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«Mission To eliminate needless blindness by providing evidence through research and evolving methods to translate existing evidence and knowledge into ...»

-- [ Page 1 ] --

Mission

To eliminate needless blindness by providing evidence

through research and evolving methods to translate

existing evidence and knowledge into effective action.

REPORT 2009-10

introduction

The Dr. G. Venkataswamy Eye Research Institute with its state-of-the-art infrastructural facility

has been able to make significant contributions in understanding the basic biological mechanisms

of eye diseases. Aravind Eye Care System is unique in having the activities of Aravind Medical Research Foundation, Aravind Eye Hospitals, Aurolab and Lions Aravind Institute of Community Ophthalmology integrated to achieve our Mission “To eliminate needless blindness” Molecular genetics of eye diseases is a proven approach to understand the disease mechanism. At AMRF considerable effort is underway to use this approach to examine several eye diseases (diabetic retinopathy, age related cataract, age related macular degeneration, leber congenital amaurosis, albinism). Apart from the generation of basic information, identification of those genes that are directly involved in the disease process as well as those genes that co-segregate with a particular disease will be of clinical importance. Single Nucleotide Polymorphism (SNP) based approaches are vigorously perused. However, the usefulness of these SNP in clinical medicine is yet to be proven for eye diseases. Recent explosion in the application of next generation and third generation sequencing technologies allows the comparative sequencing of several genomes to understand the contribution of SNPs in disease process and clinical medicine. In the coming years comparative whole genome sequencing approach will be of immense value in the examination of eye diseases.

Protein biomarkers could be used in the analysis of disease process as well as disease management.

Disease prediction, disease progression, staging of the disease state and determination of efficacy of disease treatment are all areas of protein biomarkers studies. At Aravind Medical Research Foundation all these areas are explored from the perspective of eye diseases. Protein expression, protein quantitation and determination of protein isoform changes are all areas of intense study.

A proteomics laboratory with most modern instruments such as multilaser Typhoon scanner and LC-MS/MS: nano LC- Micro ToF Q Mass Spectrometer has been in operation. Infectious fungal keratitis, diabetic retinopathy, glaucoma, CHED and FECD are some of the disease currently studied using proteomic approaches.

In addition, in the area of translational research we have developed a method to identify and expand in culture adult epithelial stem cells. The stem cell rich cultured epithelium was useful to bring back the vision to people, blind in both eyes. Now, this program is strengthened in the newly established GMP facility.

contEnts ARAvIND MEDICAL RESEARCH FOu

–  –  –

Basic rEsEarch Molecular genetics of leber congenital amaurosis in South Indian population Principal investigator : P. Sundaresan, Aravind Medical Research Foundation (AMRF)-Madurai Co-investigator : P. vijayalakshmi, Aravind-Madurai Research scholar : Anshuman verma Funding agency : ICMR, uGC (Fellowship) Duration : 2008 - 2013 Leber’s Congenital Amaurosis (LCA) is a genetic disorder in which retinal dysfunction causes severe visual impairment often from birth or early stage of childhood. The vision loss is accompanied by nystagmus and sluggish eye pupil responses. Other features like high refractive errors, photoaversion, nyctalopia, pressing and poking of eyes, keratoconus, cataract etc. may also be associated. The disease is clinically confirmed by certain additional criteria like presence of reduced ERG and exclusion of patients having hearing loss.

Currently there is no treatment available for LCA but one of the emerging possible treatments for a particular type of LCA is gene therapy which has been found successful in animal models like mice and dog. In human it is under phase 2 clinical trial after crossing the promising phase 1 trial results.

The gene therapy process essentially requires extensive genetic studies prior to its establishment and application.

So far 15 genes involved in various functional pathways have been identified for disease causing mutation. This accounts for about 60% of LCA cases and for remaining 40% the new candidate genes may have been involved. Our recent report suggests that mutations which are common in European population are rare in India. Therefore, Indian cohort of LCA patients may be useful resource for identifying novel mutations and new LCA genes. In this context we have been screening many LCA genes in Indian LCA cases which include CRX, RPE65, TuLP1, SPATA7, and some predicted LCA genes. The study is planned for screening of all known and many possible Master mix preparation for PCR unknown genes through new generation sequencing which will facilitate the identification of additional genes for LCA.

Molecular genetic analysis of fuchs endothelial corneal dystrophy Principal investigator : P. Sundaresan, AMRF-Madurai Co-investigator : M. Srinivasan, Aravind-Madurai J. Arun Kumar, Aravind-Madurai Research scholar : b. Hemadevi Funded by : Department of Science and Technology Duration : 2007 - 2010 Fuchs Endothelial Corneal Dystrophy (FECD) is a degenerative, bilateral, often asymmetric and slowly progressive disorder. Due to endothelial dysfunction and loss of cells with FECD progression leads to corneal decompensation and impaired vision. The genotypic approach will provide better understanding, identification of the underlying genetic defects and in future enhance the possibility of medical intervention using conventional pharmacological approaches or gene therapy. Heterozygous mutations in the SLC4A11 gene are known to be associated with the late-onset FECD. Therefore we screened for SLC4A11 gene variants in Indian FECD patients.





Eighty patients with clinically diagnosed FECD and 100 age matched normal individuals were recruited. Genomic DNA was isolated from peripheral blood leukocytes. Mutations in SLC4A11 coding regions were screened using bi-directional sequencing. Fischer’s exact test or Pearson’s chi squared test were used to predict the statistical association of genotypes with the phenotype. In the screening of SLC4A11 gene, novel c.1659CT, c.1974CT and reported c.405GA, c.481AC and c.639GA variants were identified. However all the variations were also present in unaffected control.

This is the first report analysing SLC4A11 gene in a larger series of Indian patients having FECD.

Merely silent changes, which showed statistically insignificant association with FECD, were identified.

These results suggest that SLC4A11 gene may not be responsible for FECD in patients examined in this study.

Association studies on diabetic retinopathy with type 2 diabetes in South Indian population Principal investigator : P. Sundaresan, AMRF-Madurai Co-investigator : P. Namperumalsamy, Aravind-Madurai : R. Kim, Aravind-Madurai : Anand Rajendran, Aravind-Madurai Collaborator : J. Fielding Hejtmancik, NEI/NIH, bethesda, uSA Research scholar : b. Suganthalakshmi Funded by : TIFAC-CORE in DR, CSIR and NIH visiting Fellowship, NIH, bethesda, Maryland, uSA The aim of the study was to evaluate SNPs in ten candidate genes, including the RAGE, PEDF or SERPINF1, AKR1b1, EPO, ICAM-1, HFE, EDN1, HTRA1, (previously reported) CFH and ARMS2 were chosen to investigate whether alleles or genotypes of these markers are associated with DR in an Indian population. The possibility of association between polymorphisms of ten genes and DR was examined by genotyping 15 single nucleotide polymorphisms and one dinucleotide repeat polymorphism in 211 diabetes patients with retinopathy (DR) and 237 diabetes patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 134 DR and 122 DNR patients. Among the ten loci (16 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.006), compared to DNR, including the genotypes (GG, P=0.006; GA, P=0.009), with the GG genotype OR being 2.25 (95% CI-1.23-4.12). SNP rs2070600 further showed significant association with DR (P=0.002) when the sample size was increased by adding the confirmation cohort (allelic P 0.01). In HTRA1, rs11200638 (GA), showed marginal significance with DR (P=0.04). No statistical Genetic analysis for Polymorphism screening significance was observed for SNPs in the other eight genes studied.

This is the first report analysing the polymorphisms in PEDF, EPO, ICAM-1, HFE, EDN1, HTRA1, CFH and ARMS2 gene in large number of samples for DR case control association study in Indian population.

Genetic and functional dissection of FOXL2 gene involved in the pathogenesis of the Blepharophimosis Syndrome (BPES) Principal investigator : P. Sundaresan, AMRF-Madurai Co-investigator : usha Kim, Aravind-Madurai Collaborator : Reiner Albert vEITIA, Paris Research scholar : C. Jayashree Funded by : Indian Council of Medical Research Duration : 2008 - 2010 25 bPES affected families and a total of 100 age matched controls were recruited for the genetic study. Among 25 bPES affected cases collected, 12 cases are familial and 13 are sporadic. In these, 4 reported mutations y91X, S217C, A179G, A224_A234dup and three novel mutations W98R, L108P, A228_A232dup in familial cases and three novel and two reported mutations from sporadic cases were identified using AbI 3130 genetic analyser.

Two novel mutations (p.Leu108Pro, DNA sequencing using ABI 3130 Genetic Analyser p.Ala253fs) and one reported mutation (pSer217Cys) were taken for functional analysis.

To assess the effect of mutations, the transiently transfected wild type and missense (S217C, L108P), frame shift (p.A253fsX272) mutants were fused with plasmid containing green fluorescent protein (GFP) in COS-7 cells. Wild type FOXL2 localises completely to the nucleus in almost all cells. In the case of L108P mutant, it produces 47% nuclear aggregates and 51% of cytoplasmic aggregates in the localisation study. Another missense mutant S217C was mislocalised in cytoplasm. In the (p.A253fsX272) 5bp out frame mutant shows that a fusion protein is indeed produced and observed as 14% cytoplasmic decoration. These findings suggest that impaired protein is unable to accomplish a normal function.

Identification of genetic defects occurring in Indian oculocutaneous (OCA) and ocular albinism (OA) families Principal investigator : P. Sundaresan, AMRF-Madurai Co-investigator : P. vijayalakshmi, Aravind-Madurai Asim Kumar Sil, vivekananda Misssion Ashram Netra Niramay Niketan, West bengal Research scholar : K. Renugadevi Funded by : Department of biotechnology, New Delhi Duration : 2006 - 2009 While the previous study for mutations in all the known TyR, P, TyRP1, MATP and GPR 143 candidate genes screened twenty three familial cases, the present study aims to screen for the sporadic cases in OCA and OA.

Large panels of sporadic samples were collected from 60 different families in southern and eastern part of Indian cohort. One hundred normal individuals without any ocular anomalies were recruited as a control to confirm the sequence pattern of the novel mutations or polymorphisms Sample preparation for sequencing reactions which were identified in the study cases. Genomic DNA was isolated from peripheral blood leukocytes and used as a template for Polymerase Chain Reactions. Mutations in exon-intron boundaries and exonic regions were analysed by bi-directional sequencing using AbI 3130 genetic analyzer. Screening of TyR gene in these sporadic cases revealed the previously reported Arg278X, Arg299His, Gly419Arg, Gln326X, Asp383Asn, Arg402X, c.1379del2bp (TT) mutations and Asp125Asn, Tyr192Ser, Arg402Gln SNPs.

The following SNPs were identified in other candidate genes: OCA2 gene - one novel SNP IvSXX+4A/G; TyRP1 gene - one reported SNP Arg87Arg; MATP gene - three reported SNPs-Thr 329Thr, Leu374Phe, rs45552240-3’uTR and GPR143 gene, one reported SNP - IvS6+10C/G. Among these candidate genes, TyR gene mutations were observed in most of the sporadic cases. Therefore results suggest that prevalence of OCA type 1 is higher than the other OCA types in Indian cohort.

Molecular genetics of keratoconus Principal investigator : P. Sundaresan, AMRF-Madurai Co-investigator : M. Srinivasan, Aravind-Madurai Manoranjan Das, Aravind-Madurai Research scholar : P. Mohanapriya Funded by : ALCON - Aravind Eye Care System Duration : 2008 - 2011 Keratoconus is a bilateral, non-inflammatory, chronic and asymmetric thinning disorder of the cornea that leads to progressive myopic and irregular astigmatism.

visual system homeobox gene (vSX1), which is expressed in developing cornea, is known to be associated with keratoconus. Therefore, the main objective of the study is to screen for the mutations in the vSX1 gene. So far, 100 patients with clinically diagnosed keratoconus, 100 age matched controls were recruited for the study. Genomic DNA was isolated from peripheral blood leukocytes. Entire coding regions of vSX1 gene were screened for mutations in 26 keratoconus patients and 5 controls by bidirectional sequencing using AbI 3130 genetic analyser.

Among 26 samples screened, two reported SNPs, rs12480307 (A/G) in exon 3 and rs6138482 (G/A) in intron 3 have been identified. One variation IvS3-23CT has also identified in one sample, which needs to be confirmed by screening more number of samples. We are in the process of screening the remaining samples to identify the possibility of association of these polymorphisms and keratoconus in our population.

Biophysical characterisation of human myocilin and glaucoma database Principal investigator : S. Krishnaswamy, Madurai Kamaraj university, Madurai Co-investigator : P. Sundaresan, AMRF-Madurai S. R. Krishnadas, Aravind-Madurai Research scholars : Prasanthi N, Eswari P.J, Rangachari K Funded by : Department of biotechnology, New Delhi Duration : 2006 - 2009 The importance of the present study is to characterise human myocilin protein (55 kDa mol wt, 504aa, Swissprot Q99972) encoded by MyOC gene, which is directly linked to both juvenile and primary open-angle glaucomas.



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