2. Academic Validation
  3. Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies

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

  • Neuromuscul Disord. 2014 Jul;24(7):624-33. doi: 10.1016/j.nmd.2014.04.007.
Gulsum Kayman-Kurekci 1,  Beril Talim 2,  Petek Korkusuz 3,  Nilufer Sayar 4,  Turkan Sarioglu 5,  Ibrahim Oncel 6,  Parisa Sharafi 1,  Hulya Gundesli 1,  Burcu Balci-Hayta 1,  Nuhan Purali 7,  Piraye Serdaroglu-Oflazer 8,  Haluk Topaloglu 6,  Pervin Dincer 9
Affiliations

Affiliations

  • 1 Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
  • 2 Department of Pediatrics, Pathology Unit, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
  • 3 Department of Histology and Embryology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
  • 4 Department of Molecular Biology and Genetics, Bilkent University, Faculty of Science, Bilkent, 06800 Ankara, Turkey.
  • 5 Department of Histology and Embryology, Istanbul University, Istanbul Medical Faculty, Capa, 34093 Istanbul, Turkey.
  • 6 Department of Pediatrics, Neurology Unit, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
  • 7 Department of Biophysics, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
  • 8 Department of Neurology, Istanbul University, Istanbul Medical Faculty, Capa, 34093 Istanbul, Turkey.
  • 9 Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey. Electronic address: pdincer@hacettepe.edu.tr.
PMID: 24856141 DOI: 10.1016/j.nmd.2014.04.007
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.

Keywords

LAP1; Muscular dystrophy; Myopathy; TOR1AIP1.

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