title: The R439C mutation in LMNA causes lamin oligomerization and susceptibility to oxidative stress.
abstract: Dunnigan-type familial partial lipodystrophy (FPLD) is a laminopathy characterized by an aberrant fat distribution and a metabolic syndrome for which oxidative stress has recently been suggested as one of the disease-causing mechanisms. In a family affected with FPLD, we identified a heterozygous missense mutation c.1315C>T in the LMNA gene leading to the p.R439C substitution. Cultured patient fibroblasts do not show any prelamin A accumulation and reveal honeycomb-like lamin A/C formations in a significant percentage of nuclei. The mutation affects a region in the C-terminal globular domain of lamins A and C, different from the FPLD-related hot spot. Here, the introduction of an extra cysteine allows for the formation of disulphide-mediated lamin A/C oligomers. This oligomerization affects the interaction properties of the C-terminal domain with DNA as shown by gel retardation assays and causes a DNA-interaction pattern that is distinct from the classical R482W FPLD mutant. Particularly, whereas the R482W mutation decreases the binding efficiency of the C-terminal domain to DNA, the R439C mutation increases it. Electron spin resonance spectroscopy studies show significantly higher levels of reactive oxygen species (ROS) upon induction of oxidative stress in R439C patient fibroblasts compared to healthy controls. This increased sensitivity to oxidative stress seems independent of the oligomerization and enhanced DNA binding typical for R439C, as both the R439C and R482W mutants show a similar and significant increase in ROS upon induction of oxidative stress by H2O2.
authors.affiliation: Department of Dermatology, University Hospital Maastricht, The Netherlands. vverstraeten@rics.bwh.harvard.edu
authors.forename: Valerie L R M
authors.initials: VL
authors.lastname: Verstraeten
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caputo
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Duband-Goulet
authors.forename: Sophie
authors.initials: S
authors.lastname: Zinn-Justin
authors.forename: Miriam
authors.initials: M
authors.lastname: Kamps
authors.forename: Helma J H
authors.initials: HJ
authors.lastname: Kuijpers
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ostlund
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Worman
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Briedé
authors.forename: Caroline
authors.initials: C
authors.lastname: Le Dour
authors.forename: Carlo L M
authors.initials: CL
authors.lastname: Marcelis
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: Arthur
authors.initials: A
authors.lastname: van den Wijngaard
authors.forename: Frans C S
authors.initials: FC
authors.lastname: Ramaekers
authors.forename: Jos L V
authors.initials: JL
authors.lastname: Broers
mesh_terms: D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D034904:Lamin Type A / Q000235:genetics / Q000502:physiology*; D052496:Lipodystrophy, Familial Partial / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D011498:Protein Precursors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D011498:Protein Precursors; D017382:Reactive Oxygen Species; C090764:prelamin A; D006861:Hydrogen Peroxide