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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
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.
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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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