title: Lamins A and C are differentially dysfunctional in autosomal dominant Emery-Dreifuss muscular dystrophy.
abstract: Mutations in the LMNA gene, which encodes nuclear lamins A and C by alternative splicing, can give rise to Emery-Dreifuss muscular dystrophy. The mechanism by which lamins A and C separately contribute to this molecular phenotype is unknown. To address this question we examined ten LMNA mutations exogenously expressed as lamins A and C in COS-7 cells. Eight of the mutations when expressed in lamin A, exhibited a range of nuclear mislocalisation patterns. However, two mutations (T150P and delQ355) almost completely relocated exogenous lamin A from the nuclear envelope to the cytoplasm, disrupted nuclear envelope reassembly following cell division and altered the protein composition of the mid-body. In contrast, exogenously expressed DsRed2-tagged mutant lamin C constructs were only inserted into the nuclear lamina if co-expressed with any EGFP-tagged lamin A construct, except with one carrying the T150P mutation. The T150P, R527P and L530P mutations reduced the ability of lamin A, but not lamin C from binding to emerin. These data identify specific functional roles for the emerin-lamin C- and emerin-lamin A- containing protein complexes and is the first report to suggest that the A-type lamin mutations may be differentially dysfunctional for the same LMNA mutation.
authors.affiliation: The Randall Division of Cell and Molecular Biophysics, Kings College, New Hunts House, Guy's Campus, London SE1 1UL, UK.
authors.forename: Isabell
authors.initials: I
authors.lastname: Motsch
authors.forename: Manuja
authors.initials: M
authors.lastname: Kaluarachchi
authors.forename: Lindsay J
authors.initials: LJ
authors.lastname: Emerson
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Brown
authors.forename: Susan C
authors.initials: SC
authors.lastname: Brown
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Dabauvalle
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
mesh_terms: D000818:Animals; D019556:COS Cells; D018076:DNA, Complementary / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D034904:Lamin Type A / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000378:metabolism*; D009154:Mutation; D034881:Nuclear Lamina / Q000378:metabolism; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013946:Thymopoietins / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D018076:DNA, Complementary; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D013946:Thymopoietins; C092710:emerin; C485184:enhanced green fluorescent protein; C440308:lamin C; D049452:Green Fluorescent Proteins