Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis

Purpose: Leber congenital amaurosis (LCA) is one of the most common causes of hereditary blindness in infants. To date, mutations in 13 known genes and at two other loci have been implicated in LCA causation. An examination of the known genes highlights several processes which, when defective, cause LCA, including photoreceptor development and maintenance, phototransduction, vitamin A metabolism, and protein trafficking. In addition, it has been known for some time that defects in sensory cilia can cause syndromes involving hereditary blindness. More recently evidence has come to light that non-syndromic LCA can also be a “ciliopathy.” Methods: Here we present a homozygosity mapping analysis in a consanguineous sibship that led to the identification of a mutation in the recently discovered LCA5 gene. Homozygosity mapping was done using Affymetrix 10K Xba I Gene Chip and a 24.5cM region on chromosome 6 (6q12- q16.3) was identified to be significantly homozygous. The LCA5 gene on this region was sequenced and cDNA sequencing also done to characterize the mutation. Results: A c.955G>A missense mutation in the last base of exon 6 causing disruption of the splice donor site was identified in both the affected sibs. Since there is a second consensus splice donor sequence 5 bp into the adjacent intron, this mutation results in a transcript with a 5 bp insertion of intronic sequence, leading to a frameshift and premature truncation. Conclusions: We report a missense mutation functionally altering the splice donor site and leading to a truncated protein. This is the second report of LCA5 mutations causing LCA. It may also be significant that one affected child died at eleven months of age due to asphyxia during sleep. To date the only phenotype unambiguously associated with mutations in this gene is LCA. However the LCA5 gene is known to be expressed in nasopharynx, trachea and lungs and was originally identified in the proteome of bronchial epithelium ciliary axonemes. The cause of death in this child may therefore imply that LCA5 mutations can in fact cause a wider spectrum of phenotypes including respiratory disease

A 32 kb Critical Region Excluding Y402H in CFH Mediates Risk for Age-Related Macular Degeneration

Complement factor H shows very strong association with Age-related Macular Degeneration (AMD), and recent data suggest that multiple causal variants are associated with disease. To refine the location of the disease associated variants, we characterized in detail the structural variation at CFH and its paralogs, including two copy number polymorphisms (CNP), CNP147 and CNP148, and several rare deletions and duplications. Examination of 34 AMD-enriched extended families (N = 293) and AMD cases (White N = 4210 Indian = 134; Malay = 140) and controls (White N = 3229; Indian = 117; Malay = 2390) demonstrated that deletion CNP148 was protective against AMD, independent of SNPs at CFH. Regression analysis of seven common haplotypes showed three haplotypes, H1, H6 and H7, as conferring risk for AMD development. Being the most common haplotype H1 confers the greatest risk by increasing the odds of AMD by 2.75-fold (95% CI = [2.51, 3.01]; p = 8.31×10−109); Caucasian (H6) and Indian-specific (H7) recombinant haplotypes increase the odds of AMD by 1.85-fold (p = 3.52×10−9) and by 15.57-fold (P = 0.007), respectively. We identified a 32-kb region downstream of Y402H (rs1061170), shared by all three risk haplotypes, suggesting that this region may be critical for AMD development. Further analysis showed that two SNPs within the 32 kb block, rs1329428 and rs203687, optimally explain disease association. rs1329428 resides in 20 kb unique sequence block, but rs203687 resides in a 12 kb block that is 89% similar to a noncoding region contained in ΔCNP148. We conclude that causal variation in this region potentially encompasses both regulatory effects at single markers and copy number

Knowledge Priorities on Climate Change and Water in the Upper Indus Basin: A Horizon Scanning Exercise to Identify the Top 100 Research Questions in Social and Natural Sciences

River systems originating from the Upper Indus Basin (UIB) are dominated by runoff from snow and glacier melt and summer monsoonal rainfall. These water resources are highly stressed as huge populations of people living in this region depend on them, including for agriculture, domestic use, and energy production. Projections suggest that the UIB region will be affected by considerable (yet poorly quantified) changes to the seasonality and composition of runoff in the future, which are likely to have considerable impacts on these supplies. Given how directly and indirectly communities and ecosystems are dependent on these resources and the growing pressure on them due to ever-increasing demands, the impacts of climate change pose considerable adaptation challenges. The strong linkages between hydroclimate, cryosphere, water resources, and human activities within the UIB suggest that a multi- and inter-disciplinary research approach integrating the social and natural/environmental sciences is critical for successful adaptation to ongoing and future hydrological and climate change. Here we use a horizon scanning technique to identify the Top 100 questions related to the most pressing knowledge gaps and research priorities in social and natural sciences on climate change and water in the UIB. These questions are on the margins of current thinking and investigation and are clustered into 14 themes, covering three overarching topics of ‘governance, policy, and sustainable solutions’, ‘socioeconomic processes and livelihoods’, and ‘integrated Earth System processes’. Raising awareness of these cutting-edge knowledge gaps and opportunities will hopefully encourage researchers, funding bodies, practitioners, and policy makers to address them

Stage 5 retinopathy of prematurity: An update

Retinopathy of prematurity (ROP) is one of the most common causes of preventable blindness in children. In spite of the availability of various treatment options, and favorable results with timely intervention, many infants present to the ophthalmologists in the advanced end stage of the disease due to lack of awareness especially in the developing nations. This blinding or Stage 5 of ROP presents with total retinal detachment and has to be managed surgically. The surgical techniques for Stage 5 ROP are unique and demanding. The successful anatomical results after surgery are only seen in 20%–50% of cases. In spite of a successful anatomical result, the visual outcome may be slow and limited. The use of newer pharmacological adjuncts has shown promising results. Because of heterogeneity of presentation of the disease severity, a genetic predisposition has also been proposed. A concerted effort from the pediatricians, ophthalmologists, and healthcare workers is required to establish effective screening and treatment guidelines to prevent blindness due to ROP. Till then surgical management has to be done. Parents must be educated regarding the limited visual benefits of surgery and the need for prolonged follow-up. This review gives a comprehensive overview of the pathogenesis, clinical aspects, surgical interventions, and their outcomes and future prospects of Stage 5 ROP

Paediatric choroidal neovascular membrane secondary to toxoplasmosis treated successfully with anti-vascular endothelial growth factor

The purpose of this report was to evaluate the role anti-VEGF in management of CNVM secondary to ocular toxoplasmosis. Young female diagnosed as a case of bilateral ocular toxoplasmosis presented with complaints of diminution of vision in the right eye. Fundus examination showed an active CNVM adjacent to toxoplasmosis scar. In view of active CNVM, patient was administered intravitreal ranibizumab. A total of 2 injections of intravitreal ranibizumab were given. Fundus showed a scarred CNVM adjacent to the toxoplasma scar with no clinical signs of activity. Anti-VEGF therapy has been successfully used to improve visual and anatomical outcome in juxtafoveal (deleted subfoveal)CNVM secondary to toxoplasmosis

Late dislocation of in-the-bag intraocular lenses in uveitic eyes: An analysis of management and complications

Aim: An analysis of late in-the-bag dislocation of intraocular lenses (IOL), in uveitic eyes. Setting: Referral uveitis clinic. Design: Retrospective case series. Materials and Methods: All case records of eyes with chronic uveitis that had phacoemulsification with IOL implantation, at a referral uveitis clinic between February 1997 and January 2015 were retrieved and analyzed. Only those eyes with no documented intraoperative complication and no predisposing risks to IOL dislocation, such as pseudoexfoliation, high myopia, trauma, and prior VR surgery were included in this study. Results: A total of 581 eyes with chronic uveitis underwent phacoemulsification with IOL implantation under steroid cover from February 1997 to December 2015. Out of these 581 eyes, 10 patients (11 eyes) had experienced late in-the-bag IOL dislocation (1.89%). All 11 eyes had chronic intermediate uveitis. The mean duration from the time of cataract surgery to IOL dislocation was 11.24 years. 5 out of 11 eyes had pars plana vitrectomy (PPV) with IOL removal with 4-point sutured scleral fixated IOL. Two out of 11 eyes had PPV with in-the-bag IOL re-fixation. Out of 11, 2 eyes had PPV with IOL removal only. Remaining 2 eyes of 2 patients did not opt for surgery. Out of 11, 8 eyes had improved vision at last follow-up. Conclusions: In-the-bag dislocation of IOL is a rare late complication in uveitic eyes. With tight perioperative inflammatory control, scleral-fixated posterior chamber intraocular lens or IOL re-fixation are good options of restoring vision in these high-risk eyes