METTL23 mutation alters histone H3R17 methylation in normal-tension glaucoma

Abstract

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 a three-generation Japanese NTG family. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23 knock-in (Mettl23 +/G & Mettl23 G/G ) and knockout (Mettl23 +/-& 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 Mettl23 G/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 α target gene that was critical to RGC homeostasis through the negative regulation of NF-κB-mediated TNF-α/IL-1β feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Epigenetics in glaucoma: a link between DNA methylation and neurodegeneration

“…This study by Pan et al highlights the role of histone arginine methylation in neurodegenerative processes and raises important questions for the field ( 8 ). Are there other targets of METTL23 that play critical roles in RGC survival?…”

“…The elegant study by Pan et al in this issue of the JCI describes a genetic cause of NTG and reports a mutant histone methyltransferase leading to NTG ( 8 ). The investigators identified a family of three generations of Japanese patients with NTG and a splicing mutation in the methyltransferase-like 23 ( METTL23 ) gene, which encodes a histone arginine methyltransferase.…”

“…A notable contribution of Pan et al ( 8 ) is the link between histone methylation and glaucoma, which may have implications for other forms of neurodegenerative disorders. There has been increasing evidence that alterations in DNA methylation play an important role in neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyloid lateral sclerosis (ALS) ( 9 ).…”

“…Will METTL23 be a more viable target? The study by Pan and colleagues ( 8 ) opens new areas of epigenetics as therapeutic targets for glaucomatous neurodegeneration and provides important evidence for the role of histone arginine methylation in neuronal survival and function.…”

Posttranslational modifications of proteins in diseased retina

“…Their conclusion aligns with that of a 2012 study by Zhang et al (2012) who report the RGC neuroprotective effects of broad-spectrum HDAC inhibitors following optic nerve crush. Pan et al (2022) mapped a mutation in the gene encoding Methyltransferase-like 23 ( METTL23 ) in a familial case of normal tension glaucoma. That research group demonstrated the possible significance of this mutation by demonstrating that mice overexpressing or lacking in Mettl23 develop glaucoma-like phenotypes in the absence of elevated IOP.…”