title: Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies.
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.
authors.affiliation: Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Gulsum
authors.initials: G
authors.lastname: Kayman-Kurekci
authors.affiliation: Department of Pediatrics, Pathology Unit, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.affiliation: Department of Histology and Embryology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Petek
authors.initials: P
authors.lastname: Korkusuz
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Faculty of Science, Bilkent, 06800 Ankara, Turkey.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Sayar
authors.affiliation: Department of Histology and Embryology, Istanbul University, Istanbul Medical Faculty, Capa, 34093 Istanbul, Turkey.
authors.forename: Turkan
authors.initials: T
authors.lastname: Sarioglu
authors.affiliation: Department of Pediatrics, Neurology Unit, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Oncel
authors.affiliation: Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Parisa
authors.initials: P
authors.lastname: Sharafi
authors.affiliation: Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Gundesli
authors.affiliation: Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Burcu
authors.initials: B
authors.lastname: Balci-Hayta
authors.affiliation: Department of Biophysics, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Nuhan
authors.initials: N
authors.lastname: Purali
authors.affiliation: Department of Neurology, Istanbul University, Istanbul Medical Faculty, Capa, 34093 Istanbul, Turkey.
authors.forename: Piraye
authors.initials: P
authors.lastname: Serdaroglu-Oflazer
authors.affiliation: Department of Pediatrics, Neurology Unit, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey.
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.affiliation: Department of Medical Biology, Hacettepe University, Faculty of Medicine, Sihhiye, 06100 Ankara, Turkey. Electronic address: pdincer@hacettepe.edu.tr.
authors.forename: Pervin
authors.initials: P
authors.lastname: Dincer
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D005455:Fluorescent Antibody Technique; D016368:Frameshift Mutation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009685:Nuclear Envelope / Q000378:metabolism / Q000648:ultrastructure*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012333:RNA, Messenger; D012518:Sarcomeres / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; C486250:TOR1AIP1 protein, human; C500006:TOR1AIP2 protein, human
keywords: LAP1; Muscular dystrophy; Myopathy; TOR1AIP1