Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I
Abstract Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinica...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012619 |
| _version_ | 1797284723439960064 |
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| author | Ahmad Alahmad Alessia Nasca Juliana Heidler Kyle Thompson Monika Oláhová Andrea Legati Eleonora Lamantea Jana Meisterknecht Manuela Spagnolo Langping He Seham Alameer Fahad Hakami Abeer Almehdar Anna Ardissone Charlotte L Alston Robert McFarland Ilka Wittig Daniele Ghezzi Robert W Taylor |
| author_facet | Ahmad Alahmad Alessia Nasca Juliana Heidler Kyle Thompson Monika Oláhová Andrea Legati Eleonora Lamantea Jana Meisterknecht Manuela Spagnolo Langping He Seham Alameer Fahad Hakami Abeer Almehdar Anna Ardissone Charlotte L Alston Robert McFarland Ilka Wittig Daniele Ghezzi Robert W Taylor |
| author_sort | Ahmad Alahmad |
| collection | DOAJ |
| description | Abstract Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects’ fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects’ fibroblasts with wild‐type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module. |
| first_indexed | 2024-03-07T17:52:53Z |
| format | Article |
| id | doaj.art-8060cfefccbf4f1692d0ea57083765cf |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:52:53Z |
| publishDate | 2020-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-8060cfefccbf4f1692d0ea57083765cf2024-03-02T13:39:19ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-11-011211n/an/a10.15252/emmm.202012619Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex IAhmad Alahmad0Alessia Nasca1Juliana Heidler2Kyle Thompson3Monika Oláhová4Andrea Legati5Eleonora Lamantea6Jana Meisterknecht7Manuela Spagnolo8Langping He9Seham Alameer10Fahad Hakami11Abeer Almehdar12Anna Ardissone13Charlotte L Alston14Robert McFarland15Ilka Wittig16Daniele Ghezzi17Robert W Taylor18Wellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalySFB815 Core Unit Functional Proteomics Medical School Goethe‐Universität Frankfurt am Main GermanyWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalySFB815 Core Unit Functional Proteomics Medical School Goethe‐Universität Frankfurt am Main GermanyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKPediatric Department Ministry of National Guard Health Affairs Jeddah Saudi ArabiaSection of Molecular Medicine King Abdulaziz Medical City‐WR King Saud bin Abdulaziz University for Health Sciences Jeddah Saudi ArabiaDepartment of Medical Imaging King Saud bin Abdulaziz University for Health Sciences King Abdulaziz Medical City‐WR National Guard Health Affairs Jeddah Saudi ArabiaChild Neurology Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKSFB815 Core Unit Functional Proteomics Medical School Goethe‐Universität Frankfurt am Main GermanyUnit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan ItalyWellcome Centre for Mitochondrial Research Newcastle University Newcastle upon Tyne UKAbstract Leigh syndrome is a progressive neurodegenerative disorder, most commonly observed in paediatric mitochondrial disease, and is often associated with pathogenic variants in complex I structural subunits or assembly factors resulting in isolated respiratory chain complex I deficiency. Clinical heterogeneity has been reported, but key diagnostic findings are developmental regression, elevated lactate and characteristic neuroimaging abnormalities. Here, we describe three affected children from two unrelated families who presented with Leigh syndrome due to homozygous variants (c.346_*7del and c.173A>T p.His58Leu) in NDUFC2, encoding a complex I subunit. Biochemical and functional investigation of subjects’ fibroblasts confirmed a severe defect in complex I activity, subunit expression and assembly. Lentiviral transduction of subjects’ fibroblasts with wild‐type NDUFC2 cDNA increased complex I assembly supporting the association of the identified NDUFC2 variants with mitochondrial pathology. Complexome profiling confirmed a loss of NDUFC2 and defective complex I assembly, revealing aberrant assembly intermediates suggestive of stalled biogenesis of the complex I holoenzyme and indicating a crucial role for NDUFC2 in the assembly of the membrane arm of complex I, particularly the ND2 module.https://doi.org/10.15252/emmm.202012619complex ILeigh syndromemitochondrial diseaseNDUFC2OXPHOS |
| spellingShingle | Ahmad Alahmad Alessia Nasca Juliana Heidler Kyle Thompson Monika Oláhová Andrea Legati Eleonora Lamantea Jana Meisterknecht Manuela Spagnolo Langping He Seham Alameer Fahad Hakami Abeer Almehdar Anna Ardissone Charlotte L Alston Robert McFarland Ilka Wittig Daniele Ghezzi Robert W Taylor Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I EMBO Molecular Medicine complex I Leigh syndrome mitochondrial disease NDUFC2 OXPHOS |
| title | Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I |
| title_full | Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I |
| title_fullStr | Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I |
| title_full_unstemmed | Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I |
| title_short | Bi‐allelic pathogenic variants in NDUFC2 cause early‐onset Leigh syndrome and stalled biogenesis of complex I |
| title_sort | bi allelic pathogenic variants in ndufc2 cause early onset leigh syndrome and stalled biogenesis of complex i |
| topic | complex I Leigh syndrome mitochondrial disease NDUFC2 OXPHOS |
| url | https://doi.org/10.15252/emmm.202012619 |
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