Universität zu Köln

Li, Ping, Meinke, Peter, Wehnert, Manfred and Noegel, Angelika A. (2014). Contribution of SUN1 Mutations to the Pathomechanism in Muscular Dystrophies. Hum. Mutat., 35 (4). S. 452 - 462. HOBOKEN: WILEY. ISSN 1098-1004

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Li, Ping UNSPECIFIED UNSPECIFIED UNSPECIFIED Meinke, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Wehnert, Manfred UNSPECIFIED UNSPECIFIED UNSPECIFIED Noegel, Angelika A. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-441603
DOI:	10.1002/humu.22504
Journal or Publication Title:	Hum. Mutat.
Volume:	35
Number:	4
Page Range:	S. 452 - 462
Date:	2014
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1098-1004
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INNER NUCLEAR-MEMBRANE; LINC COMPLEX; PROTEIN SUN1; NESPRIN-2; CENTROSOME; MIGRATION; ACTIN; ASSOCIATION; FIBROBLASTS; CONNECTIONS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44160