LiNC Complex and Human Genetic Muscular Disease

Abstract

The linker of nucleoskeleton and cytoskeleton (LiNC) complex is a proposed mechanical link tethering the nucleo‐ and cytoskeleton via the nuclear envelope (NE). The LiNC components emerin, lamin A/C, SUN1, SUN2, nesprin 1 and nesprin 2 interact with each other at the NE and also with other binding partners including actin filaments and B‐type lamins. Besides the mechanostructural functions, cell‐ or tissue‐specific LiNC complexes are also involved in signalling pathways and gene regulation. Emerin was the first LiNC component associated with a human disease, namely Emery–Dreifuss muscular dystrophy (EDMD). Later on, other components of a hypothetically muscle‐specific LiNC complex, such as lamins A/C and small muscle‐specific isoforms of nesprin 1 and nesprin 2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 47% of the EDMD patients can be linked to genes of LiNC and non‐LiNC components, probably interacting with muscle‐specific LiNC(s) involved in the pathology of muscular disorders.

Key Concepts:

  • Linker of nucleoskeleton and cytoskeleton (LiNC) complexes are tethering the nucleo‐ and cytoskeleton via the nuclear envelope.

  • The inhibition of LiNC components results in changes of the biomechanical behaviour of contractile cells.

  • Mutations in genes encoding muscle‐specific LiNC components lead to a variety of inherited human muscular disorders, in particular Emery–Dreifuss muscular dystrophy.

  • The wide phenotypic variability of LiNC‐associated muscular diseases can be explained by digenic inheritance.

  • The association of LiNC and LiNC‐related components with human disease helps to resolve genetic heterogeneity and clinical variability and provides tools to understand their functions within the cell as well.

Keywords: LiNC complex; Emery–Dreifuss muscular dystrophy; neuromuscular disorders; lamin A/C; emerin; nesprin 1; nesprin 2; SUN1; SUN2

Figure 1.

A Linker of Nucleoskeleton and Cytoskeleton (LiNC) complex at the nuclear envelope.

Figure 2.

Clinical picture of Emery–Dreifuss muscular dystrophy in a 22‐year‐old patient: (a) Mild wasting of the upper arm and the lower leg muscles, contracture of the elbow tendons, pacemaker (arrow). (b) Rigid spine, mild contractures of the Achilles tendons. © Manfred Wehnert.

Figure 3.

Segregation of mutations LMNA p.M348I and STA p.0 in a Belgian family. (Empty symbols – healthy individuals; filled symbols – affected individuals; hatched symbol – mildly affected individuals.)

Figure 4.

Outcome of routine mutational analysis in 195 EDMD patients.

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How to Cite close
Wehnert, Manfred S, and Meinke, Peter(Dec 2012) LiNC Complex and Human Genetic Muscular Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024451]