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      Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

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      Author(s)
      Kayman-Kurekci G.
      Talim, B.
      Korkusuz P.
      Sayar, N.
      Sarioglu, T.
      Oncel I.
      Sharafi P.
      Gundesli H.
      Balci-Hayta, B.
      Purali, N.
      Serdaroglu-Oflazer P.
      Topaloglu H.
      Dincer P.
      Date
      2014
      Source Title
      Neuromuscular Disorders
      Print ISSN
      0960-8966
      Publisher
      Elsevier Ltd
      Volume
      24
      Issue
      7
      Pages
      624 - 633
      Language
      English
      Type
      Article
      Item Usage Stats
      274
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      431
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      Abstract
      We performed genome-wide homozygosity mapping and mapped a novel myopathic phenotype to chromosomal region 1q25 in a consanguineous family with three affected individuals manifesting proximal and distal weakness and atrophy, rigid spine and contractures of the proximal and distal interphalangeal hand joints. Additionally, cardiomyopathy and respiratory involvement were noted. DNA sequencing of torsinA-interacting protein 1 (TOR1AIP1) gene encoding lamina-associated polypeptide 1B (LAP1B), showed a homozygous c.186delG mutation that causes a frameshift resulting in a premature stop codon (p.E62fsTer25). We observed that expression of LAP1B was absent in the patient skeletal muscle fibres. Ultrastructural examination showed intact sarcomeric organization but alterations of the nuclear envelope including nuclear fragmentation, chromatin bleb formation and naked chromatin. LAP1B is a type-2 integral membrane protein localized in the inner nuclear membrane that binds to both A- and B-type lamins, and is involved in the regulation of torsinA ATPase. Interestingly, luminal domain-like LAP1 (LULL1)-an endoplasmic reticulum-localized partner of torsinA-was overexpressed in the patient's muscle in the absence of LAP1B. Therefore, the findings suggest that LAP1 and LULL1 might have a compensatory effect on each other. This study expands the spectrum of genes associated with nuclear envelopathies and highlights the critical function for LAP1B in striated muscle. © 2014 Elsevier B.V.
      Keywords
      LAP1
      Muscular dystrophy
      Myopathy
      TOR1AIP1
      lamin A
      lamin B
      lamina associated polypeptide 1B
      membrane protein
      unclassified drug
      carrier protein
      LAP1B protein, human
      membrane protein
      messenger RNA
      nuclear protein
      TOR1AIP2 protein, human
      article
      binding affinity
      binding site
      case report
      clinical feature
      controlled study
      disease activity
      disease association
      echography
      female
      frameshift mutation
      gene
      gene function
      gene identification
      gene location
      gene mapping
      gene mutation
      genetic association
      histopathology
      human
      human tissue
      male
      molecular dynamics
      molecular pathology
      muscle biopsy
      muscle disease
      muscular dystrophy
      nuclear envelopathy
      phenotype
      priority journal
      promoter region
      protein binding
      protein determination
      protein expression
      protein function
      protein localization
      sequence analysis
      stop codon
      torsin A interacting protein 1 gene
      transmission electron microscopy
      adolescent
      adult
      amino acid sequence
      cell nucleus membrane
      family
      fluorescent antibody technique
      genetics
      metabolism
      molecular genetics
      muscular dystrophy
      nucleotide sequence
      pathology
      pedigree
      sarcomere
      skeletal muscle
      ultrastructure
      Adolescent
      Adult
      Amino Acid Sequence
      Carrier Proteins
      DNA Mutational Analysis
      Family
      Female
      Fluorescent Antibody Technique
      Frameshift Mutation
      Humans
      Male
      Membrane Proteins
      Microscopy, Electron, Transmission
      Molecular Sequence Data
      Muscle Fibers, Skeletal
      Muscular Dystrophies
      Nuclear Envelope
      Nuclear Proteins
      Pedigree
      RNA, Messenger
      Sarcomeres
      Permalink
      http://hdl.handle.net/11693/26568
      Published Version (Please cite this version)
      http://dx.doi.org/10.1016/j.nmd.2014.04.007
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