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The BAF A12T mutation disrupts lamin A/C interaction, impairing robust repair of nuclear envelope ruptures in Nestor-Guillermo progeria syndrome cells.

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Janssen, Anne 
Marcelot, Agathe 
Breusegem, Sophia 
Zinn-Justin, Sophie  ORCID logo


Nestor-Guillermo progeria syndrome (NGPS) is caused by a homozygous alanine-to-threonine mutation at position 12 (A12T) in barrier-to-autointegration factor (BAF). It is characterized by accelerated aging with severe skeletal abnormalities. BAF is an essential protein binding to DNA and nuclear envelope (NE) proteins, involved in NE rupture repair. Here, we assessed the impact of BAF A12T on NE integrity using NGPS-derived patient fibroblasts. We observed a strong defect in lamin A/C accumulation to NE ruptures in NGPS cells, restored upon homozygous reversion of the pathogenic BAF A12T mutation with CRISPR/Cas9. By combining in vitro and cellular assays, we demonstrated that while the A12T mutation does not affect BAF 3D structure and phosphorylation by VRK1, it specifically decreases the interaction between BAF and lamin A/C. Finally, we revealed that the disrupted interaction does not prevent repair of NE ruptures but instead generates weak points in the NE that lead to a higher frequency of NE re-rupturing in NGPS cells. We propose that this NE fragility could directly contribute to the premature aging phenotype in patients.


Funder: Université Paris-Saclay

Funder: FEBS


Humans, Nuclear Envelope, Lamin Type A, Progeria, Aging, Premature, Nuclear Proteins, DNA-Binding Proteins, Mutation, Membrane Proteins, Protein Serine-Threonine Kinases, Intracellular Signaling Peptides and Proteins

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Nucleic Acids Res

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Oxford University Press (OUP)
Wellcome Trust (206242/Z/17/Z)
Federation of the European Biochemical Societies (FEBS) (Anne Janssen FEBS LTF)
Wellcome Trust (204845/Z/16/Z)
This work was supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 206242/Z/17/Z), to S.Y.B. and D.L., a Wellcome Trust Institutional Strategic Support Fund (204845/Z/16/Z) and a FEBS Long-Term Fellowship to A.F.J.J., the French Infrastructure for Integrated Structural Biology [; ANR- 10-INSB-05-01] and the European Community H2020 Programme under the project iNEXT Discovery (Grant No 871037) to S.Z.J. and A.M and by Université Paris-Saclay to A.M.