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Jurkute, N.* ; Brennenstuhl, H.* ; Kustermann, M.* ; van Haute, L.* ; Mutti, C.D.* ; Bugiardini, E.* ; Handa, T.* ; Shimura, M. ; Petzold, A.* ; Acheson, J.* ; Robson, A.G.* ; Macken, W.L.* ; Hanna, M.G.* ; Pitceathly, R.D.S.* ; Merve, A.* ; Kotzaeridou, U.* ; Kölker, S.* ; Freilinger, M.* ; Erdler, M.* ; Bittner, R.E.* ; Mayr, J.A.* ; Okazaki, Y.* ; Murayama, K.* ; Prokisch, H. ; Webster, A.R.* ; Minczuk, M.* ; Arno, G.* ; Pemp, B.* ; Hoffmann, G.F.* ; Schmidt, W.M.* ; Yu-Wai-Man, P.*

Biallelic NSUN3 variants cause diverse phenotypic spectrum disease: From isolated optic atrophy to severe early-onset mitochondrial disorder.

Invest. Ophthalmol. Vis. Sci. 66:17 (2025)
Publ. Version/Full Text DOI PMC
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Inherited Optic Neuropathy ; Mitochondrial Disorder ; Mt-trna Modification ; Nsun3 ; Optic Atrophy ; Trna Methylation; S-adenosylmethionine; Dna; Adenosylhomocysteine; Deficiency; Neuropathy; Oxidation
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 0146-0404
e-ISSN 1552-5783
Journal Investigative Ophthalmology & Visual Science, IOVS
Quellenangaben Volume: 66, Issue: 6, Pages: , Article Number: 17 Supplement: ,
Publisher Association for Research in Vision and Ophthalmology (ARVO)
Publishing Place 12300 Twinbrook Parkway, Rockville, Md 20852-1606 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-503292-001
Grants physician scientist program of the Medical Faculty of the University of Heidelberg
Moorfields Eye Charity
Isaac Newton Trust (UK)
Fight for Sight (UK)
UK National Institute of Health Research (NIHR)
Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme - UK NHS Highly Specialised Commissioners
Medical Research Council (UK)
LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito)
Medical Research Council (UK) award
Medical Research Council (UK) Transition Support award
Stoneygate Foundation
Addenbrooke's Charitable Trust
National Eye Research Centre (UK)
International Foundation for Optic Nerve Disease (IFOND)
FWF
JAM (Austrian Science Fund)
European Joint Programme on Rare Diseases
LifeArc
UCL Institute of Ophthalmology
NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust
NIHR Cambridge Biomedical Research Centre
NIHR
Rosetrees Trust
DOI 10.1167/iovs.66.6.17
WOS ID 001537564100031
Scopus ID 105007438331
PubMed ID 40465263
Erfassungsdatum 2025-06-05
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