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D. P. Dash, S. George, A. E. Hughes, G. Silvestri, J. Jackson, D. Frazer, E. Heon, C. E. Willoughby; Screening of VSX1 Gene Including 2 Novel Exons in Keratoconus Patients From the European Population. Invest. Ophthalmol. Vis. Sci. 2008;49(13):1294.
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© ARVO (1962-2015); The Authors (2016-present)
There are conflicting reports on the role of the visual system homeobox gene 1 (VSX-1; MIM#605020) in the pathogenesis of keratoconus (KC), with mutations reported in 0-8.7% of patients of various ethnicities. The purpose of this study was to screen VSX1 comprehensively, including two newly identified exons, in keratoconus patients of mixed European ethnicity.
The patient cohort consisted of KC patients of European ethnicity (Ireland, Italy, Sweden, Portugal, Belgium and Greek). All patients had a full ophthalmic examination and the diagnosis of keratoconus was made on the basis of clinical examination, a history of penetrating keratoplasty for keratoconus and corneal topography. Mutational analysis of VSX1 was performed by direct cycle sequencing of all 7 exons including two novel exons (exon 6 and 7). The ability to determine the segregation of VSX1 sequence variants in patients with familial KC provided evidence to determine pathogenicity.
All 7 exons on VSX1 were sequenced in 51 patients, comprising 25 sporadic KC patients and 26 probands with familial KC. In total 13 VSX1 sequence variants were detected in this KC cohort. One previously reported mutation (D144E) was detected in a proband with familial KC. When segregation study was carried out, this mutation did not segregate within the family suggesting that D144E is not pathogenic. A novel synonymous sequence variant (S263S) was detected in one patient with sporadic KC and absent from 100 control individuals. There were 7 previously reported polymorphisms and 4 novel polymorphisms: c.*50G>, c.*28G>T, c.844 (NM_014588)-13T>A and c.844 (NM_014588)-5_-6insT.
Mutations in VSX1 play a minor role in the pathogenesis of KC in European patients. The ability to determine segregation in familial KC increases the power of mutational analysis in KC and demonstrated that the previously reported mutation (D114E) is not pathogenic. The pathogenicity of S263S on mRNA processing remains unclear. Further studies are required to determine the genetic basis of KC in this cohort.
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