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«Aravind Medical Research Foundation is recognized as Scientific and Industrial Research Organization (SIRO) by the Department of Scientific and ...»

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Aravind Medical Research Foundation is recognized as

Scientific and Industrial Research Organization (SIRO) by the

Department of Scientific and Industrial Research (DSIR)

MISSION

To eliminate needless blindness by providing

evidence through research and evolving methods

to translate existing evidence and knowledge

into effective action.

BASIC RESEARCH IN

OPHTHALMIC SCIENCES

Annual Report 2012 - 2013 Much has been done, but much remains to be done… we look to the future with renewed strength to continue the mission of providing quality eye care and hope that some of what we have learned will be useful to other eye care workers around the world.

ARAVIND MEDICAL RESEARCH FOUNDATION

BOARD OF MANAGEMENT

mr. r.D. thulasiraj, Dr. P. NamPerumalsamy, Dr. G. Natchiar, ms, Do er. G. sriNivasaN, be, ms mba ms, fams Dr. r. Kim, Do., DNb Dr. s.r. KrishNaDas, Dr.N.veNKatesh PrajNa Dr. s. araviND, ms, mba Do., DNb., frcophth Do., DNb

RESEARCH ADVISORY COMMITTEE INSTITUTIONAL REVIEW BOARD (IRB)

MEMBERS Chairman Chairman Dr. P. NamPerumalsamy ms. shobhaNa ramaChaNDhraN Chairman - Emeritus Managing Director Aravind Eye Care System TVS Sri Chakra Ltd.

1, Anna Nagar, Madurai – 625 020 Madurai Member-Secretary Member-Secretary Dr.Vr. muthukkaruPPaN Dr. lalitha PrajNa Director - Research Chief Microbiolgist Aravind Medical Research Foundation Aravind Eye Hospital 1, Anna Nagar, Madurai – 625 020 1, Anna Nagar, Madurai - 625 020 Members Members Dr. C. mohaN rao Prof. C. sriNiVasaN Director UGC Emeritus Professor Centre for Cellular & Molecular Biology School of Chemistry, Madurai Kamaraj University Uppal Road, Hyderabad – 500 007 7th Street, Kalvi Nagar, Nagamalai, Madurai Dr. kumaraVel somasuNDaram Dr. l. thayumaNaVaN Associate professor Microbiology and Cell Biology Sr. Consultant, Gastroenterologist Indian Institute of Science Vadamalayan Hospital, Madurai - 625 002 Bangalore – 560 012 Dr. t.s.

–  –  –

Effort to understand eye diseases and application of the research findings at the patient care level has been our major focus this year also. Apart from the continuation of the ongoing activities AMRF embarked on a major research program on fungal keratitis. This group has received major funding in the form of a program support from the Department of Biotechnology, Government of India, for fungal keratitis research.

This support allowed the institute to strengthen the Proteomics research area. The grant made it possible for the institute to procure a state of art Mass spectrometer, Oribitrap Velos Pro, for the study of proteomics of eye diseases. This will allow the proteomics group to do the deep analysis of expression and quantitation of proteins and their isoforms. Having this grant allowed the proteomics group to successfully attract funding from Cognizant industry also. This group, with faculty and senior investigators with Ph.D degree, will be a model for other groups to consolidate and attract major funding.

Molecular genetics group continues to explore the genetic organization and disease specific markers for various eye diseases. Apart from looking at known and new markers and mutations this group also looks at the whole genome using genome wide association approach for the discovery of population specific mutations. They have also tried to extend their findings to clinical use with close collaboration with clinicians.

Stem cell biology group is undertaking major efforts to understand the biology of buccal stem cells and also keeps in focus the application aspects. The new area of focus is role of micro RNAs in stem cells. This is an active area of research and hopefully some novel finding will emerge from this analysis.

Ocular pharmacology group is continuing its efforts to bring about drugs based on the findings in diabetic retinopathy and age related macular degeneration. The Human Organ Culture Anterior Segment System is now optimized and new results are emerging from this novel experimental system, since there is no in vivo system available for glaucoma studies.

Microbiology group has done significant work in bacterial keratitis, particularly in the determination of virulence factors in Pseudomonas keratitis. This group is also exploring the role of micro RNAs in pathogenic process.

The new group on Bioinformatics has started its activities in the structural biology of single nucleotide variants. This group also helps in setting upvarious analysis platforms for NGS data. The analysis of whole genome sequence data on pathogenic bacteria by this group has helped in the identification novel factors involved in pathogenesis.

Faculty of the institute also has taken up various teaching activities in the form of workshops and short terms hands on training activities.

MOLECULAR GENETICS

Ongoing research programmes of this group are related to commonly occurring eye diseases in Indian population like Diabetic retinopathy, Glaucoma, Cataract, Corneal dystrophies and Retinal dystrophies.

Currently gene therapy is available for Lebers Congenital Amaurosis (LCA). To implement gene therapy in Indian population, the department has been screening RPE65 genes mutations in LCA patients who can be benefited from this therapy in future. The department has recently initiated studies to explore mitochondrial involvement in Primary Open Angle Glaucoma and association of microRNA with keratoconus in collaboration with Queens University, Belfast, UK. The department has identified a candidate gene for ocular coloboma in collaboration with Center for Human Molecular Biology and Genetics, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Sichuan, China. Recently it has also initiated the study to characterize the gene expression profile of normal, diabetic and diabetic retinopathy human donor eye balls obtained from Rotary Aravind International Eye Bank. The Department has also analysed several families with Retinoblastoma and made significant contributions in the management of Retinoblastoma by identifying RB1 mutations in new borns and treating the disease at an early stage. The department organized a workshop entitled “Vision Genomics” to motivate young researchers to involve in basic/ophthalmic research. Many of the study designs of the department emphasize the molecular mechanisms of various eye diseases at the gene expression level.





Molecular genetics of Leber Congenital Amaurosis in South Indian population Investigators : P. Sundaresan, Aravind Medical Research Foundation, Madurai P. Vijayalakshmi, Aravind Eye Hospital, Madurai Ph.D. Scholar : Anshuman Verma Funding agency : Indian Council of Medical Research (ICMR), University Grant Commission (UGC) Fellowship Background and aim Leber congenital amaurosis (LCA) is the most severe form of visual impairment found in children. At present, more than twenty genes have been reported for LCA, and among them RPE65 is a likely candidate for gene therapy. The aim of this study is to perform a comprehensive screening of LCA genes emphasizing RPE65. In this study, three sequencing technologies were applied - (a) Direct sequencing to screen RPE65 mutations in 30 LCA probands (b) Microarray based comprehensive detection of all known LCA pathogenic variations in 25 LCA patients excluded for RPE65 mutations (c) Next generation sequencing (NGS) based targeted enrichment in a separate set of 25 LCA pooled DNA samples was carried out to screen coding regions of 56 genes, including15 known and 41 predicted LCA genes. In addition, in silico characterization of the identified mutations and related clinical phenotype of patients were studied.

The combined approach of RPE65 mutational screening with Asper chip analysis revealed ten different disease causing variations in 6 LCA genes from 11 LCA patients. The targeted resequencing of 56 genes uncovered total 97 variations, mostly in known LCA genes and A few predicted genes. However, most of the variations were in flanking intronic regions and found to be as polymorphism.

Implication of the data This is the first study, which applies advanced techniques for a comprehensive mutational analysis of LCA genes in South Indian cohort. The combined approach of direct sequencing and Asper chip analysis was instrumental to identify pathogenic mutations in 36.6 % of the patients with the major involvement of RPE65 (16.6%), GUCY2D (10%), RPGRIP1 (3.3%), AIPL1 (3.3%), CRX and IQCB1 (3.3%). In this study, RPE65 mutations were found to be the main cause for LCA followed by GUCY2D. The NGS based targeted resequencing can be productive for the comprehensive screening of a large number of genes but are unfavourably influenced by various sequencing steps in pooled samples, resulting in its limitation to identify rare pathogenic variations.

Molecular genetics and functional analysis of candidate genes associated with microphthalmia, anophthalmia and coloboma Investigators : Dr. P. Sundaresan (Aravind Medical Research Foundation, Madurai) Dr. P. Vijayalakshmi (Aravind Eye Hospital, Madurai) Dr. S. K. Kedia (Sadar Hospital, Ara, Bihar) Collaborator : Dr. Yang Zhenglin, Sichuan Academy of Medical Sciences, China PhD Scholar : Mr. Sushil Kumar Dubey Funded Agency : ICMR Background and aim Microphthalmia, anophthalmia and coloboma (MAC) are a group of congenital eye diseases that represent important causes of paediatric blindness. These ocular disorders have variable and poorly understood effects that extend all the way to total blindness. Extensive studies of these ocular disorders have reported mutations in a large number of genes and also several chromosomal aberrations in various populations.

Lack of similar studies for Indian population limits the knowledge regarding the genetics of these globe anomalies. This study aims to find out the spectrum of genetic variations in candidate genes and their role in causing disease.

DNA samples of 65 MAC patients were evaluated for mutations and sequence variants in the candidate genes by direct sequencing approach. All the exons along with flanking exon- introns boundaries of RAX, OTX2, SOX2 and ABCB6 genes were screened in all MAC samples. Hundred ethnically-matched healthy control samples were also sequenced to confirm the identified variants as patient specific. Comparative sequence analysis of RAX, OTX2, SOX2 and ABCB6 genes with their homologs across different species was done to determine whether the mutations are present in the conserved domains. Mutation identified in ABCB6 gene at AMRF was functionally characterized in Zebrafish by Sichuan Provincial Key Laboratory for Human Disease Gene, Sichuan Academy of Medical Sciences Affiliated Hospital, Sichuan, China.

Five novel mutations were identified in RAX, OTX2, SOX2 and ABCB6 genes in this cohort. A homozygous substitution mutation p. Arg179Trp, found in one bilateral anophthalmia patient, was identified in RAX gene. Three heterozygous mutations p. Pro142Fs [c. 426insC (in a proband with bilateral anophthalmia)], p. Thr186Fs [c. 558delC (in one proband with microphthalmia in one eye and anophthalmia in other)] and a compound heterozygote p. Gln104X, p. Gln106 His (in one patient with microphthalmia) were identified in OTX2. These three mutations in OTX2 gene cause premature termination of the coding sequence. Mutation p. Val303Val was identified in SOX2 gene in only one patient with microphthalmia and iris coloboma. Screening of ABCB6 gene identified a heterozygous mutation (p. Ala57Thr) in exon1.

Comparative sequence analyses of RAX, OTX2, SOX2 and ABCB6 genes with their homologs showed that mutation sites are highly conserved across various species. To test the hypothesis that disruption of the normal function of ABCB6 can cause coloboma, zebrafish embryos treated with ABCB6 morpholinos (MOs) showed coloboma phenotype and retarded development. These phenotypes can be rescued by the coinjection of WT ABCB6 mRNA but not by the coinjection of human mRNA containing Ala57Thr mutation (Figure 1).

–  –  –

Compared with zebrafish embryos treated with standard control MOs (C and D), zebrafish embryos treated with abcb6MO show coloboma and retarded development in (E and F). These phenotypes can be rescued by the coinjection of WT ABCB6 mRNA (G and H), but the phenotypes could not be rescued by coinjection of the human mRNA containing Ala57Thr (K and L) mutation. This is the result of the work carried out by collaborator Sichuan Academy of Medical Sciences, China Implication of the project Five novel mutations identified in RAX, OTX2, SOX2 and ABCB6 suggest the role of these genes in ocular development. Three mutations in OTX2 gene cause premature termination of the coding sequence.

These can be a pathogenic change as the protein conformation may get altered leading to loss of function.

Morpholino knockdown and rescue studies of ABCB6 in Zebrafish demonstrated that mutations in ABCB6 gene might cause coloboma. Further in silico and in vitro studies of the normal and mutant protein will unravel the role of the mutations in disease development.

–  –  –

Background and aim Primary angle closure glaucoma (PACG) is a complex disorder and a leading cause of blindness worldwide, especially in Asians. Being a complex disease, several genetic, environmental, anatomical and physiological factors are involved in the pathogenesis of PACG. Several studies have suggested a genetic basis for PACG. But, still no specific gene for PACG has yet been identified. Recently, the association of three new loci, including SNP markers rs11024102 in PLEKHA7, rs3753841 in COL11A1 and rs1015213 located intergenically between PCMTD1 and ST18 genes has been reported with PACG. The purpose of this study is to evaluate the genetic association of these three markers with different subtypes of primary angle closure patients in a South Indian population.

A total of 351 patients were recruited from South India and divided into three groups: Primary Angle Closure Suspect (PACS; N=171), Primary Angle Closure/ Primary Angle Closure Glaucoma (PAC/PACG;



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