Jurkute Neringa, Brennenstuhl Heiko, Kustermann Monika, Van Haute Lindsey, Mutti Christian D, Bugiardini Enrico, Handa Takayuki, Shimura Masaru, Petzold Axel, Acheson James, Robson Anthony G, Macken William L, Hanna Michael G, Pitceathly Robert D S, Merve Ashirwad, Kotzaeridou Urania, Kölker Stefan, Freilinger Michael, Erdler Marcus, Bittner Reginald E, Mayr Johannes A, Okazaki Yasushi, Murayama Kei, Prokisch Holger, Webster Andrew R, Minczuk Michal, Arno Gavin, Pemp Berthold, Hoffmann Georg F, Schmidt Wolfgang M, Yu-Wai-Man Patrick
Moorfields Eye Hospital NHS Foundation Trust, London, UK.
Institute of Ophthalmology, University College London, London, UK.
Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):17. doi: 10.1167/iovs.66.6.17.
Primary mitochondrial disorders (PMDs) are a clinically heterogeneous group of genetic disorders that can affect many tissues, with a broad phenotypic spectrum ranging from isolated organ involvement to severe early-onset multisystem disease. Visual loss from optic atrophy is a frequent clinical manifestation of mitochondrial cytopathies. This study aimed to identify the missing heritability in previously unsolved cases of suspected isolated or syndromic optic neuropathy. Based on three recent reports on biallelic NSUN3 variants causing early-onset PMD, we explored in detail the genetic and clinical spectrum of NSUN3-associated disease.
Affected individuals were analyzed by exome or genome sequencing. In silico variant analysis and functional assays were performed to investigate the consequences of the identified variants. Detailed phenotyping data were collected from medical records and direct questioning after the identification of candidate-likely pathogenic variants.
Interrogation of exome and genome sequencing data led to the identification of six candidate NSUN3 variants in eight affected individuals from five unrelated families (including a previously reported case). A broad phenotypic spectrum was observed ranging from isolated optic atrophy to severe early-onset PMD. Identified NSUN3 variants impairing NSUN3 activity are located within the S-adenosylmethionine-dependent methyltransferases domain and loss of function variants were associated with a more severe phenotype. Remarkably, bilateral optic atrophy was a unifying clinical feature observed in almost all affected individuals.
Pathogenic or likely pathogenic biallelic variants in NSUN3 disrupt mt-tRNAMet methylation and mitochondrial translation leading to mitochondrial disease ranging from mild isolated optic atrophy to a severe multisystemic phenotype with possible limited life expectancy.
原发性线粒体疾病（PMDs）是一组临床异质性的遗传疾病，可影响多个组织，具有广泛的表型谱，从孤立器官受累到严重的早发性多系统疾病。视神经萎缩导致的视力丧失是线粒体细胞病的常见临床表现。本研究旨在确定先前未解决的疑似孤立性或综合征性视神经病变病例中缺失的遗传力。基于最近三篇关于双等位基因NSUN3变异导致早发性PMD的报道，我们详细探讨了NSUN3相关疾病的遗传和临床谱。
对受影响个体进行外显子组或基因组测序分析。进行了计算机变异分析和功能测定，以研究已鉴定变异的后果。在鉴定出可能的致病候选变异后，从医疗记录和直接询问中收集详细的表型数据。
对全外显子组和基因组测序数据的审查导致在来自五个无关家庭的八名受影响个体（包括一个先前报道的病例）中鉴定出六个候选NSUN3变异。观察到从孤立性视神经萎缩到严重早发性PMD的广泛表型谱。损害NSUN3活性的已鉴定NSUN3变异位于依赖S-腺苷甲硫氨酸的甲基转移酶结构域内，功能丧失变异与更严重的表型相关。值得注意的是，双侧视神经萎缩是几乎所有受影响个体中观察到的一个统一临床特征。
NSUN3中的致病或可能致病的双等位基因变异破坏线粒体tRNAMet甲基化和线粒体翻译，导致线粒体疾病，范围从轻度孤立性视神经萎缩到严重的多系统表型，预期寿命可能有限。
