METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23-knock-in (Mettl23+/G and Mettl23G/G) and-knockout (Mettl23+/- and Mettl23-/-) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor alpha target gene that was critical for RGC homeostasis through the negative regulation of NF-KB-mediated TNF-alpha and IL-1 beta feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Automated summary

Normal-tension glaucoma (NTG) is characterized by retinal ganglion cell death and visual field loss. This research identifies a mutation in the METTL23 gene associated with NTG in a Japanese family. The mutation impacts protein production and localization, leading to glaucoma phenotypes in mice. Additionally, METTL23 plays a role in transcription regulation of key genes in the retina.