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Hum Mol Genet. 2018 Apr 15;27(8):1447-1459. doi: 10.1093/hmg/ddy055.

The lipodystrophic hotspot lamin A p.R482W mutation deregulates the mesodermal inducer T/Brachyury and early vascular differentiation gene networks.

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Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, 75012 Paris, France.
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
Sorbonne Université, UPMC Université Paris 6, UMR-S1166 ICAN, 75013 Paris, France.
AP-HP Saint-Antoine Hospital, Molecular Biology and Genetics Laboratory, Endocrinology Department, National Reference Center for Insulin Secretion and Insulin Sensitivity Rare Diseases, 75012 Paris, France.
Department of Immunology and Transfusion Medicine, Norwegian Center for Stem Cell Research, Oslo University Hospital, 0424 Oslo, Norway.


The p.R482W hotspot mutation in A-type nuclear lamins causes familial partial lipodystrophy of Dunnigan-type (FPLD2), a lipodystrophic syndrome complicated by early onset atherosclerosis. Molecular mechanisms underlying endothelial cell dysfunction conferred by the lamin A mutation remain elusive. However, lamin A regulates epigenetic developmental pathways and mutations could perturb these functions. Here, we demonstrate that lamin A R482W elicits endothelial differentiation defects in a developmental model of FPLD2. Genome modeling in fibroblasts from patients with FPLD2 caused by the lamin A R482W mutation reveals repositioning of the mesodermal regulator T/Brachyury locus towards the nuclear center relative to normal fibroblasts, suggesting enhanced activation propensity of the locus in a developmental model of FPLD2. Addressing this issue, we report phenotypic and transcriptional alterations in mesodermal and endothelial differentiation of induced pluripotent stem cells we generated from a patient with R482W-associated FPLD2. Correction of the LMNA mutation ameliorates R482W-associated phenotypes and gene expression. Transcriptomics links endothelial differentiation defects to decreased Polycomb-mediated repression of the T/Brachyury locus and over-activation of T target genes. Binding of the Polycomb repressor complex 2 to T/Brachyury is impaired by the mutated lamin A network, which is unable to properly associate with the locus. This leads to a deregulation of vascular gene expression over time. By connecting a lipodystrophic hotspot lamin A mutation to a disruption of early mesodermal gene expression and defective endothelial differentiation, we propose that the mutation rewires the fate of several lineages, resulting in multi-tissue pathogenic phenotypes.

[Indexed for MEDLINE]

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