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      Mutational screening of VSX1, SPARC, SOD1, LOX, and TIMP3 in keratoconus


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          To evaluate the involvement of Visual System Homeobox 1 ( VSX1), Secreted Protein Acidic and Rich in Cysteine ( SPARC), Superoxide Dismutase 1 ( SOD1), Lysyl Oxidase ( LOX), and Tissue Inhibitor of Metalloproteinase 3 ( TIMP3) in sporadic and familial keratoconus.


          Mutational analysis of the five genes was performed by sequencing and fragment analysis in a large cohort of 302 Italian patients, with a diagnosis of keratoconus based on clinical examination and corneal topography. The variants identified in VSX1 and SPARC were also assessed in the available relatives of the probands.


          A novel mutation p.G239R and previously reported mutations were found in VSX1. Novel and already reported variants were identified in SPARC and SOD1, whose pathogenic significance has not been established. No pathogenic variants have been identified in LOX and TIMP3.


          Molecular analysis of the five genes in a cohort of 225 sporadic and 77 familial keratoconus cases confirms the possible pathogenic role of VSX1 though in a small number of patients; a possible involvement of LOX and TIMP3 could be excluded; and the role played by SOD1 and SPARC in determining the disease as not been definitively clarified. Further studies are required to identify other important genetic factors involved in the pathogenesis and progression of the disease that in the authors’ opinion, and according with several authors, should be considered as a complex disease.

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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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            SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury.

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              Keratoconus is a bilateral noninflammatory corneal ectasia with an incidence of approximately 1 per 2,000 in the general population. It has well-described clinical signs, but early forms of the disease may go undetected unless the anterior corneal topography is studied. Early disease is now best detected with videokeratography. Classic histopathologic features include stromal thinning, iron deposition in the epithelial basement membrane, and breaks in Bowman's layer. Keratoconus is most commonly an isolated disorder, although several reports describe an association with Down syndrome, Leber's congenital amaurosis, and mitral valve prolapse. The differential diagnosis of keratoconus includes keratoglobus, pellucid marginal degeneration and Terrien's marginal degeneration. Contact lenses are the most common treatment modality. When contact lenses fail, corneal transplant is the best and most successful surgical option. Despite intensive clinical and laboratory investigation, the etiology of keratoconus remains unclear. Clinical studies provide strong indications of a major role for genes in its etiology. Videokeratography is playing an increasing role in defining the genetics of keratoconus, since early forms of the disease can be more accurately detected and potentially quantified in a reproducible manner. Laboratory studies suggest a role for degradative enzymes and proteinase inhibitors and a possible role for the interleukin-1 system in its pathogenesis, but these roles need to be more clearly defined. Genes suggested by these studies, as well as collagen genes and their regulatory products, could potentially be used as candidate genes to study patients with familial keratoconus. Such studies may provide the clues needed to enable us to better understand the underlying mechanisms that cause the corneal thinning in this disorder.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                24 September 2011
                : 17
                : 2482-2494
                [1 ]Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
                [2 ]Unità di Oculistica, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
                [3 ]Unità di Oculistica, Università di Foggia, Foggia, Italy
                [4 ]Laboratorio di Oncologia, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
                Author notes
                Correspondence to: Dr. Luigi Bisceglia, Unità di Genetica Medica, IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; Phone: +39 0882 416347; FAX: +39 0882 411616; email: l.bisceglia@ 123456operapadrepio.it
                269 2011MOLVIS0315
                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.

                : 21 July 2011
                : 13 September 2011
                Research Article
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                Vision sciences
                Vision sciences


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