Abstract
Keratoconus is a bilateral ectatic disorder characterized by the central thinning of corneal tissue leading to visual impairment. To investigate the possibility of visual system homeobox 1 (VSXI) as a candidate susceptibility gene for Korean patients with keratoconus, we performed a mutation screening of the VSXI gene in 249 unrelated patients with keratoconus and 208 control subjects without the ocular disorder. We found two heterozygous novel missense mutations in exon 2: N151S and G160V. The G160V mutation was identified in 13 keratoconus patients (5.3%), and the N151S mutation was found in only one keratoconus patient (0.4%). We also detected three synonymous polymorphisms and four intragenic polymorphisms. The IVS1-11*a allele was associated with a significantly increased risk of keratoconus in Korean patients [3.6 vs. 0.5%, p = 0.001, odds ratio (OR) = 7.76, 95% confidence interval (CI) 1.989–30.241). Other polymorphisms did not show an association with keratoconus risk. Our data is the first reported VSX1 mutation screening in Korean keratoconus patients. We detected two novel missense mutations and one intragenic polymorphism in the VSX1 gene, which show a strong statistical association with unrelated keratoconus patients. Consequently, our study suggests that VSX1 gene variants seem to be significant genetic variants for keratoconus predisposition in unrelated Korean patients.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Aldave AJ (2005) VSX1 mutation and corneal dystrophies. Ophtahlmology 112:170–171
Aldave AJ, Yellore VS, Principe AH, Abedi G, Merrill K, Cjalukya M, Small KW, Udar N (2005) Candidate gene screening for posterior polymorphous dystrophy. Cornea 24:151–155
Aldave AJ, Yellore VS, Salem AK, Yoo GL, Rayner SA, Yang H, Tang GY, Piconell Y, Raninowitz YS (2006) No VSX1 gene mutations associated with keratoconus. Invest Ophthalmol Vis Sci 47:2820–2822
Barbaro V, Di Iorio E, Ferrari S, Bisceglia L, Ruzza A, De Luca M, Pellegrini G (2006) Expression of VSX1 in human corneal keratocytes during differentiation into myofibroblasts in response to wound healing. Invest Ophthalmol Vis Sci 47:5243–5250
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Bawazeer AM, Hodge WG, Lorimer B (2000) Atopy and keratoconus: a multivariate analysis. Br J Ophthalmol 84:834–836
Bisceglia L, Ciaschetti M, De Bonis P, Campo PA, Pizzicoli C, Scala C, Grifa M, Ciavarella P, Delle Noci N, Vaira F, Macaluso C, Zelante L (2005) VSX1 mutational analysis in a series of Italian patients affected by keratoconus: detection of a novel mutation. Invest Ophthalmol Vis Sci 46:39–45
Brancati F, Valente EM, Sarkozy A, Feher J, Castory M, Del Duca P, Mingarelli R, Pizzuti A, Dallapiccola B (2004) A locus for autosomal dominant keratoconus maps to human chromosome 3p14–q13. J Med Genet 41:188–192
Chwa M, Atilano SR, Reddy V, Jordan N, Kim DW, Kenney MC (2006) Increased stress-induced generation of reactive oxygen species and apoptosis in human keratoconus fibroblasts. Invest Ophthalmol Vis Sci 47:1902–1910
Dash DP, Silvestri G, Hughes AE (2006) Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis. Mol Vis 12:499–505
Edwards M, McGhee CN, Deen S (2001) The genetics of keratoconus. Clin Exp Ophthlamol 29:345–351
Elder MJ (1994) Leber congenital amaurosis and its association with keratoconus and keratoglobus. J Pediatr Ophthalmol Strabismus 31:38–40
Flanders M, Lapointe ML, Brownstein S, Little JM (1084) Keratoconus and Leber’s congenital amaurosis: a clinicopathological correlation. Can J Ophthalmol 19:310–314
Hayashi T, Huang J, Deeb SS (2000) RINX (VSX1), a novel homeobox gene expressed in the inner nuclear layer of the adult retina. Genomics 67:128–139
Hayashi T, Huang J, Deeb SS (2005) Expression of Rinx/Vsx1 during postnatal eye development in cone-bipolar, differentiating ganglion, and lens fiber cells. Jpn J Ophthalmol 49:93–105
Heon E, Greenberg A, Kopp KK, Rootman D, Vincent AL, Billingsley G, Priston M, Dorval KM, Chow RL, McInnes RR, Heathcote G, Westall C, Sutphin JE, Semina E, Bremner R, Stone EM (2002) VSX1, a gene for posterior polymorphous dystrophy and keratoconus. Hum Mol Genet 11:1029–1036
Hosseini SM, Herd S, Vincent AL, Heon E (2008) Genetic analysis of chromosome 20-related posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three candidate genes. Mol Vis 14:71–80
Hughes AE, Dash DP, Jackson AJ, Frazer DG, Silvestri G (2003) Familial keratoconus with cataract: linkage to the long arm of chromosome 15 and exclusion of candidate genes. Invest Ophthalmol Vis Sci 44:5063–5066
Hutchings H, Ginisty H, Le Gallo M, Levy D, Stoesser F, Rounland JF, Arne JL, Lalaux MH, Calvas P, Roth MP, Hovnanian A, Malecaze F (2005) Identification of a new locus for isolated familial keratoconus at 2p24. J Med Genet 42:88–94
Karseras AG, Ruben M (1976) Aetiology of keratoconus. Br J Ophthalmol 60:522–525
Kenney MC, Brown DJ (2003) The cascade hypothesis of keratoconus. Contact Lens Anterior Eye 26:139–146
Krachmer JH, Feder RS, Belin MW (1984) Keratoconus and related noninflammatory corneal thinning disorders. Surv Ophthalmol 28:293–322
Kuming BS, Joffe L (1977) Ehlers-Danlos syndrome associated with keratoconus. A case report. S Afr Med J 52:403–405
Liskova P, Ebenezer ND, Hysi PG, Gwilliam R, El-Ashry MF, Moodaley LC, Hau S, Twa M, Tuft SJ, Bhatacharya SS (2007) Molecular analysis of the VSX1 gene in familial keratoconus. Mol Vis 13:1887–1891
McMahon TT, Shin JA, Newlin A, Edrington TB, Sugar J, Zadnik K (1999) Discordance for keratoconus in two pairs of monozygotic twins. Cornea 18:444–451
McMahon TT, Szczotka-Flynn L, Barr JT, Anderson RJ, Slaughter ME, Lass JH, Iyengar SK et al (2006) A new method for grading the severity of keratoconus: the Keratoconus Severity Score (KSS). Cornea 25:794–800
Mintz-Hittner HA, Semina EV, Frishman LJ, Prager TC, Murray JC (2004) VSX1 (RINX) mutation with craniofacial anomalies, empty sella, corneal endothelial changes, an abnormal retinal and auditory bipolar cells. Ophthalmology 111:828–836
Nakamura H, Riley F, Sakai H (2005) Histopathological and immunohistochemical studies of lenticules after epikeratoplasty for keratoconus. Br J Ophthalmol 89:841–846
Parker J, Ko W, Pavlopoulos G, Wolfe PJ, Rabinowitz YS, Feldman ST (1996) Videokeratography of keratoconus in monozygotic twins. J Refract Surg 12:180–183
Passini MA, Kurtzman AL, Canger AK, Asch WS, Wray GA, Raymond PA, Schechter N (1998) Cloning of zebrafish vsx1: expression of a paired-like homeobox gene during CNS development. Dev Genet 23:128–141
Rabinowitz YS (1998) Keratoconus. Surv Ophthalmol 42:297–319
Semina EV, Mintz-Hittner HA, Murray JC (2000) Isolation and characterization of a novel human paired-like homeodomain-containing transcription factor gene, VSX1, expressed in ocular tissues. Genomics 63:289–293
Shapiro MB, France TD (1985) The ocular features of Down’s syndrome. Am J Ophthalmol 99:659–663
Sherwin T, Brookes NH (2004) Morphological changes in keratoconus: pathology or pathogenesis. Clin Experiment Ophthalmol 32:211–217
Tang YG, Picornell Y, Su X, Li X, Yang H, Rabinowitz YS (2008) Three VSX1 gene mutations, L159M, R166W, and H244R, are not associated with keratoconus. Cornea 27:189–192
Tang YG, Rabinowitz YS, Taylor KD, Li X, Hu M, Picornell Y, Yang H (2005) Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3–q21.1. Genet Med 7:397–405
Tyynismaa H, Sistonen P, Tuupanen S, Tervo T, Dammert A, Latvala T, Alitalo T (2002) A locus for autosomal dominant keratoconus: linkage to 16q22.3–23.1 in Finnish families. Invest Ophthalmol Vis Sci 43:3160–3164
Wang Y, Rabompwitz YS, Rotter JI, Yang H (2000) Genetic epidemiological study of keratoconus: evidence for major gene determination. Am J Med Genet 93:403–409
Wilson SE, Verity SM, Conger DL (1992) Accuracy and reproducibility of the corneal analysis system and topographic modeling system. Cornea 11:28–35
Acknowledgments
We thank the patients who participated in the study. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2006-E00016). We thank the Korea Eye Tissue and Gene Bank, The Catholic University of Korea, and the staff of the Department of Ophthalmology, St. Mary’s Hospital.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mok, JW., Baek, SJ. & Joo, CK. VSX1 gene variants are associated with keratoconus in unrelated Korean patients. J Hum Genet 53, 842–849 (2008). https://doi.org/10.1007/s10038-008-0319-6
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1007/s10038-008-0319-6
Keywords
This article is cited by
-
Do age-related macular degeneration genes show association with keratoconus?
Eye and Vision (2019)
-
Genetic Aspects of Keratoconus: A Literature Review Exploring Potential Genetic Contributions and Possible Genetic Relationships with Comorbidities
Ophthalmology and Therapy (2018)
-
Analysis of the VSX1 gene in sporadic keratoconus patients from China
BMC Ophthalmology (2017)
-
Genetic associations for keratoconus: a systematic review and meta-analysis
Scientific Reports (2017)
-
Genomic strategies to understand causes of keratoconus
Molecular Genetics and Genomics (2017)
