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      Accessorizing and anchoring the LINC complex for multifunctionality

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          Abstract

          The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of outer and inner nuclear membrane Klarsicht, ANC-1, and Syne homology (KASH) and Sad1 and UNC-84 (SUN) proteins, respectively, connects the nucleus to cytoskeletal filaments and performs diverse functions including nuclear positioning, mechanotransduction, and meiotic chromosome movements. Recent studies have shed light on the source of this diversity by identifying factors associated with the complex that endow specific functions as well as those that differentially anchor the complex within the nucleus. Additional diversity may be provided by accessory factors that reorganize the complex into higher-ordered arrays. As core components of the LINC complex are associated with several diseases, understanding the role of accessory and anchoring proteins could provide insights into pathogenic mechanisms.

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          Most cited references64

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          Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

          Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity 1,2 . We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk 3 . Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.
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            Nuclear positioning.

            The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Nuclear lamins and laminopathies.

              Nuclear lamins are intermediate filament proteins that polymerize to form the nuclear lamina on the inner aspect of the inner nuclear membrane. Long known to be essential for maintaining nuclear structure and disassembling/reassembling during mitosis in metazoans, research over the past dozen years has shown that mutations in genes encoding nuclear lamins, particularly LMNA encoding the A-type lamins, cause a broad range of diverse diseases, often referred to as laminopathies. Lamins are expressed in all mammalian somatic cells but mutations in their genes lead to relatively tissue-selective disease phenotypes in most cases. While mutations causing laminopathies have been shown to produce abnormalities in nuclear morphology, how these disease-causing mutations or resultant alterations in nuclear structure lead to pathology is only starting to be understood. Despite the incomplete understanding of pathogenic mechanisms underlying the laminopathies, basic research in cellular and small animal models has produced promising leads for treatments of these rare diseases. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                5 January 2015
                : 208
                : 1
                : 11-22
                Affiliations
                [1 ]Department of Pathology and Cell Biology and [2 ]Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032
                Author notes
                Correspondence to Gregg G. Gundersen: ggg1@ 123456columbia.edu
                Article
                201409047
                10.1083/jcb.201409047
                4284225
                25559183
                93af0be8-0a93-4ca4-8c3e-7a73e5cbb158
                © 2015 Chang et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 9 September 2014
                : 5 December 2014
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                Cell biology
                Cell biology

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