Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology

Sahar Elouej, Karim Harhouri, Morgane Mao, Genevieve Baujat, Sheela Nampoothiri, Hϋlya Kayserili, Nihal Al Menabawy, Laila Selim, Arianne Llamos Paneque, Christian Kubisch, Davor Lessel, Robert Rubinsztajn, Chayki Charar, Catherine Bartoli, Coraline Airault, Jean-François Deleuze, Agnes Rötig, Peter Bauer, Catarina Pereira, Abigail Loh, Nathalie Escande-Beillard, Antoine Muchir, Lisa Martino, Yosef Gruenbaum, Song-Hua Lee, Philippe Manivet, Guy Lenaers, Bruno Reversade, Nicolas Lévy and Annachiara De Sandre-Giovannoli ()
Additional contact information
Sahar Elouej: Aix Marseille Univ, INSERM, MMG, U1251
Karim Harhouri: Aix Marseille Univ, INSERM, MMG, U1251
Morgane Mao: Université d’Angers, CHU d’Angers
Genevieve Baujat: INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital
Sheela Nampoothiri: Amrita Institute of Medical Sciences & Research Centre, AIMS Ponekkara PO Cochin
Hϋlya Kayserili: Koç University, School of Medicine (KUSoM)
Nihal Al Menabawy: Cairo University Children Hospital
Laila Selim: Cairo University Children Hospital
Arianne Llamos Paneque: Medical Genetics Service Specialties Hospital FF AA No.1
Christian Kubisch: University Medical Center Hamburg-Eppendorf
Davor Lessel: University Medical Center Hamburg-Eppendorf
Robert Rubinsztajn: Necker Enfants Malades Hospital
Chayki Charar: Hebrew University of Jerusalem
Catherine Bartoli: Aix Marseille Univ, INSERM, MMG, U1251
Coraline Airault: Aix Marseille Univ, INSERM, MMG, U1251
Jean-François Deleuze: Institut de Biologie François Jacob, CEA, Université Paris-Saclay and Fondation Jean Dausset
Agnes Rötig: INSERM UMR1163, Institut Imagine
Peter Bauer: CENTOGENE AG
Catarina Pereira: CENTOGENE AG
Abigail Loh: Institute of Medical Biology, A*STAR
Nathalie Escande-Beillard: Koç University, School of Medicine (KUSoM)
Antoine Muchir: Sorbonne Université, INSERM, Institute of Myology, Center of Research in Myology
Lisa Martino: CeleScreen SAS
Yosef Gruenbaum: Hebrew University of Jerusalem
Song-Hua Lee: CeleScreen SAS
Philippe Manivet: CeleScreen SAS
Guy Lenaers: Université d’Angers, CHU d’Angers
Bruno Reversade: Koç University, School of Medicine (KUSoM)
Nicolas Lévy: Aix Marseille Univ, INSERM, MMG, U1251
Annachiara De Sandre-Giovannoli: Aix Marseille Univ, INSERM, MMG, U1251

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18146-9

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