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

dc.contributor.coauthorElouej,Sahar
dc.contributor.coauthorHarhouri, Karim
dc.contributor.coauthorLe Mao, Morgane
dc.contributor.coauthorBaujat, Genevieve
dc.contributor.coauthorNampoothiri, Sheela
dc.contributor.coauthorMenabawy, Nihal Al
dc.contributor.coauthorSelim, Laila
dc.contributor.coauthorPaneque, Arianne Llamos
dc.contributor.coauthorKubisch, Christian
dc.contributor.coauthorLessel, Davor
dc.contributor.coauthorRubinsztajn,Robert
dc.contributor.coauthorCharar, Chayki
dc.contributor.coauthorBartoli, Catherine
dc.contributor.coauthorAirault, Coraline
dc.contributor.coauthorDeleuze, Jean-François
dc.contributor.coauthorRötig, Agnes
dc.contributor.coauthorBauer, Peter
dc.contributor.coauthorPereira, Catarina
dc.contributor.coauthorLoh, Abigail
dc.contributor.coauthorMuchir, Antoine
dc.contributor.coauthorMartino, Lisa
dc.contributor.coauthorGruenbaum, Yosef
dc.contributor.coauthorLee, Song-Hua
dc.contributor.coauthorManivet, Philippe
dc.contributor.coauthorLenaers, Guy
dc.contributor.coauthorLévy, Nicolas
dc.contributor.coauthorDe Sandre-Giovannoli, Annachiara
dc.contributor.departmentSchool of Medicine
dc.contributor.kuauthorKayserili, Hülya
dc.contributor.kuauthorReversade, Bruno
dc.contributor.schoolcollegeinstituteSCHOOL OF MEDICINE
dc.date.accessioned2024-11-09T11:52:23Z
dc.date.issued2020
dc.description.abstractMandibuloacral 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.
dc.description.fulltextYES
dc.description.indexedbyScopus
dc.description.indexedbyPubMed
dc.description.openaccessYES
dc.description.publisherscopeInternational
dc.description.sponsoredbyTubitakEuN/A
dc.description.sponsorshipAssociation Française contre les Myopathies (AFM)
dc.description.sponsorshipDeutsche Forschungsgemeinschaft
dc.description.sponsorshipGENMED Laboratory of Excellence on Medical Genomics, Agence Nationale de la Recherche
dc.description.sponsorshipInstitut National de la Santé et de la Recherche Médicale (INSERM)
dc.description.sponsorshipAix-Marseille University (AMU) by the RAREMED Amidex Project
dc.description.versionPublisher version
dc.description.volume11
dc.identifier.doi10.1038/s41467-020-18146-9
dc.identifier.embargoNO
dc.identifier.filenameinventorynoIR02405
dc.identifier.issn2041-1723
dc.identifier.quartileQ1
dc.identifier.scopus2-s2.0-85090799320
dc.identifier.urihttps://hdl.handle.net/20.500.14288/740
dc.language.isoeng
dc.publisherNature Publishing Group (NPG)
dc.relation.grantnoAFM grant MNH‐Decrypt 2011‐2015 and TRIM‐RD 2016‐2020
dc.relation.grantnoLE4223/1-1
dc.relation.grantnoANR-10-LABX0013
dc.relation.ispartofNature Communications
dc.relation.urihttp://cdm21054.contentdm.oclc.org/cdm/ref/collection/IR/id/9041
dc.subjectMedicine
dc.titleLoss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology
dc.typeJournal Article
dspace.entity.typePublication
local.contributor.kuauthorKayserili, Hülya
local.contributor.kuauthorBeillard, Nathalie Sonia Escande
local.contributor.kuauthorReversade, Bruno
local.publication.orgunit1SCHOOL OF MEDICINE
local.publication.orgunit2School of Medicine
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relation.isOrgUnitOfPublication.latestForDiscoveryd02929e1-2a70-44f0-ae17-7819f587bedd
relation.isParentOrgUnitOfPublication17f2dc8e-6e54-4fa8-b5e0-d6415123a93e
relation.isParentOrgUnitOfPublication.latestForDiscovery17f2dc8e-6e54-4fa8-b5e0-d6415123a93e

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