Muscular Dystrophy-Associated SUN1 and SUN2 Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization

Cox, Gregory A., Meinke, Peter, Mattioli, Elisabetta , Haque, Farhana, Antoku, Susumu, Columbaro, Marta, Straatman, Kees R., Worman, Howard J., Gundersen, Gregg G., Lattanzi, Giovanna, Wehnert, Manfred and Shackleton, Sue (2014) Muscular Dystrophy-Associated SUN1 and SUN2 Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization. PLoS Genetics, 10 (9). e1004605. ISSN 1553-7390

Full content URL: https://doi.org/10.1371/journal.pgen.1004605

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Muscular Dystrophy-Associated SUN1 and SUN2 Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization
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Abstract

Proteins of the nuclear envelope (NE) are associated with a range of inherited disorders, most commonly involving muscular
dystrophy and cardiomyopathy, as exemplified by Emery-Dreifuss muscular dystrophy (EDMD). EDMD is both genetically
and phenotypically variable, and some evidence of modifier genes has been reported. Six genes have so far been linked to
EDMD, four encoding proteins associated with the LINC complex that connects the nucleus to the cytoskeleton. However,
50% of patients have no identifiable mutations in these genes. Using a candidate approach, we have identified putative
disease-causing variants in the SUN1 and SUN2 genes, also encoding LINC complex components, in patients with EDMD and
related myopathies. Our data also suggest that SUN1 and SUN2 can act as disease modifier genes in individuals with cosegregating mutations in other EDMD genes. Five SUN1/SUN2 variants examined impaired rearward nuclear repositioning
in fibroblasts, confirming defective LINC complex function in nuclear-cytoskeletal coupling. Furthermore, myotubes from a
patient carrying compound heterozygous SUN1 mutations displayed gross defects in myonuclear organization. This was
accompanied by loss of recruitment of centrosomal marker, pericentrin, to the NE and impaired microtubule nucleation at
the NE, events that are required for correct myonuclear arrangement. These defects were recapitulated in C2C12 myotubes
expressing exogenous SUN1 variants, demonstrating a direct link between SUN1 mutation and impairment of nuclearmicrotubule coupling and myonuclear positioning. Our findings strongly support an important role for SUN1 and SUN2 in
muscle disease pathogenesis and support the hypothesis that defects in the LINC complex contribute to disease pathology
through disruption of nuclear-microtubule association, resulting in defective myonuclear positioning.

Keywords:Myoblasts, Muscular dystrophies, Microtubules, Centrosomes Fibroblasts, Immunoprecipitation, Mutation, Lamins
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > Lincoln Medical School
ID Code:43839
Deposited On:28 Jan 2021 16:07

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