family. Materials and Methods: Five affected patients from two families were recruited for this study. Whole-exome sequencing was applied to the probands, and Sanger sequencing was performed for validation. Stringent whole-exome sequence data analyses were performed to evaluate all of the identified pathogenic variants. Results: Two novel variants in the TSPAN12 gene, were identified: a missense variant c.437 T > G (p.Leu146Arg); and a nonsense variant c.477 C > A (p.Cys159*). Both variants cosegregated with the disease in the investigated FEVR-affected families. Additionally, both variants inactivated the ability of TSPAN12 protein to enhance Norrin/ß-catenin signaling. Conclusion: This study expands the mutational spectrum of TSPAN12 for FEVR.

Clinical exome sequencing facilitates the understanding of genetic heterogeneity in Leber congenital amaurosis patients with variable phenotype in southern India.

BACKGROUND: Leber congenital amaurosis (LCA), primarily characterized by retinal degeneration is the most severe form of inherited retinal dystrophy (IRD) responsible for congenital blindness. The presence of phenotypic heterogeneity makes the diagnosis of LCA challenging, especially in the absence of pronounced disease pathognomonic, yet it can be well comprehended by employing molecular diagnosis. Therefore, the present study aimed to reveal the causative mutations in ten LCA patients with variable phenotypes using clinical exome sequencing (CES). METHODS: CES was performed in ten unrelated LCA patients. Ophthalmic information and family history of all patients were obtained to make a meaningful interpretation. The clinical exome data was analyzed and prioritized using a bioinformatics pipeline to identify mutations, which was further validated by Sanger sequencing. Segregation analysis was also performed on available family members. RESULTS: CES led to the identification of causative mutations in nine LCA patients. Seven patients harbored a mutation in six LCA candidate genes, including RPE65, LCA5 (n = 2), CRX, PRPH2, CEP290, and ALMS1, while two patients possess a mutation in IFT80 and RP1, known to cause other diseases. Three novel mutations in LCA5 (c.1823del), CRX (c.848del) and CEP290 (c.2483G > T) were identified. The current study reports for the first time, a mutation in PRPH2, CEP290, and ALMS1 from the Indian population. Additionally, we observed a novel association of LCA phenotype with IFT80 known to cause Jeune syndrome. Based on the genetic finding, the patient AS09, who harbored a mutation in the RP1 gene, was re-diagnosed with early-onset retinitis pigmentosa. CONCLUSION: In conclusion, the results underline the importance of CES in clinically diagnosed LCA patients with variable phenotypes. The correlation between mutations in candidate genes and clinical phenotypes, helps to refine the clinical diagnosis. However, molecular evaluation with a larger cohort of LCA patients is needed for better understanding of the mutational spectrum in southern India.

Catenin α 1 mutations cause familial exudative vitreoretinopathy by overactivating Norrin/ß-catenin signaling.

Familial exudative vitreoretinopathy (FEVR) is a severe retinal vascular disease that causes blindness. FEVR has been linked to mutations in several genes associated with inactivation of the Norrin/ß-catenin signaling pathway, but these account for only approximately 50% of cases. We report that mutations in α-catenin (CTNNA1) cause FEVR by overactivating the ß-catenin pathway and disrupting cell adherens junctions. We identified 3 heterozygous mutations in CTNNA1 (p.F72S, p.R376Cfs*27, and p.P893L) by exome sequencing and further demonstrated that FEVR-associated mutations led to overactivation of Norrin/ß-catenin signaling as a result of impaired protein interactions within the cadherin-catenin complex. The clinical features of FEVR were reproduced in mice lacking Ctnna1 in vascular endothelial cells (ECs) or with overactivated ß-catenin signaling by an EC-specific gain-of-function allele of Ctnnb1. In isolated mouse lung ECs, both CTNNA1-P893L and F72S mutants failed to rescue either the disrupted F-actin arrangement or the VE-cadherin and CTNNB1 distribution. Moreover, we discovered that compound heterozygous Ctnna1 F72S and a deletion allele could cause a similar phenotype. Furthermore, in a FEVR family, we identified a mutation of LRP5, which activates Norrin/ß-catenin signaling, and the corresponding knockin mice exhibited a partial FEVR-like phenotype. Our study demonstrates that the precise regulation of ß-catenin activation is critical for retinal vascular development and provides new insights into the pathogenesis of FEVR.

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract.

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10-16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 10-19), TMPRSS5 (rs4936279, P = 2.5 × 10-10), LINC01412 (rs16823886, P = 1.3 × 10-9), GLTSCR1 (rs1005911, P = 9.8 × 10-9), and COMMD1 (rs62149908, P = 1.2 × 10-8). The results suggest a strong link of age-related nuclear cataract with congenital cataract and eye development genes, and the importance of common genetic variants in maintaining crystalline lens integrity in the aging eye.

A hospital-based five-year prospective study on the prevalence of Leber's hereditary optic neuropathy with genetic confirmation.

Purpose: To estimate the prevalence of Leber hereditary optic neuropathy (LHON) along with genetic screening at a tertiary eye care center in southern India. Methods: Patients with LHON were identified at the Neuro-Ophthalmology Clinic, Aravind Eye Hospital (AEH; Madurai, India) from 2015 to 2019. Clinical data were collected along with blood samples. Genetic testing was performed for the confirmation of LHON using a multiplex PCR restriction fragment length polymorphism (RFLP) approach to detect the primary mutations 3460A, 11778A, and 14484C in mitochondrial DNA (mtDNA). Results: During the study period, 1,598,441 outpatients attended AEH of whom 40,527 were referred to the Neuro-Ophthalmology Clinic. Among them, 55 patients were diagnosed with LHON. The male to female ratio was 8.2:1.0, and the mean age at onset was 20.95 years (SD 8.940). The estimated prevalence was 1:737 or 13.57 per 10,000 (95% confidence intervals [CI] 10.23-17.66) at the Neuro-Ophthalmology Clinic. The frequency of primary mutations in the patients with LHON was determined as 43.6% (24/55), giving a prevalence of 1:1689 or 5.92 per 10,000 (95% CI 3.78-8.81). Conclusions: The high prevalence of LHON observed at a single hospital highlights the impact of the disease in southern India. As the epidemiology of LHON remains unexplored in this region, these findings will pave the way to evaluate the national prevalence. Further, screening the whole mitochondrial genome may help to increase the detection of mutations to estimate the accurate prevalence of the disease.

Prevalence and Pattern of Geographic Atrophy in Asia: The Asian Eye Epidemiology Consortium.

PURPOSE: Although there have been many population-based studies of age-related macular degeneration (AMD), only limited information is available in Asia on the epidemiology of geographic atrophy (GA). We aimed to determine the prevalence and patterns of GA through an analysis of multiple studies conducted within the Asian Eye Epidemiology Consortium (AEEC). DESIGN: Cross-sectional meta-analyses. PARTICIPANTS: A total of 97 213 individuals aged 40 years and older. METHODS: Data from 22 population-based studies from countries belonging to the AEEC were included. In all studies, AMD was defined on the basis of standardized grading systems. Geographic atrophy was defined as an area of pallor in the fundus with visibility of the underlying choroidal blood vessels and sharply defined borders. Random-effects meta-analysis was performed to estimate overall and age-, gender-, and region-specific pooled prevalence of GA. MAIN OUTCOME MEASURES: Prevalence of GA per 1000 persons. RESULTS: The mean age was 60.8 ± 10.0 years, and 42 673 (43.9%) were male. Overall, a total of 223 individuals (0.2%) had GA. The pooled overall prevalence of GA was 1.57 per 1000 persons (95% confidence interval [CI], 1.04-2.10), which was 3 times less than that of neovascular AMD of 5.20 per 1000 persons (95% CI, 3.97-6.43). Compared with those aged 50 to 59 years, the prevalence of GA increased from 0.34 per 1000 persons (95% CI, 0.07-0.62) to 2.90 per 1000 persons (95% CI, 1.55-4.25) in those aged ≥70 years. The GA prevalence per 1000 persons was similar between urban (2.22; 95% CI, 1.22-3.23) and rural residents (1.33; 95% CI, 0.70-1.96). Geographic atrophy was more prevalent in South Asia (based on studies from India and Nepal, 3.82 per 1000 persons; 95% CI, 1.72-5.93) compared with East Asia (based on studies from China, Korea, Hong Kong, Taiwan, and Japan, and the Singapore Chinese Eye Study, 0.76 per 1000 persons; 95% CI, 0.31-1.22, P = 0.005). CONCLUSIONS: Geographic atrophy is uncommon in Asian populations compared with those of European ancestry. Even within Asia, geographic differences in GA prevalence were seen. The findings of this meta-analysis suggest that better dissection of risk factors in the Asian population for GA may provide insights into the biological pathways that drive these late-stage manifestations, thus suggesting better targets for prevention.

Genetic characterization of Stargardt clinical phenotype in South Indian patients using sanger and targeted sequencing.

BACKGROUND: Stargardt disease 1 (STGD1; MIM 248200) is a monogenic form of autosomal recessive genetic disease caused by mutation in ABCA4. This gene has a major role in hydrolyzing N-retinylidene-phosphatidylethanolamine to all-trans-retinal and phosphatidylethanolamine. The purpose of this study is to identify the frequency of putative disease-causing mutations associated with Stargardt disease in a South Indian population. METHODS: A total of 28 clinically diagnosed Stargardt-like phenotype patients were recruited from south India. Ophthalmic examination of all patients was carefully carried out by a retina specialist based on the stages of fundus imaging and ERG grouping. Genetic analysis of ABCA4 was performed for all patients using Sanger sequencing and clinical exome sequencing. RESULTS: This study identified disease-causing mutations in ABCA4 in 75% (21/28) of patients, 7% (2/28) exhibited benign variants and 18% (5/28) were negative for the disease-causing mutation. CONCLUSION: This is the first study describing the genetic association of ABCA4 disease-causing mutation in South Indian Stargardt 1 patients (STGD1). Our findings highlighted the presence of two novel missense mutations and an (in/del, single base pair deletion & splice variant) in ABCA4. However, genetic heterogeneity in ABCA4 mutants requires a larger sample size to establish a true correlation with clinical phenotype.

Identification of Novel Mutations in the FZD4 and NDP Genes in Patients with Familial Exudative Vitreoretinopathy in South India.

Background: Familial exudative vitreoretinopathy (FEVR) is an inheritable retinal vascular disease, which often leads to severe vision loss and blindness in children. However, reported mutations can only account for 50-60% of patients with FEVR. The purpose of this study was to identify novel frizzled class receptor 4 (FZD4) and Norrin cystine knot growth factor NDP (NDP) mutations in a cohort of Indian patients with FEVR by whole-exome sequencing. Methods: We performed data filtering and bioinformatic analyses. Results: Two novel heterozygous mutations in FZD4 gene were identified, each in two different families: c.1499_1500del [p.500_500del] and c.G296C [p.C99S]. One novel mutation in NDP in another family was identified: c.A256G [p.K86E]. All FZD4 mutations affected conserved amino acid residues and were absent in 1000 control individuals. To assess the effect of these FZD4 mutations on the biological activity of the protein, we introduced each FZD4 mutation into FZD4 cDNA by the site-directed mutagenesis techniques. A Norrin/beta-catenin pathway-based luciferase reporter assay revealed that the c.1499_1500del failed to activate the luciferase reporter; in contrast, compared with the wild-type FZD4 protein, the, c.G296C [p.C99S] mutation exhibited increased luciferase reporter activity. Conclusion: Our study found two novel FZD4 mutations, with opposite effects regarding functional expression levels in Indian patients with FEVR and expands on the mutational spectrum of FZD4 in Indian FEVR patients.

Mutant RAMP2 causes primary open-angle glaucoma via the CRLR-cAMP axis.

PURPOSE: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease. METHODS: Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study. RESULTS: Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice. CONCLUSION: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.

The protective variant rs7173049 at LOXL1 locus impacts on retinoic acid signaling pathway in pseudoexfoliation syndrome.

LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A>G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10-31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

Genetic variants in a sodium-dependent vitamin C transporter gene and age-related cataract.

BACKGROUND: Cataract is a major health burden in many countries and a significant problem in India. While observational studies show lower cataract risk with increasing dietary or plasma vitamin C, randomised controlled trials of supplements have been negative. Genetic variants in vitamin C transporter proteins (SLC23A1), especially rs33972313, may provide evidence on a causal association of vitamin C with cataract. METHODS: We used data from a randomly selected population-based study in people aged 60 years and above in north and south India. Of 7518 sampled, 5428 (72%) were interviewed for socioeconomic and lifestyle factors, attended hospital for lens imaging and blood collection and were subsequently genotyped for rs33972313 and rs6596473. Mixed or pure types of cataract were graded by the Lens Opacity Classification System III as nuclear (2404), cortical (494) or posterior subcapsular cataract (PSC) (1026); 1462 had no significant cataract and no history of cataract surgery and 775 had bilateral aphakia/pseudophakia. RESULTS: rs33972313 was associated with cortical (OR 2.16; 95% CI 1.34 to 3.49, p=0.002) and PSC (OR 1.68; 95% CI 1.06 to 2.65, p=0.03) but not with nuclear cataract. In analyses of pure cataracts, associations were found only between rs33972313 and pure cortical cataracts (OR 2.29; 95% CI 1.12 to 4.65, p=0.03) and with a standardised cortical opacity score. There was no association with rs6596473 and any cataract outcomes. CONCLUSIONS: Using an established genetic variant as a proxy for lifetime ascorbate concentrations, our results support a causal association of vitamin C with cataract.