Fine-mapping and cell-specific enrichment at corneal resistance factor loci prioritize candidate causal regulatory variants

Jiang, Xinyi; Dellepiane, Nefeli; Pairo-Castineira, Erola; Boutin, Thibaud; Kumar, Yatendra; Bickmore, Wendy A.; Vitart, Véronique

doi:10.1038/s42003-020-01497-w

“…This study is the first to show a direct impact of LOF of Zfp469 upon cornea biomechanical strength. However, the genetic association of regulatory variants for ZNF469 with corneal resistance factor in genome-wide association studies indicates that ZNF469 also plays a role in determining the biomechanical properties of the cornea in humans ( Jiang et al, 2020 ; Khawaja et al, 2019 ; Simcoe et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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

Stanton

¹

,

Findlay

²

,

Drake

³

et al. 2021

Disease Models &Amp; Mechanisms

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Brittle Cornea Syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene, Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the type I:type V collagen ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of type I collagen offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus where the cornea thins progressively.

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“…This study is the first to show a direct impact of LOF of Zfp469 upon cornea biomechanical strength. However, the genetic association of regulatory variants for ZNF469 with corneal resistance factor (CRF) in genome-wide association studies indicates that ZNF469 also plays a role in determining biomechanical properties of the cornea in humans (Jiang et al, 2020; Khawaja et al, 2019; Simcoe et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model of Brittle Cornea Syndrome caused by mutation in Zfp469

Stanton

¹

,

Findlay

²

,

Drake

³

et al. 2021

Preprint

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Brittle Cornea Syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene, Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the type I:type V collagen ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of type I collagen offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus where the cornea thins progressively.Summary statementA mouse model of Brittle Cornea Syndrome was created to elucidate molecular mechanisms underlying pathology of this rare connective tissue disorder in which extremely thin corneas rupture, causing irreversible blindness.

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