METTL23 mutations and normal tension glaucoma (NTG) in a United States population

Abstract

Purpose : Recently, a mutation in the methyltransferase-like 23 (METTL23) gene was discovered in a single normal tension glaucoma (NTG) pedigree (Pan, 2022). We sought to confirm the association of METTL23 mutations with NTG and determine their prevalence.

Methods : We tested patients with NTG and normal controls for mutations in the METTL23 gene using a combination of whole exome sequencing and Sanger sequencing. Identified mutations were evaluated for potential pathogenicity using five different mutation analysis algorithms, sequence conservation analysis, molecular analysis of mutant METTL23 protein structure, and by investigating mutation frequency in large public databases.

Results : We tested 331 NTG patients and 362 normal controls for METTL23 mutations. A total of 5 instances of 4 missense mutations were discovered among NTG patients (p.Arg7Val, p.Pro22Arg, p.Arg63Trp, and p.Asp166Asn). No METTL23 mutations were detected among NTG patients. METTL23 mutations were detected in NTG patients, 5 of 331 (1.5%) a significantly greater frequency than in normal controls, 0 of 396 (0%) with p = 0.025. Mutation analyses all strongly suggested that the p.Arg63Trp METTL23 mutation is pathogenic. The vast majority of mutation analyses suggested that p.Asp166Asn mutation is benign, while the data were mixed for pArg7Val and p.Pro22Arg.

Conclusions : We provide the first confirmation that mutations in METTL23 are a cause of NTG and the first estimate of their prevalence. Mutations in METTL23 may be responsible for up to 1.5% of NTG cases, a mutation frequency similar to that observed in other known NTG-causing genes (OPTN and TBK1).

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.