title: Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies.
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.
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Meinke
authors.forename: Le Thi Thanh
authors.initials: le TT
authors.lastname: Huong
authors.forename: Manfred
authors.initials: M
authors.lastname: Wehnert
authors.forename: Angelika A
authors.initials: AA
authors.lastname: Noegel
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D020389:Muscular Dystrophy, Emery-Dreifuss / Q000235:genetics* / Q000473:pathology*; D009154:Mutation; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D013946:Thymopoietins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C494847:LMNA protein, human; D034904:Lamin Type A; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; C506117:SUN1 protein, human; D013946:Thymopoietins; C092710:emerin; C093413:lamina-associated polypeptide 2; C097345:TMPO protein, human
keywords: Emerin; LINC complex; Lamin; Nesprin; SUN1; laminopathy; nuclear envelope