Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Xu, Liyan; Yang, Kaili; Yin, Shanshan; Gu, Yuwei; Fan, Qi; Wang, Yawen; Zhao, Dongqing; Ren, Shuxin

doi:10.3389/fgene.2022.988620

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Furthermore, we identified changes in DNA methylation level in WNT3 and WNT5A genes encoding Wnt ligands, which might be an explanation for the Wnt signaling pathway dysregulation in KTCN ( Kabza et al, 2019 ). Several other studies support our results ( Khaled et al, 2018 ; Xu L. et al, 2022 ; Dou et al, 2022 ; Akoto et al, 2023 ), including Bykhovskaya et al claiming that the development of KTCN results in deregulation of gene expression of ECM and adhesion molecules ( Bykhovskaya et al, 2016 ). The result highlighting the pathway of response to mechanical stimuli is consistent with the existing literature and our current studies on environmental factors and habits of patients with KTCN, which have pointed to repetitive mechanical corneal injuries caused by eye rubbing as a factor contributing to the development of KTCN, potentially through the alteration of gene expression in corneal epithelium ( Najmi et al, 2019 ; Jaskiewicz et al, 2023c ).…”

Section: Discussionsupporting

confidence: 90%

Differentially expressed microRNAs targeting genes in key pathways in keratoconus

Nowak-Malczewska,

Swierkowska,

Gajecka

2024

Front. Genet.

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Introduction: Keratoconus (KTCN) is a corneal ectasia, characterized by a progressive thinning and protrusion of the cornea, with a complex etiology involving genetic, behavioral, lifestyle, and environmental factors. Previous studies indicated that microRNAs (miRNAs) could be involved in KTCN pathogenesis. This in silico study aimed to identify precursor microRNAs (pre-miRNAs) differentially expressed in KTCN corneas and to characterize mature miRNAs and their target genes.Materials and methods: Expression levels of pre-miRNAs were retrieved from our previously obtained RNA sequencing data of 25 KTCN and 25 non-KTCN human corneas (PMID:28145428, PMID:30994860). Differential expression with FDR ≤0.01 and ≥1.5-fold changes were considered significant. Lists of target genes (target score ≥90) of mature miRNAs were obtained from miRDB. Revealed up-/downregulated miRNAs and their target genes were assessed in databases and literature. Enrichment analyses were completed applying the DAVID database.Results: From a total of 47 pre-miRNAs, six were remarkably upregulated (MIR184, MIR548I1, MIR200A, MIR6728, MIR429, MIR1299) and four downregulated (MIR6081, MIR27B, MIR23B, MIR23A) in KTCN corneas. Out of the 1,409 target genes, 220 genes with decreased and 57 genes with increased expression levels in KTCN samples vs non-KTCN samples were found. The extracellular matrix (ECM) organization, response to mechanical stimulus, regulation of cell shape, and signal transduction processes/pathways were identified as distinctive in enrichment analyses. Also, processes associated with the regulation of transcription and DNA binding were listed.Conclusion: Indicated miRNAs and their target genes might be involved in KTCN pathogenesis via disruption of crucial molecular processes, including ECM organization and signal transduction.

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Section: Discussionsupporting

confidence: 90%

Differentially expressed microRNAs targeting genes in key pathways in keratoconus

Nowak-Malczewska,

Swierkowska,

Gajecka

2024

Front. Genet.

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“…Notably, SHROOM3 has also been implicated in facial development, as evidenced by signi cant association between SHROOM3 and HFM 89 , cleft lip with or without cleft palate or cleft palate 1213 , orofacial clefts 14 , neural tube defects 1516 , and Keratoconus 17 . However, no study has yet investigated whether pathogenic variants in SHROOM3 contribute to HFM.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Variants in SHROOM3 Associated with Hemifacial Microsomia

Wang

Li²,

Zhang³

et al. 2023

Preprint

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Purpose: Hemifacial microsomia (HFM) is a rare congenital disorder that affects facial symmetry, ear development, and other congenital features. However, known causal genes only account for approximately 3% of patients, indicating the need to discover more pathogenic genes. Methods: We performed target capture sequencing on SHROOM3 in 320 Chinese HFM patients and evaluated the expression pattern of SHROOM3 and the consequences of deleterious mutations. Results: Our study identified 9 deleterious mutations in SHROOM3 in 320 Chinese HFM patients. These mutations were predicted to significantly impact SHROOM3 function. Furthermore, the gene expression pattern of SHROOM3 in pharyngeal arches and the presence of facial abnormalities in gene-edited mice suggest important roles of SHROOM3in facial development. Conclusion: Our findings suggest that SHROOM3 is a likely pathogenic gene for HFM.

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“…The protein also interacts directly with the CAPN3 protein, which is involved in the organization of the extracellular matrix. Therefore, TTN is suggested as a possible candidate gene due to its indirect action in the organization of the ECM [50].…”

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confidence: 99%

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus

González-Atienza,

Sánchez-Cazorla,

Villoldo-Fernández

et al. 2023

Genes

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Keratoconus is a corneal dystrophy that is one of the main causes of corneal transplantation and for which there is currently no effective treatment for all patients. The presentation of this disease in pediatric age is associated with rapid progression, a worse prognosis and, in 15–20% of cases, the need for corneal transplantation. It is a multifactorial disease with genetic variability, which makes its genetic study difficult. Discovering new therapeutic targets is necessary to improve the quality of life of patients. In this manuscript, we present the results of whole-exome sequencing (WES) of 24 pediatric families diagnosed at the University Hospital La Paz (HULP) in Madrid. The results show an oligogenic inheritance of the disease. Genes involved in the structure, function, cell adhesion, development and repair pathways of the cornea are proposed as candidate genes for the disease. Further studies are needed to confirm the involvement of the candidate genes described in this article in the development of pediatric keratoconus.

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Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Cited by 4 publications

References 46 publications

Differentially expressed microRNAs targeting genes in key pathways in keratoconus

Differentially expressed microRNAs targeting genes in key pathways in keratoconus

Pathogenic Variants in SHROOM3 Associated with Hemifacial Microsomia

Whole-Exome Sequencing of 24 Spanish Families: Candidate Genes for Non-Syndromic Pediatric Keratoconus

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