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Fiorini, C.* ; Jurkute, N.* ; Torraco, A.* ; La Morgia, C.* ; Ghezzi, D.* ; Tioli, G.* ; Rigobello, L.* ; Ormanbekova, D.* ; Berghella, A.* ; Pietro Pasti, A.* ; Palombo, F.* ; Barboni, P.* ; Lucia Cascavilla, M.* ; Sudan, F.* ; De Negri, A.* ; Bertini, E.* ; Musumeci, O.* ; Ardissone, A.* ; Rizza, T.* ; Iarossi, G.* ; Silvestri, G.* ; Rossi, S.* ; Altobelli, A.* ; Moore, A.T.* ; Cullup, T.* ; Webster, A.R.* ; Davagnanam, I.* ; Michaelides, M.* ; Malka, S.* ; Ptackova, H.* ; Stufkova, H.* ; Tesarova, M.* ; Liskova, P.* ; Zeng, L.* ; Klopstock, T.* ; Kopajtich, R. ; Neuhofer, C. ; Prokisch, H. ; Lamperti, C.* ; Sadun, A.A.* ; Yu-Wai-Man, P.* ; Carelli, V.* ; Musiani, F.* ; Iommarini, L.* ; Carrozzo, R.* ; Arno, G.* ; Caporali, L.*

Recessive variants in mitochondrial Complex I nuclear subunits are an underrated cause of optic atrophy.

Brain 149, 2463-2479 (2025)
Postprint Research data DOI PMC
Open Access Hybrid
Our understanding of the genetic landscape of inherited optic neuropathies has grown significantly over the past decades, and it is now known to involve many genes found in both the nuclear and mitochondrial genomes, exhibiting all possible inheritance patterns. Furthermore, pathogenic variants in nuclear genes of mitochondrial respiratory Complex I (CI) subunits have been identified in some cases of ION, in addition to the more common severe presentation of CI deficiencies, usually with early onset. We conducted NGS screening of CI genes to identify potential causative variants in patients with optic atrophy, also performing comprehensive clinical assessments, including neuroimaging studies (MRI) and neurological evaluations. Detailed molecular structure modeling was performed to better evaluate the damaging effects of both novel and previously reported variants in the relevant CI subunits. We identified and characterized candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear CI-related genes encoding polypeptides involved in the structure of CI, including 3 core subunits (NDUFS7, NDUFV1, NDUFV2), 4 accessory subunits (NDUFA1, NDUFA10, NDUFA12, NDUFB11), and 4 assembly factors (NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF8). Notably, defects in core CI subunits in this cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defects. Our case series broadens the genetic spectrum of inherited optic neuropathies, emphasizing the crucial role of nuclear CI genes in its pathogenesis. The arLHON phenotype emerges as linked to numerous nuclear CI genes for which an insidious onset of optic atrophy is also reported, and in some cases the same variant may underlie both phenotypes. Overall, we highlight the possibly so far underestimated prevalence of CI nuclear subunits in the molecular diagnosis of ION, prompting to include all CI-related genes in the standard diagnostic screening.
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Publication type Article: Journal article
Document type Scientific Article
Keywords optic atrophy; mitochondria; mitochondrial complex I; Leber hereditary optic neuropathy; LHON; Leigh-syndrome; Oxidative-phosphorylation; Protein Stability; Dna Mutation; Neuropathy; Pathogenicity; Siblings; Tmem126a; Server
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Quellenangaben Volume: 149, Issue: 7, Pages: 2463-2479 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Grants Moorfields Eye Charity
National Institute of Health and Care Research
General University Hospital Prague
Isaac Newton Trust
LifeArc
Addenbrooke's Charitable Trust
German Center for Child and Adolescent Health
Charles University
Italian Ministry of Health
UCL Institute of Ophthalmology, University College London
NextGenerationEU
German Federal Ministry of Education and Research
Moorfields Eye Hospital NHS Foundation Trust
Horizon 2020
Fight for Sight UK
NIHR Cambridge Biomedical Research Centre
International Foundation for Optic Nerve Disease
DZKJ
European Union
Italian Ministry for University and Research
GENOMIT
Czech Ministry of Health
National Eye Research Centre