Abstract
ABSTRACTBrittle 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 collagen type I/collagen type V 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 collagen type I, 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 in which the cornea thins progressively. This article has an associated First Person interview with the first author of the paper.
Highlights
Brittle cornea syndrome (BCS; OMIM 229200; OMIM 614170) is a rare autosomal recessive disorder that is characterised by extreme thinning of the cornea and sclera
Of the 30 genetic variants that have been reported as homozygous or compound heterozygous mutations in BCS cases, 27 (90%) result in either nonsense or frameshift mutations in ZNF469, which are predicted to result in the production of a truncated protein
BCS was first reported in 1968 (Stein et al, 1968) but it was another 40 years until mutations in ZNF469 were identified as a cause of this rare condition
Summary
Brittle cornea syndrome (BCS; OMIM 229200; OMIM 614170) is a rare autosomal recessive disorder that is characterised by extreme thinning of the cornea and sclera. Since mutations in ZNF469 were first reported to cause BCS (Abu et al, 2008), 30 pathogenic compound heterozygous or homozygous mutations have been identified in the single coding exon of ZNF469 spanning 13 kb on chromosome 16q24.2 (Abu et al, 2008; AlOwain et al, 2012; Christensen et al, 2010; Dhooge et al, 2021; Khan et al, 2012, 2010; Menzel-Severing et al, 2019; Micheal et al, 2019; Ramappa et al, 2014; Rohrbach et al, 2013; Rolvien et al, 2020; Skalicka et al, 2020) The majority of these mutations result in premature stop codons that are hypothesised to lead to the production of truncated and non-functional protein (Rohrbach et al, 2013), and are considered as LOF mutations
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