A mouse model of brittle cornea syndrome caused by mutation in <i>Zfp469</i>

Stanton, Chloe; Findlay, Amy S.; Drake, Camilla; Mustafa, Mohammad Z.; Gautier, Philippe; McKie, Lisa; Jackson, Ian J.; Vitart, Véronique

doi:10.1242/dmm.049175

Cited by 10 publications

(24 citation statements)

References 63 publications

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“…S3A and S3B). The latter point is particularly important for genes such as ZNF469, as its transcript harbors one large coding exon and CRISPR mutations do not lead to nonsense mediated mRNA decay as previously demonstrated for the mouse homolog ( 30 ). Notably, only the targeting of three TFs ( ZNF469 , RUNX1 , TBX3 ) resulted in a significant (FDR < 0.01) downregulation of COL1A1 mRNA (Fig.…”

Section: Resultsmentioning

confidence: 83%

“…Both are developmental disorders that feature organ dysfunction from loss of collagen in the eye and musculoskeletal system, respectively. Moreover, deletion of ZNF469 in developing zebrafish decreases synthesis of collagen and proteoglycans ( 39 ); and knockout of Zfp469 in mice recapitulates BCS with decreased collagen deposition in the cornea ( 30 ). No liver phenotypes in the KO mice were described and no adverse effects on viability or fertility were observed ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, deletion of ZNF469 in developing zebrafish decreases synthesis of collagen and proteoglycans ( 39 ); and knockout of Zfp469 in mice recapitulates BCS with decreased collagen deposition in the cornea ( 30 ). No liver phenotypes in the KO mice were described and no adverse effects on viability or fertility were observed ( 30 ). In addition, it was shown that targeting ZNF469 with siRNAs decreases COL1A1 and COL1A2 in dermal fibroblasts ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

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The transcription factor ZNF469 regulates collagen production in liver fibrosis

Steinhauser,

Estoppey,

Buehler

et al. 2024

Preprint

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Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

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Section: Resultsmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The transcription factor ZNF469 regulates collagen production in liver fibrosis

Steinhauser,

Estoppey,

Buehler

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…This group demonstrated that induced mutations in a dermal fibroblast ZNF469 gene lead to significant increases in Clusterin, Glypican, and Procollagen C-endopeptidase enhancer 2, and a significant reduction in Thrombospondin while immunofluorescence staining showed a disarray of Collagens I and III, fibronectin, and their receptor integrins [11]. Stanton et al demonstrated in a murine knockout model that an induced loss of function mutation in ZNF469 leads to decreased biomechanical strength of the cornea, likely through ECM dysfunction [12].…”

Section: Discussionmentioning

confidence: 99%

Identification of Single-Nucleotide Polymorphisms in ZNF469 in a Patient with Aortoiliac Aneurysmal Disease

2022

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Thoracic aortic aneurysms and dissections often have inter-related pathologies that are increasingly recognized to have a genetic basis. A patient with a vascular history consisting of a spontaneous aorto-iliac dissection and thoracic aortic aneurysm belonged to a family with a significant self-reported history of aneurysmal disease. Suspecting a genetic component, genetic investigation was undertaken. Three variants of unknown significance were found in the ZNF469 gene, which is responsible for the production of a collagen-related zinc finger protein involved in multiple aspects of the development and regulation of major extracellular matrix components. This is the first report to associate this gene with vasculopathy, and further investigation by our group is underway to understand the role it plays in the development of aneurysmal diseases.

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“…As a result, the corneal stroma thickness of homozygous mutants is reduced by approximately 50% after conversion according to the thickness ratio of the epithelium and stroma. 18 In this study, we generated a znf469 mutant zebrafish line to elucidate its roles in zebrafish corneal development and applied RNA-sequencing (RNA-seq) to elucidate the possible pathogenesis of BCS induced by znf469 mutations.…”

mentioning

confidence: 99%

Znf469 Plays a Critical Role in Regulating Synthesis of ECM: A Zebrafish Model of Brittle Cornea Syndrome

Bao

Ping

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by extreme thinning and fragility of the cornea, and mutations in ZNF469 cause BCS-1. We aimed to establish a znf469 mutant zebrafish line to explore its roles and possible pathogenic mechanism in cornea development and disorder. Methods znf469 4del/4del mutant zebrafish was generated using the CRISPR/Cas9 technology. Transmission electron microscopy (TEM) was performed to examine the phenotype of the cornea in different developmental stages. RNA sequencing and quantitative real-time polymerase chain reaction were used to reveal the molecular mechanism. Results Macroscopically, homozygous znf469 mutant zebrafish larvae exhibited a curved body from 72 hours postfertilization, similar to kyphoscoliosis, and a noninflated swimbladder at 7 days postfertilization (dpf). TEM revealed an extreme reduction of corneal stroma thickness in homozygous znf469 mutant zebrafish in both the central and peripheral cornea from the early development stage. RNA-sequencing analysis demonstrated that the znf46 9 mutation leads to the decreased synthesis of various extracellular matrix (ECM) components, such as collagens and proteoglycans, but increased synthesis of 26S proteasome family members. Conclusions The results of our work indicate that znf469 is a critical gene that, as a widely considered transcription factor, may regulate the synthesis and degradation of a large number of ECM components that play an important role in corneal development.

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A mouse model of brittle cornea syndrome caused by mutation in Zfp469

Cited by 10 publications

References 63 publications

The transcription factor ZNF469 regulates collagen production in liver fibrosis

The transcription factor ZNF469 regulates collagen production in liver fibrosis

Identification of Single-Nucleotide Polymorphisms in ZNF469 in a Patient with Aortoiliac Aneurysmal Disease

Znf469 Plays a Critical Role in Regulating Synthesis of ECM: A Zebrafish Model of Brittle Cornea Syndrome

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