Evidence map›Paper›PMID 40465263›Full record

ArticleInvestigative ophthalmology & visual science2025

Biallelic NSUN3 Variants Cause Diverse Phenotypic Spectrum Disease: From Isolated Optic Atrophy to Severe Early-Onset Mitochondrial Disorder.

Neringa Jurkute, Heiko Brennenstuhl, Monika Kustermann, Lindsey Van Haute, Christian D Mutti, Enrico Bugiardini, Takayuki Handa, Masaru Shimura, Axel Petzold, James Acheson and 21 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Investigative ophthalmology & visual science, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Review
  2. Review
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

31 authors.

Neringa JurkuteMoorfields Eye Hospital NHS Foundation Trust, London, UK.
Heiko BrennenstuhlDepartment of General Pediatrics, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Monika KustermannNeuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Lindsey Van HauteMedical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
Christian D MuttiMedical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
Enrico BugiardiniDepartment of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
Takayuki HandaDepartment of Pediatrics, Toho University Ohashi Medical Center, Tokyo, Japan.
Masaru ShimuraInstitute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
Axel PetzoldMoorfields Eye Hospital NHS Foundation Trust, London, UK.
James AchesonMoorfields Eye Hospital NHS Foundation Trust, London, UK.
Anthony G RobsonMoorfields Eye Hospital NHS Foundation Trust, London, UK.
William L MackenDepartment of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
Michael G HannaDepartment of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
Robert D S PitceathlyDepartment of Neuromuscular Diseases, University College London Queen Square Institute of Neurology, London, UK.
Ashirwad MerveDepartment of Neuropathology, The National Hospital for Neurology and Neurosurgery, London, UK.
Urania KotzaeridouDepartment of General Pediatrics, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Stefan KölkerDepartment of General Pediatrics, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Michael FreilingerDepartment of Paediatrics and Adolescent Medicine, Neuropediatrics, Medical University of Vienna, Vienna, Austria.
Marcus ErdlerDepartment of Neurology, Klinik Donaustadt, Karl-Landsteiner-Institut, Vienna, Austria.
Reginald E BittnerNeuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Johannes A MayrDepartment of Pediatrics, University Hospital Salzburg, Paracelsus Medical University, Salzburg, Austria.
Yasushi OkazakiDiagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Kei MurayamaDiagnostics and Therapeutic of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
Holger ProkischSchool of Medicine, Institute of Human Genetics, Technische Universität München, Munich, Germany.
Andrew R WebsterMoorfields Eye Hospital NHS Foundation Trust, London, UK.
Michal MinczukMedical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
Gavin ArnoMoorfields Eye Hospital NHS Foundation Trust, London, UK.
Berthold PempDepartment of Ophthalmology and Optometry, Medical University of Vienna, Vienna, Austria.
Georg F HoffmannDepartment of General Pediatrics, Division of Pediatric Neurology and Metabolic Medicine, Heidelberg University Hospital, Heidelberg, Germany.
Wolfgang M SchmidtNeuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Patrick Yu-Wai-ManMoorfields Eye Hospital NHS Foundation Trust, London, UK.

Funding

Wellcome Trust
6 · The paper itself

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Indexed as

MethyltransferasesMitochondrial DiseasesMutationOptic AtrophyAdolescentAdultChildChild, PreschoolExome SequencingFemaleHumansMaleMiddle AgedPedigreePhenotypeYoung AdultMethyltransferases

Identifiers

PMID40465263
PMCPMC12147050

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.