Nagasamy Soumittra

Bio: Nagasamy Soumittra is an academic researcher from Oil and Natural Gas Corporation. The author has contributed to research in topics: Disease gene identification & Penetrance. The author has an hindex of 12, co-authored 28 publications receiving 473 citations. Previous affiliations of Nagasamy Soumittra include Cancer Institute & Sankara Nethralaya.

Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India

Abstract: Pseudoexfoliation syndrome (XFS) is an age-related,systemic, elastic microfibrillopathy affecting both intraocularand extraocular tissues [1]. In the eye, XFS is characterizedby the presence of fibrogranular extracellular debris in theanterior segment, which is composed of a complexglycoprotein–proteoglycan structure having epitopes of abasement membrane, elastic fiber system, and components ofelastic microfibrils [ 2]. The average worldwide prevalence ofXFS is 10%–20% of the general population over the age of 60years. However, studies have shown much higher prevalencein certain populations like Scandinavian countries and Greece[3-5].Glaucoma, the second most common cause of blindness,is a heterogeneous group of disorders characterized by opticnerve damage [ 6]. XFS is the most common identifiable causeof secondary glaucoma such as pseudoexfoliation glaucoma(XFG), which is due to the accumulation of the exfoliativematerial [ 7]. The risk of XFS converting to XFG over a periodof 15 years is about 60% [8,9].Linkage studies on a large Finnish family showing anautosomal dominant mode of inheritance for XFS traitidentified a locus, 18q12.1–21.33, with a two point LOD scoreof 3.45 and a multipoint LOD score of 4.2 and few other loci

CERKL mutations cause an autosomal recessive cone-rod dystrophy with inner retinopathy.

Abstract: Purpose To define the phenotype of the retinal degeneration associated with mutations in the CERKL gene. Methods Six patients (ages, 26-54 years) from three unrelated families with CERKL mutations were studied clinically and by electroretinography, kinetic, and chromatic static perimetry, autofluorescence (AF) imaging, and optical coherence tomography (OCT). Results Three siblings were homozygotes for p.R257X mutation; two siblings were compound heterozygotes for p.R257X and a novel p.C362X mutation; and one patient had only p.R257X mutation identified to date. There was a spectrum of severity: from mild visual acuity loss to light perception; from full kinetic fields with relative central scotomas to remnant peripheral islands; from reduced ERGs (some with negative waveforms) to nondetectable signals. Maculopathy showed residual foveal islands or extensive central rod and cone scotomas. With AF imaging, there was evidence of hyperautofluorescence at earlier and hypoautofluorescence at later disease stages. Peripheral function was generally less affected than central function. With OCT there were small foveal islands of outer nuclear layer (ONL) in those with preserved acuity. Eccentric to an annular region with no discernible ONL, there could be ONL in the midperiphery. At early disease stages, ganglion cell layer thickness was less affected than ONL. Later disease stages were accompanied by inner nuclear layer and nerve fiber layer abnormalities. Conclusions CERKL mutations are associated with widespread retinal degeneration with prominent maculopathy. The clinical presentation is that of an autosomal recessive cone-rod dystrophy. Photoreceptor loss appears at all stages of disease and inner laminopathy complicates the phenotype at later stages.

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

Abstract: Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

A missense mutation in the nuclear localization signal sequence of CERKL (p.R106S) causes autosomal recessive retinal degeneration.

Abstract: Eye Department, Chancellor Wing, St. James’s University Hospital,Leeds, United KingdomPurpose: To investigate the genetic basis of autosomal recessive retinal degeneration in a large consanguineous familyfrom Pakistan.Methods: Ophthalmic examinations were conducted on family members to establish their diagnosis. Genomic DNAextracted from peripheral blood was used for homozygosity mapping to discover the chromosomal region that harborsthe defective gene. Direct sequence analysis and restriction enzyme digestion were used to identify and confirm the defectin the gene.Results: There were three affected siblings in the family, each with limited peripheral vision and impaired visual acuity.We established linkage to a region on chromosome 2 that encompasses the RP26 locus. Upon sequencing the ceramidekinase-like (CERKL) gene, which is mutated in the original RP26 family, we identified a C>A transversion in exon 2 (c.316C>A) that substitutes an arginine residue with a serine (p.R106S) in the conserved nuclear localization signal sequence(KLKRR) of the protein. This mutation segregated with retinal degeneration in the Pakistani family and was not observedin the DNA of 174 ethnically matched unaffected controls.Conclusions: This is the third reported mutation in CERKL causing retinal degeneration but is the first report to showthat a single amino acid change in CERKL, rather than a null mutation, can cause retinal disease. Although the functionof CERKL is still unknown, the mutation described herein confirms that the nuclear localization signal sequence isimportant in the physiologic function of the protein.

Biosynthetic and functional defects in newly identified SLC4A11 mutants and absence of COL8A2 mutations in Fuchs endothelial corneal dystrophy

Abstract: Late-onset Fuchs endothelial corneal dystrophy (FECD) shows genetic heterogeneity. Identification of SLC4A11 as a candidate gene for congenital hereditary endothelial dystrophy with similar corneal endothelial defects as FECD and reduced mRNA expression of SLC4A11 in the endothelium of FECD cases suggested that this gene may also be involved in pathogenesis of FECD. Mutations in SLC4A11 give rise to SLC4A11 protein marked by retention in the endoplasmic reticulum as a result of mis-folding. We screened 45 sporadic late-onset, 4 early-onset FECD patients and an early-onset autosomal dominant FECD family. We identified three previously unreported missense mutations: c.719G>C (p.W240S), c.1519G>A (p.V507I) and c.1304C>T (p.T434I) in unrelated individuals. These SLC4A11 mutants, expressed in HEK293 cells, had defects in either their cell surface expression or functional activity (rate of osmotically driven water flux). SLC4A11 mutations contribute to 11% (5/45) of sporadic late-onset FECD in the cohort studied. COL8A2, which causes some cases of early-onset FECD, was also screened in this cohort. No mutations were identified in COL8A2, in neither the late-onset cohort nor the early-onset family, suggesting genetic heterogeneity in this FECD family.

The Retinal Pigment Epithelium in Health and Disease

Abstract: Retinal pigment epithelial cells (RPE) constitute a simple layer of cuboidal cells that are strategically situated behind the photoreceptor (PR) cells. The inconspicuousness of this monolayer contrasts sharply with its importance [1]. The relationship between the RPE and PR cells is crucial to sight; this is evident from basic and clinical studies demonstrating that primary dysfunctioning of the RPE can result in visual cell death and blindness. RPE cells carry out many functions including the conversion and storage of retinoid, the phagocytosis of shed PR outer segment membrane, the absorption of scattered light, ion and fluid transport and RPE-PR apposition. The magnitude of the demands imposed on this single layer of cells in order to execute these tasks, will become apparent to the reader of this review as will the number of clinical disorders that take origin from these cells.

The rationale for targeting the LOX family in cancer.

Abstract: The therapeutic targeting of extracellular proteins is becoming hugely attractive in light of evidence implicating the tumour microenvironment as pivotal in all aspects of tumour initiation and progression. Members of the lysyl oxidase (LOX) family of proteins are secreted by tumours and are the subject of much effort to understand their roles in cancer. In this Review we discuss the roles of members of this family in the remodelling of the tumour microenvironment and their paradoxical roles in tumorigenesis and metastasis. We also discuss how targeting this family of proteins might lead to a new avenue of cancer therapeutics.

Short linear motifs: ubiquitous and functionally diverse protein interaction modules directing cell regulation.

Abstract: Interaction Modules Directing Cell Regulation Kim Van Roey,† Bora Uyar,† Robert J. Weatheritt,‡ Holger Dinkel,† Markus Seiler,† Aidan Budd,† Toby J. Gibson,† and Norman E. Davey*,†,§ †Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany ‡MRC Laboratory of Molecular Biology (LMB), Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom Department of Physiology, University of California, San Francisco, San Francisco, California 94143, United States

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

Abstract: We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10-10) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10-9). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10-14, OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10-14, OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma. © 2011 Nature America, Inc. All rights reserved.