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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.

Author information

1
Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway.
2
Sorbonne Université, Inserm UMR S938, Saint-Antoine Research Centre, Institute of Cardiometabolism and Nutrition, 75012 Paris, France.
3
Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
4
Sorbonne Université, UPMC Université Paris 6, UMR-S1166 ICAN, 75013 Paris, France.
5
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.
6
Department of Immunology and Transfusion Medicine, Norwegian Center for Stem Cell Research, Oslo University Hospital, 0424 Oslo, Norway.

Abstract

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.

PMID:
29438482
DOI:
10.1093/hmg/ddy055
[Indexed for MEDLINE]

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