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

Sahar Elouej, Karim Harhouri, Morgane Le Mao, Genevieve Baujat, Sheela Nampoothiri, Hϋlya U. 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 LohNathalie Escande-Beillard, Antoine Muchir, Lisa Martino, Yosef Gruenbaum, Song Hua Lee, Philippe Manivet, Guy Lenaers, Bruno Reversade, Nicolas Lévy, Annachiara De Sandre-Giovannoli

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.
Original languageEnglish (US)
JournalNature Communications
Issue number1
StatePublished - Dec 1 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Chemistry
  • General Physics and Astronomy


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