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      A novel VSX1 mutation identified in an individual with keratoconus in India


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          To evaluate the possible role of the VSX1 gene in a group of patients from the Indian subcontinent with keratoconus.


          Molecular analysis of 66 patients with a diagnosis of keratoconus, based on clinical examination and corneal topography, was carried out. DNA extraction from peripheral blood followed by Polymerase Chain Reaction (PCR) amplification of the VSX1 gene was performed. The entire coding region and the exon–intron junctions of the VSX1 gene were analyzed by direct sequencing.


          A novel change at c.525G>C, replacing amino acid glutamine at position 175 with histidine, was found in one affected individual. One of the previously reported SNPs (rs12480307) was found with equal frequency in both patients and controls.


          This is the first report from the Indian subcontinent exploring the role of VSX1 in the causation of keratoconus. One novel mutation (Q175H) predicted to be a potentially damaging change was seen in an affected individual; this substantiates the importance of this gene but its precise role in disease causation needs further investigation.

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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.
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            Baseline findings in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study.

            To describe the baseline findings in patients enrolled in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study. This is a longitudinal observational study of 1209 patients with keratoconus enrolled at 16 clinical centers. Its main outcome measures are corneal scarring, visual acuity, keratometry, and quality of life. The CLEK Study patients had a mean age of 39.29+/-10.90 years with moderate to severe disease, assessed by a keratometric-based criterion (95.4% of patients had steep keratometric readings of at least 45 D) and relatively good visual acuity (77.9% had best corrected visual acuity of at least 20/40 in both eyes). Sixty-five percent of the patients wore rigid gas-permeable contact lens, and most of those (73%) reported that their lenses were comfortable. Only 13.5% of patients reported a family history of keratoconus. None reported serious systemic diseases that had been previously reported to be associated with keratoconus. Many (53%) reported a history of atopy. Fifty-three percent had corneal scarring in one or both eyes. Baseline findings suggest that keratoconus is not associated with increased risk of connective tissue disease and that most patients in the CLEK Study sample represent mild to moderate keratoconus. Additional follow-up of at least 3 years will provide new information about the progression of keratoconus, identify factors associated with progression, and assess its impact on quality of life.
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              VSX1: a gene for posterior polymorphous dystrophy and keratoconus.

              We identified mutations in the VSX1 homeobox gene for two distinct inherited corneal dystrophies; posterior polymorphous dystrophy (PPD) and keratoconus. One of the mutation (R166W) responsible for keratoconus altered the homeodomain and impaired DNA binding. Two other sequence changes (L159M and G160D) were associated with keratoconus and PPD, respectively, and involved a region adjacent to the homeodomain. The G160D substitution, and a fourth defect affecting the highly conserved CVC domain (P247R), occurred in a child with very severe PPD who required a corneal transplant at 3 months of age. In this family, relatives with the G160D change alone had mild to moderate PPD, while P247R alone caused no corneal abnormalities. However, with either the G160D or P247R mutation, electroretinography detected abnormal function of the inner retina, where VSX1 is expressed. These data define the molecular basis of two important corneal dystrophies and reveal the importance of the CVC domain in the human retina.

                Author and article information

                Mol Vis
                Molecular Vision
                Molecular Vision
                28 November 2009
                : 15
                : 2475-2479
                [1 ]Laboratory of Cyto-Molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India
                [2 ]Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India
                Author notes

                The first two authors contributed equally to the manuscript

                Correspondence to: Dr. Arundhati Sharma, Associate Professor (Genetics), Laboratory of Cyto-Molecular genetics, Room No. 1015, Department of Anatomy, All India Institute of Medical Sciences, New Delhi; Phone: +91-11-26593489 or +91-9868397547; FAX: +91-11-26864851 or +91-11-26521041; email: arundhati_sharma@yahoo.com or arundhatisharma1@gmail.com
                264 2009MOLVIS0323
                Copyright © 2008 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.

                : 08 September 2009
                : 20 November 2009
                Research Article
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                Vision sciences
                Vision sciences


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