title: Mutations in LMNA modulate the lamin A--Nesprin-2 interaction and cause LINC complex alterations.
abstract: BACKGROUND
  In eukaryotes the genetic material is enclosed by a continuous membrane system, the nuclear envelope (NE). Along the NE specific proteins assemble to form meshworks and mutations in these proteins have been described in a group of human diseases called laminopathies. Laminopathies include lipodystrophies, muscle and cardiac diseases as well as metabolic or progeroid syndromes. Most laminopathies are caused by mutations in the LMNAgene encoding lamins A/C. Together with Nesprins (Nuclear Envelope Spectrin Repeat Proteins) they are core components of the LINC complex (Linker of Nucleoskeleton and Cytoskeleton). The LINC complex connects the nucleoskeleton and the cytoskeleton and plays a role in the transfer of mechanically induced signals along the NE into the nucleus, and its components have been attributed functions in maintaining nuclear and cellular organization as well as signal transduction.
  
  
  RESULTS
  Here we narrowed down the interaction sites between lamin A and Nesprin-2 to aa 403-425 in lamin A and aa 6146-6347 in Nesprin-2. Laminopathic mutations in and around the involved region of lamin A (R401C, G411D, G413C, V415I, R419C, L421P, R427G, Q432X) modulate the interaction with Nesprin-2 and this may contribute to the disease phenotype. The most notable mutation is the lamin A mutation Q432X that alters LINC complex protein assemblies and causes chromosomal and transcription factor rearrangements.
  
  
  CONCLUSIONS
  Mutations in Nesprin-2 and lamin A are characterised by complex genotype phenotype relations. Our data show that each mutation in LMNAanalysed here has a distinct impact on the interaction among both proteins that substantially explains how distinct mutations in widely expressed genes lead to the formation of phenotypically different diseases.
authors: Institute for Biochemistry I, Medical Faculty, University of Cologne, and Center for Molecular Medicine Cologne (CMMC) and Cologne Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Medical Faculty, University of Cologne, Cologne, Germany.
authors: Liu
authors: L
authors: Yang
authors: Martina
authors: M
authors: Munck
authors: Karthic
authors: K
authors: Swaminathan
authors: Larisa E
authors: LE
authors: Kapinos
authors: Angelika A
authors: AA
authors: Noegel
authors: Sascha
authors: S
authors: Neumann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport
chemical_list: D002843:Chromatin; C494847:LMNA protein, human; D034904:Lamin Type A; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C485904:SYNE2 protein, human
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