<i>VSX1</i>Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation

Bisceglia, Luigi; Ciaschetti, Marilena; Bonis, Patrizia De; Campo, Pablo Alberto Perafan; Pizzicoli, Costantina; Scala, Costanza; Grifa, Michele; Ciavarella, Pio; Noci, Nicola Delle; Vaira, Filippo; Macaluso, Claudio; Zelante, Leopoldo

doi:10.1167/iovs.04-0533

Cited by 95 publications

(94 citation statements)

References 21 publications

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“…unc-45 encodes a protein of unknown molecular function, but one of its human orthologs, UNC45B, has been associated with cataracts (91). Vsx1 is a transcription factor with two human orthologs: VSX1 is associated with keratoconus, anterior segment dysgenesis syndrome (which affect multiple eye tissues) (92,93), and posterior polymorphous corneal dystrophy (94), whereas VSX2 is associated with microphthalmia (95,96). Thus, naturally occurring genetic variation affecting Drosophila phototaxis and senescence for phototaxis encompasses evolutionarily conserved genes that contribute to visual senescence in humans.…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of natural variation in visual senescence in Drosophila

Carbone

Yamamoto

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Senescence, i.e., functional decline with age, is a major determinant of health span in a rapidly aging population, but the genetic basis of interindividual variation in senescence remains largely unknown. Visual decline and age-related eye disorders are common manifestations of senescence, but disentangling age-dependent visual decline in human populations is challenging due to inability to control genetic background and variation in histories of environmental exposures. We assessed the genetic basis of natural variation in visual senescence by measuring age-dependent decline in phototaxis using Drosophila melanogaster as a genetic model system. We quantified phototaxis at 1, 2, and 4 wk of age in the sequenced, inbred lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and found an average decline in phototaxis with age. We observed significant genetic variation for phototaxis at each age and significant genetic variation in senescence of phototaxis that is only partly correlated with phototaxis. Genome-wide association analyses in the DGRP and a DGRP-derived outbred, advanced intercross population identified candidate genes and genetic networks associated with eye and nervous system development and function, including seven genes with human orthologs previously associated with eye diseases. Ninety percent of candidate genes were functionally validated with targeted RNAi-mediated suppression of gene expression. Absence of candidate genes previously implicated with longevity indicates physiological systems may undergo senescence independent of organismal life span. Furthermore, we show that genes that shape early developmental processes also contribute to senescence, demonstrating that senescence is part of a genetic continuum that acts throughout the life span.aging | behavioral genetics | DGRP GWA analysis | phototaxis | xQTL mapping

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Section: Discussionmentioning

confidence: 99%

Genetic architecture of natural variation in visual senescence in Drosophila

Carbone

Yamamoto

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Two mutations, L159M and G160D, near the nuclear localization signal of the VSX1 gene were associated with keratoconus and PPCD, respectively. Bisceglia et al (2005) evaluated the role of the VSX1 gene in a series of 80 keratoconus-affected Italian subjects. Three described missense mutations, D144E, G160D, and P247R, were identified, and the novel mutation L17P was found in 8.7% of unrelated patients and three families.…”

Section: Discussionmentioning

confidence: 99%

“…All polymerase chain reaction (PCR) studies were carried out with 25 ng of genomic DNA as a template in a mixture of PCR buffer, 2.5 mM magnesium chloride (MgCl 2 ), 200 nM deoxynucleotide triphosphate (dNTP), 0.4 pmol of each primer, and 0.75 U of h-Taq polymerase (Solgent, Daejeon, Korea). To search mutations in this gene, we designed seven sets of primers that were used to amplify the PCR products of the entire coding region as well as exon-intron junctions of the gene (Table 1) (Bisceglia et al 2005). The genotypes of single nucleotide polymorphisms (SNPs) spanning the coding region of the VSX1 gene were determined by single-strand conformational polymorphism (SSCP) analysis and direct sequencing.…”

Section: Subjectsmentioning

confidence: 99%

“…Based on studies reporting significant linkage of keratoconus, several pathogenic mutations in VSX1 (MIM 605020; visual system homeobox gene 1, zebrafish, homolog of), located on 20p11.21, have been detected in multigenerational pedigrees of keratoconus, with a strong association and genetic variants of VSX1 that has been validated by multiple studies (Aldave et al 2006;Bawazeer et al 2000;Bisceglia et al 2005;Chwa et al 2006;Heon et al 2002;Kenney and Brown 2003;Kuming and Joffe 1977;Liskova et al 2007;Tang et al 2008). Although several variants of VSX1, e.g., L17P, L159 M, and R166 W, have been reported to be pathogenic in multigenerational pedigrees of keratoconus with various associations, the identified pathogenic mutations has shown various associations in familial keratoconus patients with different ethnicities (Aldave et al 2006;Bisceglia et al 2005;Heon et al 2002;Liskova et al 2007;Tang et al 2008). The association between variations in the VSX1 gene and keratoconus in Korean patients, however, has yet to be investigated.…”

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VSX1 gene variants are associated with keratoconus in unrelated Korean patients

2008

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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.

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“…61 To date, more than 1500 KC patients have been screened for VSX1 and potentially pathogenic mutations have been identified in less than 2% of cases suggesting that this gene does not have a major role in the molecular pathology of KC. 60,[62][63][64] Other candidate genes screened in KC cohorts include TIMP3, 65 TGFBI, 66,67 ZEB1, 68 FLG 69 and several collagen genes. 46,70,71 Despite these efforts, potentially pathogenic variants have only been identified in a very small number of individuals with KC.…”

Section: Geneticsmentioning

confidence: 99%

The pathogenesis of keratoconus

Davidson¹,

Hayes

Hardcastle³

et al. 2013

Eye

293

200

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Keratoconus (KC) is a common degenerative condition that frequently results in visual loss with an onset typically in early adulthood. It is the single most common reason for keratoplasty in the developed world. The cause and underlying pathological mechanism are unknown, but both environmental and genetic factors are thought to contribute to the development of the disease. Various strategies have been employed to address the gap in our understanding of this complex disease, with the expectation that over time more sophisticated therapies will be developed. In this review we summarise our current knowledge of the aetiology and risk factors associated with KC.

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VSX1Mutational Analysis in a Series of Italian Patients Affected by Keratoconus: Detection of a Novel Mutation

Cited by 95 publications

References 21 publications

Genetic architecture of natural variation in visual senescence in Drosophila

Genetic architecture of natural variation in visual senescence in Drosophila

VSX1 gene variants are associated with keratoconus in unrelated Korean patients

The pathogenesis of keratoconus

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