Substitution at<i>IL1RN</i>and Deletion at<i>SLC4A11</i>Segregating with Phenotype in Familial Keratoconus

Nowak, Dorota; Karolak, Justyna A.; Kubiak, Joanna; Gut, Marta; Pitarque, Jose A.; Molinari, Andrea; Bejjani, Bassem A.; Gajęcka, Marzena

doi:10.1167/iovs.13-11592

Cited by 40 publications

(35 citation statements)

References 68 publications

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“…At least 60 mutations have been identified as being associated with corneal endothelial dystrophy and/or perceptive deafness (40). A recent clinical study suggests that homozygous SLC4A11 mutated congenital hereditary endothelial dystrophy patients progress to Harboyan syndrome at a later age (perceptive deafness and corneal endothelial dystrophy (41)), whereas another study associated SLC4A11 mutants with the corneal ectasia disorder keratoconus (42). In the kidney, SLC4A11 is highly expressed in the thin descending limb of loop of Henle (7).…”

Section: Discussionmentioning

confidence: 99%

Human SLC4A11 Is a Novel NH3/H+ Co-transporter

Zhang

Ogando

Bonanno

et al. 2015

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Human SLC4A11 Is a Novel NH3/H+ Co-transporter

Zhang

Ogando

Bonanno

et al. 2015

Journal of Biological Chemistry

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“…On the other hand, in all KTCN patients, we found a c.214+242C4T variant in the IL1RN gene, whose protein product modulates the effect of IL-1. 15 The c.527G4A in IL17B is the second variant in interleukin genes family segregating with KTCN in the Ecuadorian families and the first with predicted pathogenicity for the protein structure and function. However, it is not clear whether the interleukin alteration contributes to KTCN.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15] Whole-exome sequencing (WES), which allows determination of the rare and unique coding sequence variants in an individual personal genome, can be also utilized in familial studies. However, due to a number of candidate genes generated by linkage analysis or WES, the evaluation of each individual variant is challenging.…”

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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“…Усиленный апоптоз кератиноцитов рогови-цы, наблюдаемый в 60 % случаев кератоконуса и вызывающий стромальное истончение, об-условлен высвобождением интерлейкина IL-1b вследствие хронической механической травмы эпителия роговицы [13,25]. Мутации в регуля-торной области гена IL1B (-31С > T, rs1143627; -511С > T, rs16944) повышают концентрацию цитокина и риск кератоконуса.…”

Section: генетика кератоконусаunclassified

“…Интронный полиморфизм 376C > А в гене IL1А (интерлейкин-1) снижает риск заболевания [1]. Анализ сцепления идентифицировал замену 242С > T в гене IL1RN, которая сегрегирует с фе-нотипом кератоконуса [25]. Таким образом, по-лиморфизм генов, кодирующих белки семейства IL-1, является фактором предрасположенности к кератоконусу.…”

Section: генетика кератоконусаunclassified

Molecular genetic aspects of keratoconus pathogenesis

Kulikov

Churashov

Kamilova

et al. 2017

Ophthalmology Reports

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Keratoconus is a bilateral, progressive corneal disease affecting all ethnic groups around the world. It is one of the major ocular problems with significant social impacts as the disease affects young generation, and is the leading cause of corneal transplantation. Although keratoconus is associated with genetic and environmental factors, its precise etiology is not yet established. Results from complex segregation analysis and patterns of gene expression show that genetic abnormalities may play an essential role in the susceptibility to keratoconus. There is a strong association between the polymorphism of a number of genes and corneal curvature. These polymorphisms explain only a small percentage of keratoconus cases, so genetic influences on keratoconus are most likely complex and varied. The aim of this review is to briefly provide the current knowledge on the genetic keratoconus basis - to understand the disease pathogenesis.

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Substitution atIL1RNand Deletion atSLC4A11Segregating with Phenotype in Familial Keratoconus

Cited by 40 publications

References 68 publications

Human SLC4A11 Is a Novel NH3/H+ Co-transporter

Human SLC4A11 Is a Novel NH3/H+ Co-transporter

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

Molecular genetic aspects of keratoconus pathogenesis

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