VADROT, Nathalie; ADER, Flavie; MOULIN, Maryline; MERLANT, Marie; CHAPON, Françoise; GANDJBAKHCH, Estelle; LABOMBARDA, Fabien; MARAGNES, Pascale; RÉANT, Patricia; ROORYCK, Caroline; PROBST, Vincent; DONAL, Erwan; RICHARD, Pascale; FERREIRO, Ana; BUENDIA, Brigitte

doi:10.3390/cells12020337

Langue

Article de revue

Ce document a été publié dans

Cells. 2023-01-16, vol. 12, n° 2, p. 337

Résumé en anglais

A single missense variant of the /LAP2α gene, encoding LAP2 proteins, has been associated with cardiomyopathy in two brothers. To further evaluate its role in cardiac muscle, we included in our cardiomyopathy diagnostic gene panel. A screening of ~5000 patients revealed three novel rare heterozygous variants in six males diagnosed with hypertrophic or dilated cardiomypathy. We identified in different cellular models that (1) the frameshift variant LAP2α p.(Gly395Glufs*11) induced haploinsufficiency, impeding cell proliferation and/or producing a truncated protein mislocalized in the cytoplasm; (2) the C-ter missense variant LAP2α p.(Ala240Thr) led to a reduced proximity events between LAP2α and the nucleosome binding protein HMGN5; and (3) the LEM-domain missense variant p.(Leu124Phe) decreased both associations of LAP2α/β with the chromatin-associated protein BAF and inhibition of the E2F1 transcription factor activity which is known to be dependent on Rb, partner of LAP2α. Additionally, the LAP2α expression was lower in the left ventricles of male mice compared to females. In conclusion, our study reveals distinct altered properties of LAP2 induced by these /LAP2 variants, leading to altered cell proliferation, chromatin structure or gene expression-regulation pathways, and suggests a potential sex-dependent role of LAP2 in myocardial function and disease.< Réduire

Mots clés en anglais

TMPO gene

LAP2 proteins

Nuclear alterations

Chromatin-associated proteins

E2F1 regulation

Gender

Cardiomyopathy

URI

https://oskar-bordeaux.fr/handle/20.500.12278/188188

DOI

http://dx.doi.org/10.3390/cells12020337

Unités de recherche

Maladies Rares : Génétique et Métabolisme (MRGM) - UMR 1211

Voir/Ouvrir

Métadonnées

Partager cette publication !

Licence d’utilisation du document

Abnormal Cellular Phenotypes Induced by Three /LAP2 Variants Identified in Men with Cardiomyopathies.

Langue

Ce document a été publié dans

Résumé en anglais

Mots clés en anglais

URI

DOI

Unités de recherche