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

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Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy A novel gene related to nuclear envelopathies.pdf (2.34 MB)

Date

2014

Authors

Kayman-Kurekci G.
Talim, B.
Korkusuz P.
Sayar, N.
Sarioglu, T.
Oncel I.
Sharafi P.
Gundesli H.
Balci-Hayta, B.
Purali, N.

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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.

Source Title

Neuromuscular Disorders

Publisher

Elsevier Ltd

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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

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http://hdl.handle.net/11693/26568

Published Version (Please cite this version)

http://dx.doi.org/10.1016/j.nmd.2014.04.007

Collections

Scholarly Publications - Molecular Biology and Genetics

Language

English

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Article