Mutational Analysis of<i>MIR184</i>in Sporadic Keratoconus and Myopia

Lechner, Judith; Bae, Ha Ae; Guduric-Fuchs, Jasenka; Rice, Anthony J.; Govindarajan, Gowthaman; Siddiqui, Salina; Farraj, Layal Abi; Yip, Shea Ping; Yap, Maurice; Das, Manoranjan; Souzeau, Emmanuelle; Coster, D. J.; Mills, Richard A.; Lindsay, Richard; Phillips, Tony; Mitchell, Paul; Ali, Manir; Inglehearn, Chris F.; Sundaresan, Periasamy; Craig, Jamie E; Simpson, David; Burdon, Kathryn P.; Willoughby, Colin E.

doi:10.1167/iovs.13-12035

Cited by 71 publications

(66 citation statements)

References 42 publications

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“…Iliff et al reported the same mutation as the cause of EDICT syndrome, an autosomal dominant anterior segment dysgenesis syndrome characterized by endothelial dystrophy, iris hypoplasia, congenital cataract and stromal thinning (37). A further two novel heterozygous substitution variants, neither of which were located within the seed region, were later identified in MIR184 in two patients with isolated keratoconus (38).…”

Section: Discussionmentioning

confidence: 97%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

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

100

111

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Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.

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Section: Discussionmentioning

confidence: 97%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

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

100

111

View full text Add to dashboard Cite

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“…50,82,83 To establish whether mutations in mir-184 were associated with KC, mir-184 was subsequently screened in a cohort of 780 KC patients. 84 Rare variants were identified in two (0.25%) patients, but the variants did not fully segregate with disease, suggesting that mir-184 variants are not a common cause of isolated KC. 84 Genome-wide association studies (GWAS) are a powerful tool to identify common variants of relatively low effect as risk factors for complex disease.…”

Section: Geneticsmentioning

confidence: 94%

“…84 Rare variants were identified in two (0.25%) patients, but the variants did not fully segregate with disease, suggesting that mir-184 variants are not a common cause of isolated KC. 84 Genome-wide association studies (GWAS) are a powerful tool to identify common variants of relatively low effect as risk factors for complex disease. 85 Several KC GWAS have been performed, but with relatively small numbers of patients.…”

Section: Geneticsmentioning

confidence: 94%

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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“…[53][54][55] Recently, mutations in MIR184 have been identified as an uncommon cause of keratoconus. 55,56 LOX (locus 5q23.2), the gene encoding lysyl oxidase (LOX) enzyme, which is involved in collagen and elastin cross-linking, have also been related to keratoconus. 57 Association between single-nucleotide polymorphisms in the hepatocyte growth factor (HGF) gene and keratoconus has been found.…”

Section: Geneticsmentioning

confidence: 99%

Keratoconus: an inflammatory disorder?

Galvis

Sherwin

Tello

et al. 2015

Eye

301

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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Mutational Analysis ofMIR184in Sporadic Keratoconus and Myopia

Abstract: Two novel heterozygous substitution mutations in MIR184 were identified in two patients with isolated keratoconus: miR-184(+8C>A) and miR-184(+3A>G). Mutations in MIR184 are a rare cause of keratoconus and were found in 2 of 780 (0.25%) cases.

Cited by 71 publications

References 42 publications

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

The pathogenesis of keratoconus

Keratoconus: an inflammatory disorder?

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