title: Accumulation of the inner nuclear envelope protein Sun1 is pathogenic in progeric and dystrophic laminopathies.
abstract: Human LMNA gene mutations result in laminopathies that include Emery-Dreifuss muscular dystrophy (AD-EDMD) and Hutchinson-Gilford progeria, the premature aging syndrome (HGPS). The Lmna null (Lmna(-/-)) and progeroid LmnaΔ9 mutant mice are models for AD-EDMD and HGPS, respectively. Both animals develop severe tissue pathologies with abbreviated life spans. Like HGPS cells, Lmna(-/-) and LmnaΔ9 fibroblasts have typically misshapen nuclei. Unexpectedly, Lmna(-/-) or LmnaΔ9 mice that are also deficient for the inner nuclear membrane protein Sun1 show markedly reduced tissue pathologies and enhanced longevity. Concordantly, reduction of SUN1 overaccumulation in LMNA mutant fibroblasts and in cells derived from HGPS patients corrected nuclear defects and cellular senescence. Collectively, these findings implicate Sun1 protein accumulation as a common pathogenic event in Lmna(-/-), LmnaΔ9, and HGPS disorders.
authors.affiliation: National Institute of Allergy and Infectious Diseases, The National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chia-Yen
authors.initials: CY
authors.lastname: Chen
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
authors.forename: Rafidah Abdul
authors.initials: RA
authors.lastname: Mutalif
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Myers
authors.forename: Stasia A
authors.initials: SA
authors.lastname: Anderson
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
mesh_terms: D000818:Animals; D002460:Cell Line; D016922:Cellular Senescence; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism*; D011371:Progeria / Q000378:metabolism* / Q000473:pathology
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C506117:SUN1 protein, human; C464932:SUN1 protein, mouse