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Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology
Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486921/ https://www.ncbi.nlm.nih.gov/pubmed/32917887 http://dx.doi.org/10.1038/s41467-020-18146-9 |
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author | Elouej, Sahar Harhouri, Karim Le Mao, Morgane Baujat, Genevieve Nampoothiri, Sheela Kayserili, Hϋlya Menabawy, Nihal Al Selim, Laila Paneque, Arianne Llamos Kubisch, Christian Lessel, Davor Rubinsztajn, Robert Charar, Chayki Bartoli, Catherine Airault, Coraline Deleuze, Jean-François Rötig, Agnes Bauer, Peter Pereira, Catarina Loh, Abigail Escande-Beillard, Nathalie Muchir, Antoine Martino, Lisa Gruenbaum, Yosef Lee, Song-Hua Manivet, Philippe Lenaers, Guy Reversade, Bruno Lévy, Nicolas De Sandre-Giovannoli, Annachiara |
author_facet | Elouej, Sahar Harhouri, Karim Le Mao, Morgane Baujat, Genevieve Nampoothiri, Sheela Kayserili, Hϋlya Menabawy, Nihal Al Selim, Laila Paneque, Arianne Llamos Kubisch, Christian Lessel, Davor Rubinsztajn, Robert Charar, Chayki Bartoli, Catherine Airault, Coraline Deleuze, Jean-François Rötig, Agnes Bauer, Peter Pereira, Catarina Loh, Abigail Escande-Beillard, Nathalie Muchir, Antoine Martino, Lisa Gruenbaum, Yosef Lee, Song-Hua Manivet, Philippe Lenaers, Guy Reversade, Bruno Lévy, Nicolas De Sandre-Giovannoli, Annachiara |
author_sort | Elouej, Sahar |
collection | PubMed |
description | Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features. |
format | Online Article Text |
id | pubmed-7486921 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-74869212020-09-25 Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology Elouej, Sahar Harhouri, Karim Le Mao, Morgane Baujat, Genevieve Nampoothiri, Sheela Kayserili, Hϋlya Menabawy, Nihal Al Selim, Laila Paneque, Arianne Llamos Kubisch, Christian Lessel, Davor Rubinsztajn, Robert Charar, Chayki Bartoli, Catherine Airault, Coraline Deleuze, Jean-François Rötig, Agnes Bauer, Peter Pereira, Catarina Loh, Abigail Escande-Beillard, Nathalie Muchir, Antoine Martino, Lisa Gruenbaum, Yosef Lee, Song-Hua Manivet, Philippe Lenaers, Guy Reversade, Bruno Lévy, Nicolas De Sandre-Giovannoli, Annachiara Nat Commun Article Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients’ primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients’ fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features. Nature Publishing Group UK 2020-09-11 /pmc/articles/PMC7486921/ /pubmed/32917887 http://dx.doi.org/10.1038/s41467-020-18146-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Elouej, Sahar Harhouri, Karim Le Mao, Morgane Baujat, Genevieve Nampoothiri, Sheela Kayserili, Hϋlya Menabawy, Nihal Al Selim, Laila Paneque, Arianne Llamos Kubisch, Christian Lessel, Davor Rubinsztajn, Robert Charar, Chayki Bartoli, Catherine Airault, Coraline Deleuze, Jean-François Rötig, Agnes Bauer, Peter Pereira, Catarina Loh, Abigail Escande-Beillard, Nathalie Muchir, Antoine Martino, Lisa Gruenbaum, Yosef Lee, Song-Hua Manivet, Philippe Lenaers, Guy Reversade, Bruno Lévy, Nicolas De Sandre-Giovannoli, Annachiara Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title | Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title_full | Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title_fullStr | Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title_full_unstemmed | Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title_short | Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
title_sort | loss of mtx2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486921/ https://www.ncbi.nlm.nih.gov/pubmed/32917887 http://dx.doi.org/10.1038/s41467-020-18146-9 |
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