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      Mutation analysis of VSX1 and SOD1 in Iranian patients with keratoconus


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          To evaluate mutations in the visual system homeobox gene 1 ( VSX1) and superoxide dismutase 1 ( SOD1) genes with keratoconus (KTCN), direct sequencing was performed in an Iranian population.


          One hundred and twelve autosomal dominant KTCN patients and fifty-two unaffected individuals from twenty-six Iranian families, as well as one hundred healthy people as controls were enrolled. Genomic DNA was extracted from whole blood sample. Then to study the possible linkage between KTCN and six known loci linkage analysis was performed using 12 short tandem repeat (STR) markers. Also, the entire coding region and intron-exon boundaries of VSX1 and SOD1 were amplified by the PCR technique in each proband. Subsequently, PCR products were subjected to direct sequencing. Co-segregation analysis of the identified mutation was conducted in the family members. An Amplification Refractory Mutation System PCR (ARMS-PCR) was additionally employed for detection of the identified mutation in healthy controls.


          Linkage analysis of aforementioned loci did not detect evidence for linkage to KTCN. Direct PCR sequencing revealed two single nucleotide polymorphisms (SNPs; g.1502T>G and g.9683C>T), as well as two missense mutations that have been previously reported (R166W and H244R) in VSX1. We also found three undescribed SNPs (g.4886G>A, g.4990C>G, and g.9061T>A) in SOD1. The R166W and H244R mutations were co-segregated in affected family members but not in those that were unaffected. Moreover, the ARMS-PCR strategy did not detect the identified mutations in controls.


          Our data suggest a significant association between KTCN patients and VSX1 genetic alterations (p.R166W and p.H244R). Although our findings support VSX1 as a plausible candidate gene responsible for keratoconus, other chromosomal loci and genes could be involved in KTCN development. Taken together, our results suggest that p.R166W and p.H244R could have possible pathogenic influences on KTCN.

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          Most cited references33

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          Keratoconus: a review.

          Keratoconus is the most common primary ectasia. It usually occurs in the second decade of life and affects both genders and all ethnicities. The estimated prevalence in the general population is 54 per 100,000. Ocular signs and symptoms vary depending on disease severity. Early forms normally go unnoticed unless corneal topography is performed. Disease progression is manifested with a loss of visual acuity which cannot be compensated for with spectacles. Corneal thinning frequently precedes ectasia. In moderate and advance cases, a hemosiderin arc or circle line, known as Fleischer's ring, is frequently seen around the cone base. Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign. Most patients eventually develop corneal scarring. Munson's sign, a V-shape deformation of the lower eyelid in downward position; Rizzuti's sign, a bright reflection from the nasal area of the limbus when light is directed to the limbus temporal area; and breakages in Descemet's membrane causing acute stromal oedema, known as hydrops, are observed in advanced stages. Classifications based on morphology, disease evolution, ocular signs and index-based systems of keratoconus have been proposed. Theories into the genetic, biomechanical and biochemical causes of keratoconus have been suggested. Management varies depending on disease severity. Incipient cases are managed with spectacles, mild to moderate cases with contact lenses and severe cases can be treated with keratoplasty. This article provides a review on the definition, epidemiology, clinical features, classification, histopathology, aetiology and pathogenesis, and management and treatment strategies for keratoconus. 2010 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.
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            Does ethnic origin influence the incidence or severity of keratoconus?

            Keratoconus affects all races, yet very little information exists as to the relative frequency in patients of different ethnic origin. We aimed to establish the incidence and severity of keratoconus in Asian and white patients. The hospital records of the ophthalmology department of a large Midlands hospital with a catchment population of approximately 900,000 (87% white, 11% Asian, 2% other) were examined retrospectively for the 10 year period from 1989 to 1998. For the age group 10-44 years the prevalence of keratoconus in Asians and whites was 229 and 57 per 100,000 respectively, a relative prevalence of 4 to 1. The incidence of keratoconus in the same age group was 19.6 and 4.5 per 100,000 per year respectively, a relative incidence of 4.4 to 1. Asians were significantly younger at presentation compared with whites (mean 22.3 +/- 6.5 vs 26.5 +/- 8.5 years, p < 0.0001). A first corneal graft was carried out on 14% of the Asian and 15% of the white patients. Of those having grafts, Asians were significantly younger than white patients at the time of diagnosis (mean 19.1 +/- 4.8 vs 25.7 +/- 7.3 years, p = 0.005) and at operation (mean 21.4 +/- 5.0 vs 28.7 +/- 7.7 years, p = 0.004). The interval from diagnosis to operation, though shorter for Asians, was not significantly different (mean 1.8 +/- 1.4 vs 2.5 +/- 1.7 years, p = 0.2). The results show previously unrecognised racial differences in the hospital presentation of keratoconus in the UK. Compared with white patients, Asians have a fourfold increase in incidence, are younger at presentation and require corneal grafting at an earlier age.
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              Genetic epidemiological study of keratoconus: evidence for major gene determination.

              Keratoconus (KC) is a noninflammatory corneal thinning disorder and the major cause of cornea transplantation in the Western world. Genetic factors have been suggested in the cause of KC. We conducted a family study to investigate genetic contributions to the development of KC by evaluating familial aggregation and testing genetic models with segregation analysis. KC was diagnosed based on clinical criteria. Familial aggregation of KC was evaluated using both clinical status and three videokeratography indices generated by the Topographic Modeling System (TMS-1). The estimated KC prevalence in first-degree relatives was 3.34% (41/1,226, 95% CI: 3. 22-3.46%), which is 15 to 67 times higher than that in the general population (0.23-0.05%). For all three videokeratography indices, CK, IS, and KISA, KC propositi had significantly higher mean values than controls (all P 0.1). Additionally, the most parsimonious model was autosomal recessive. In conclusion, we observed strong evidence of familial aggregation in KC and its subclinical indices and this aggregation is likely due to a major gene effect. Copyright 2000 Wiley-Liss, Inc.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                30 November 2011
                : 17
                : 3128-3136
                [1 ]Department of Medical Genetics, Tehran University of Medical Sciences, Tehran, Iran
                [2 ]Farabi Eye Hospital, Eye Research Center, Tehran University of Medical Sciences, Tehran, Iran
                [3 ]Noor Ophthalmology Research Center, Noor Eye Hospital, Tehran, Iran
                [4 ]Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
                [5 ]Biomedical Science, School of Veterinary and Biomedical Sciences, Murdoch University, South Street, Murdoch, Western Australia
                Author notes
                Correspondence to: Dr Mansour Heidari, Department of Medical Genetics, Tehran University of Medical Sciences, Pour Sina Ave, Tehran, Iran; Phone: 98-21-8895- 3005; FAX: 98-21-8895- 3005; email: mheidari@ 123456sina.tums.ac.ir
                337 2011MOLVIS0393
                Copyright © 2011 Molecular Vision.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 06 September 2011
                : 27 November 2011
                Research Article
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                Vision sciences
                Vision sciences


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