title: Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.
abstract: Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Zhang
authors.forename: Cornelia
authors.initials: C
authors.lastname: Bethmann
authors.forename: Nathalie F
authors.initials: NF
authors.lastname: Worth
authors.forename: John D
authors.initials: JD
authors.lastname: Davies
authors.forename: Christina
authors.initials: C
authors.lastname: Wasner
authors.forename: Anja
authors.initials: A
authors.lastname: Feuer
authors.forename: Cassandra D
authors.initials: CD
authors.lastname: Ragnauth
authors.forename: Qijian
authors.initials: Q
authors.lastname: Yi
authors.forename: Jason A
authors.initials: JA
authors.lastname: Mellad
authors.forename: Derek T
authors.initials: DT
authors.lastname: Warren
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wheeler
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Ellis
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: Beate
authors.initials: B
authors.lastname: Schlotter-Weigel
authors.forename: Peter L
authors.initials: PL
authors.lastname: Weissberg
authors.forename: Roland G
authors.initials: RG
authors.lastname: Roberts
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D003598:Cytoskeletal Proteins; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006579:Heterozygote; D006801:Humans; D034882:Lamins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D034741:RNA, Small Interfering / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D003598:Cytoskeletal Proteins; D034882:Lamins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C415465:SYNE1 protein, human; C485904:SYNE2 protein, human; C092710:emerin; D004247:DNA