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

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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Journal
Brain
Published
2025-11-13
DOI
https://doi.org/10.1093/brain/awaf422
Primary Topic
Mitochondrial Function and Pathology
Type
article
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0.00

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article

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

Thomas Cullup, Alfredo Altobelli, Neringa Jurkutė, Federico Sadun et al.
Brain
Mitochondrial Function and Pathology
article

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

Thomas Cullup, Alfredo Altobelli, Neringa Jurkutė, Federico Sadun, Anna Ardissone, Salvatore Rossi, Samantha Malka, Maria Lucia Cascavilla, Claudio Fiorini, Indran Davagnanam, Piero Barboni, Petra Lišková, Thomas Klopstock, Francesco Musiani, Rosalba Carrozzo, Giancarlo Iarossi, Markéta Tesařová, Alessandra Torraco, Danara Ormanbekova, Christiane Neuhofer, Leonardo Caporali, Olimpia Musumeci, Hana Štufková, Chiara La Morgia, Michel Michaelides, Laura Rigobello, Holger Prokisch, Hana Ptáčková, Luisa Iommarini, Enrico Bertini, Teresa Rizza, Flavia Palombo, Gabriella Silvestri, Gavin Arno, Alfredo A. Sadun, Gaia Tioli, Daniele Ghezzi, Valério Carelli, Robert Kopajtich, Andrew R. Webster, Li Zeng, Patrick Yu‐Wai‐Man, A. T. Moore, Costanza Lamperti, A. De Negri, Alberto Pietro Pasti, Alessandro Berghella
article en

Abstract

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.

Brain
Università Cattolica del Sacro Cuore (IT), University of Messina (IT), Allen Institute for Brain Science (US), Moorfields Eye Hospital NHS Foundation Trust (GB), University College London Hospitals NHS Foundation Trust (GB), University of California, Los Angeles (US), University of Milan (IT), Charles University (CZ), Great Ormond Street Hospital (GB), German Center for Neurodegenerative Diseases (DE), Cambridge University Hospitals NHS Foundation Trust (GB), Agostino Gemelli University Polyclinic (IT), Helmholtz Zentrum München (DE), University Hospital Regensburg (DE), Azienda Ospedaliera San Camillo-Forlanini (IT), Doheny Eye Institute (US), Munich Cluster for Systems Neurology (DE), German Center for Infection Research (DE), Institute of Human Genetics (PL), Istituto delle Scienze Neurologiche di Bologna (IT), Bambino Gesù Children's Hospital (IT), German Centre for Cardiovascular Research (DE), Institute of Ophthalmology (MX), IRCCS Ospedale San Raffaele (IT), Friedrich Baur Stiftung (DE), Greenwood Genetic Center (US), National Hospital for Neurology and Neurosurgery (GB), Addenbrooke's Hospital (GB), Azienda Sanitaria Locale Roma 3 (IT), General University Hospital in Prague (CZ), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), University College London (GB), University of Regensburg (DE), Technical University of Munich (DE), MRC Mitochondrial Biology Unit (GB), Ludwig-Maximilians-Universität München (DE), University of Bologna (IT)
LifeArc, E-Rare, National Institute for Health and Care Research, Department of Health and Social Care, Sight Research UK, Rosetrees Trust, Bundesministerium für Bildung und Forschung, Ministero della Salute, Isaac Newton Trust, Moorfields Eye Hospital NHS Foundation Trust, Moorfields Eye Charity, NIHR Cambridge Biomedical Research Centre
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Mitochondrial Function and Pathology
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