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Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.
Hum Mol Genet. 2007 Dec 01; 16(23):2816-33.HM

Abstract

Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions.

Authors+Show Affiliations

Department of Medicine, University of Cambridge, Cambridge, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17761684

Citation

Zhang, Qiuping, et al. "Nesprin-1 and -2 Are Involved in the Pathogenesis of Emery Dreifuss Muscular Dystrophy and Are Critical for Nuclear Envelope Integrity." Human Molecular Genetics, vol. 16, no. 23, 2007, pp. 2816-33.
Zhang Q, Bethmann C, Worth NF, et al. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Hum Mol Genet. 2007;16(23):2816-33.
Zhang, Q., Bethmann, C., Worth, N. F., Davies, J. D., Wasner, C., Feuer, A., Ragnauth, C. D., Yi, Q., Mellad, J. A., Warren, D. T., Wheeler, M. A., Ellis, J. A., Skepper, J. N., Vorgerd, M., Schlotter-Weigel, B., Weissberg, P. L., Roberts, R. G., Wehnert, M., & Shanahan, C. M. (2007). Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. Human Molecular Genetics, 16(23), 2816-33.
Zhang Q, et al. Nesprin-1 and -2 Are Involved in the Pathogenesis of Emery Dreifuss Muscular Dystrophy and Are Critical for Nuclear Envelope Integrity. Hum Mol Genet. 2007 Dec 1;16(23):2816-33. PubMed PMID: 17761684.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity. AU - Zhang,Qiuping, AU - Bethmann,Cornelia, AU - Worth,Nathalie F, AU - Davies,John D, AU - Wasner,Christina, AU - Feuer,Anja, AU - Ragnauth,Cassandra D, AU - Yi,Qijian, AU - Mellad,Jason A, AU - Warren,Derek T, AU - Wheeler,Matthew A, AU - Ellis,Juliet A, AU - Skepper,Jeremy N, AU - Vorgerd,Matthias, AU - Schlotter-Weigel,Beate, AU - Weissberg,Peter L, AU - Roberts,Roland G, AU - Wehnert,Manfred, AU - Shanahan,Catherine M, Y1 - 2007/08/29/ PY - 2007/9/1/pubmed PY - 2008/1/23/medline PY - 2007/9/1/entrez SP - 2816 EP - 33 JF - Human molecular genetics JO - Hum Mol Genet VL - 16 IS - 23 N2 - Emery-Dreifuss muscular dystrophy (EDMD) is a heterogeneous late-onset disease involving skeletal muscle wasting and heart defects caused, in a minority of cases, by mutations in either of two genes encoding the inner nuclear membrane (INM) proteins, emerin and lamins A/C. Nesprin-1 and -2 are multi-isomeric, spectrin-repeat proteins that bind both emerin and lamins A/C and form a network in muscle linking the nucleoskeleton to the INM, the outer nuclear membrane, membraneous organelles, the sarcomere and the actin cytoskeleton. Thus, disruptions in nesprin/lamin/emerin interactions might play a role in the muscle-specific pathogenesis of EDMD. Screening for DNA variations in the genes encoding nesprin-1 (SYNE1) and nesprin-2 (SYNE2) in 190 probands with EDMD or EDMD-like phenotypes identified four heterozygous missense mutations. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization. In addition, diminished nuclear envelope localization of nesprins and impaired nesprin/emerin/lamin binding interactions were common features of all EDMD patient fibroblasts. siRNA knockdown of nesprin-1 or -2 in normal fibroblasts reproduced the nuclear morphological changes and mislocalization of emerin and SUN2 observed in patient fibroblasts. Taken together, these data suggest that EDMD may be caused, in part, by uncoupling of the nucleoskeleton and cytoskeleton because of perturbed nesprin/emerin/lamin interactions. SN - 0964-6906 UR - https://www.unboundmedicine.com/medline/citation/17761684/Nesprin_1_and__2_are_involved_in_the_pathogenesis_of_Emery_Dreifuss_muscular_dystrophy_and_are_critical_for_nuclear_envelope_integrity_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddm238 DB - PRIME DP - Unbound Medicine ER -