title: Nuclear envelope alterations in fibroblasts from LGMD1B patients carrying nonsense Y259X heterozygous or homozygous mutation in lamin A/C gene.
abstract: Mutations in the LMNA gene encoding nuclear lamins A and C are responsible for seven inherited disorders affecting specific tissues. We have analyzed skin fibroblasts from a patient with type 1B limb-girdle muscular dystrophy and from her deceased newborn grandchild carrying, respectively, a heterozygous (+/mut) and a homozygous (mut/mut) nonsense Y259X mutation. In fibroblasts(+/mut), the presence of only 50% lamins A and C promotes no detectable abnormality, whereas in fibroblasts(mut/mut) the complete absence of lamins A and C leads to abnormally shaped nuclei with lobules in which none of the analyzed nuclear proteins were detected, i.e., B-type lamins, emerin, nesprin-1alpha, LAP2beta, and Nup153. These lobules perturb cell division as fibroblast(mut/mut) cultures with large proportions of cells with dysmorphic nuclei grow more slowly than controls and the cell proliferation normalizes when the number of these abnormally shaped nuclei declines. In all fibroblasts(mut/mut), nesprin-1alpha-like emerin exhibited aberrant localization in the endoplasmic reticulum. Transfection of wild-type lamin A or C cDNAs restored the correct localization of both emerin and nesprin-1alpha. These data demonstrate that lamin C, like lamin A, interacts in vivo directly with nesprin-1alpha and with emerin and that lamin A or C is sufficient for the correct anchorage of emerin and nesprin-1alpha at the nuclear envelope in human cells.
authors.affiliation: INSERM U582, Institut de Myologie, Groupe Hospitalier Pitié-Salpétrière, 75013, Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Muchir
authors.forename: Baziel G
authors.initials: BG
authors.lastname: van Engelen
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: John M
authors.initials: JM
authors.lastname: Mislow
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McNally
authors.forename: Ketty
authors.initials: K
authors.lastname: Schwartz
authors.forename: Gisèle
authors.initials: G
authors.lastname: Bonne
mesh_terms: D002352:Carrier Proteins / Q000032:analysis; D002455:Cell Division; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000648:ultrastructure*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007231:Infant, Newborn; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000032:analysis / Q000172:deficiency; D009136:Muscular Dystrophies / Q000235:genetics / Q000473:pathology*; D009419:Nerve Tissue Proteins; D009685:Nuclear Envelope / Q000473:pathology*; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D013946:Thymopoietins / Q000032:analysis / Q000172:deficiency
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; D034904:Lamin Type A; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C415465:SYNE1 protein, human; D013946:Thymopoietins; C092710:emerin; C440308:lamin C