title: Prelamin A and lamin A appear to be dispensable in the nuclear lamina.
abstract: Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna(LCO/LCO)), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna(LCO/LCO) mice were entirely healthy, and Lmna(LCO/LCO) cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna(LCO) allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24-/- mice. Moreover, treating Zmpste24-/- cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. lfong@mednet.ucla.edu
authors.forename: Loren G
authors.initials: LG
authors.lastname: Fong
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Ng
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Vickers
authors.forename: Margarita
authors.initials: M
authors.lastname: Meta
authors.forename: Nathan
authors.initials: N
authors.lastname: Coté
authors.forename: Bryant
authors.initials: B
authors.lastname: Gavino
authors.forename: Xin
authors.initials: X
authors.lastname: Qiao
authors.forename: Sandy Y
authors.initials: SY
authors.lastname: Chang
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Young
authors.forename: Shao H
authors.initials: SH
authors.lastname: Yang
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Martin O
authors.initials: MO
authors.lastname: Bergo
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018908:Muscle Weakness / Q000235:genetics; D034881:Nuclear Lamina / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012886:Skull / Q000002:abnormalities; D013131:Spine / Q000002:abnormalities
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; D012333:RNA, Messenger; C440308:lamin C; C090764:prelamin A