Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies

Authors

  • Ping Li,

    1. Institute for Biochemistry I, Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany
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  • Peter Meinke,

    1. Ernst-Moritz-Arndt-University, Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Greifswald, Germany
    Current affiliation:
    1. The Wellcome Trust Centre for Cell Biology, University of Edinburgh, Edinburgh, EH9 3JR, UK
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  • Le Thi Thanh Huong,

    1. Ernst-Moritz-Arndt-University, Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Greifswald, Germany
    Current affiliation:
    1. National Institute of Hygiene and Epidemiology, Hà Nôi, Vietnam
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  • Manfred Wehnert,

    1. Ernst-Moritz-Arndt-University, Institute of Human Genetics and Interfaculty Institute of Genetics and Functional Genomics, Greifswald, Germany
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    • Author currently retired.

  • Angelika A. Noegel

    Corresponding author
    1. Institute for Biochemistry I, Center for Molecular Medicine Cologne (CMMC) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany
    • Correspondence to: Angelika A. Noegel, Institute for Biochemistry I, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, 50931 Cologne, Germany. E-mail: noegel@uni-koeln.de

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  • Contract grant sponsors: Joint Graduate Education Program of Deutscher Akademischer Austauschdienst (VNM 04/A17).

  • Communicated by Arnold Munnich

ABSTRACT

Mutations in several genes encoding nuclear envelope (NE) associated proteins cause Emery–Dreifuss muscular dystrophy (EDMD). We analyzed fibroblasts from a patient who had a mutation in the EMD gene (p.L84Pfs*6) leading to loss of Emerin and a heterozygous mutation in SUN1 (p.A203V). The second patient harbored a heterozygous mutation in LAP2alpha (p.P426L) and a further mutation in SUN1 (p.A614V). p.A203V is located in the N-terminal domain of SUN1 facing the nucleoplasm and situated in the vicinity of the Nesprin-2 and Emerin binding site. p.A614V precedes the SUN domain, which interacts with the KASH domain of Nesprins in the periplasmic space and forms the center of the LINC complex. At the cellular level, we observed alterations in the amounts for several components of the NE in patient fibroblasts and further phenotypic characteristics generally attributed to laminopathies such as increased sensitivity to heat stress. The defects were more severe than observed in EDMD cells with mutations in a single gene. In particular, in patient fibroblasts carrying the p.A203V mutation in SUN1, the alterations were aggravated. Moreover, SUN1 of both patient fibroblasts exhibited reduced interaction with Lamin A/C and when expressed ectopically in wild-type fibroblasts, the SUN1 mutant proteins exhibited reduced interactions with Emerin as well.

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