Genetics of Keratoconus: Where Do We Stand?

Abu-Amero, Khaled K.; Al-Muammar, Abdulrahman; Kondkar, Altaf A.

doi:10.1155/2014/641708

Cited by 77 publications

(82 citation statements)

References 98 publications

(120 reference statements)

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“…All of these could probably be the result of a complex interaction of both genetic predisposition and environmental triggering factors, such as eye rubbing and contact lenses wear (the 'two-hit hypothesis') in keratoconus. 42,52,100,113,119,120 conditions in the cornea, will contribute to elucidate these questions and ultimately help to unravel the etiological mysteries of keratoconus. The tear film proteome has become and will stay as an area of high interest for the identification of potential targets for early diagnosis and therapy in these patients, due to its non-invasive nature.…”

Section: Resultsmentioning

confidence: 99%

“…3 An important number of locations for genes on chromosomes (loci), 17 of them until now, have been related to keratoconus, thus showing genetic heterogeneity rather than a single major gene effect responsible for development and progression of the disease. 51,52 Some of the genes with reported mutations are SOD1 (locus 21q22.11), VSX1 (locus 20p11.2), and DOCK9 (locus 13q32), which regulate the expression of superoxide dismutase (SOD), photoreceptor cells, and G protein, respectively. [53][54][55] Recently, mutations in MIR184 have been identified as an uncommon cause of keratoconus.…”

Section: Geneticsmentioning

confidence: 99%

“…[63][64][65][66] In addition, it has been also established that the mean relative mtDNA content is higher in patients with the disease. 67 Genetics of keratoconus has been recently extensively reviewed by Abu-Amero et al 52 …”

Section: Geneticsmentioning

confidence: 99%

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Keratoconus: an inflammatory disorder?

Galvis

Sherwin

Tello

et al. 2015

Eye

302

199

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Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.

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Section: Resultsmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

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Keratoconus: an inflammatory disorder?

Galvis

Sherwin

Tello

et al. 2015

Eye

302

199

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“…2 KTCN development may be related to environmental factors such as constant eye rubbing or contact lens wear, or it may be genetically controlled. 3 Recently, it was suggested that KTCN could be a quasiinflammatory condition. 4 However, the exact causes of this disease are not well characterized, and its complexity and heterogeneity make it difficult to discover the factors that unambiguously trigger the KTCN phenotype.…”

Section: Introductionmentioning

confidence: 99%

Collagen synthesis disruption and downregulation of core elements of TGF-β, Hippo, and Wnt pathways in keratoconus corneas

et al. 2017

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To understand better the factors contributing to keratoconus (KTCN), we performed comprehensive transcriptome profiling of human KTCN corneas for the first time using an RNA-Seq approach. Twenty-five KTCN and 25 non-KTCN corneas were enrolled in this study. After RNA extraction, total RNA libraries were prepared and sequenced. The discovery RNA-Seq analysis (in eight KTCN and eight non-KTCN corneas) was conducted first, after which the replication RNA-Seq experiment was performed on a second set of samples (17 KTCN and 17 non-KTCN corneas). Over 82% of the genes and almost 75% of the transcripts detected as differentially expressed in KTCN and non-KTCN corneas were confirmed in the replication study using another set of samples. We used these differentially expressed genes to generate a network of KTCN-deregulated genes. We found an extensive disruption of collagen synthesis and maturation pathways, as well as downregulation of the core elements of the TGF-β, Hippo, and Wnt signaling pathways influencing corneal organization. This first comprehensive transcriptome profiling of human KTCN corneas points further to a complex etiology of KTCN.

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“…However, other patterns of inheritance have also been described. 8 Genetic contribution to the pathogenesis of KTCN is supported by studies showing higher concordance of disease in monozygotic than in dizygotic twins. 9 Several loci implicated in a familial form of KTCN have been reported and there is now a growing list of candidate KTCN genes.…”

Section: Introductionmentioning

confidence: 99%

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

et al. 2016

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Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1-q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency o0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T4G in SKP1, c.671G4A in PROB1, and c.527G4A in IL17B in the 5q31.1-q35.3 linkage region, and c.850G4A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1-q35.3 locus might be linked with KTCN.

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Genetics of Keratoconus: Where Do We Stand?

Cited by 77 publications

References 98 publications

Keratoconus: an inflammatory disorder?

Keratoconus: an inflammatory disorder?

Collagen synthesis disruption and downregulation of core elements of TGF-β, Hippo, and Wnt pathways in keratoconus corneas

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1–q35.3 susceptibility locus identified by whole-exome sequencing

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