Author currently retired.
Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies
Article first published online: 13 JAN 2014
© 2013 WILEY PERIODICALS, INC.
Volume 35, Issue 4, pages 452–461, April 2014
How to Cite
Li, P., Meinke, P., Huong, L. T. T., Wehnert, M. and Noegel, A. A. (2014), Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies. Hum. Mutat., 35: 452–461. doi: 10.1002/humu.22504
Contract grant sponsors: Joint Graduate Education Program of Deutscher Akademischer Austauschdienst (VNM 04/A17).
Communicated by Arnold Munnich
- Issue published online: 17 MAR 2014
- Article first published online: 13 JAN 2014
- Accepted manuscript online: 25 DEC 2013 06:30AM EST
- Manuscript Accepted: 19 DEC 2013
- Manuscript Received: 1 AUG 2013
- Joint Graduate Education Program of Deutscher Akademischer Austauschdienst. Grant Number: VNM 04/A17
- nuclear envelope;
- LINC complex;
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.