RRC ID 19239
Author Kono S, Nishio T, Takahashi Y, Goto-Inoue N, Kinoshita M, Zaima N, Suzuki H, Fukutoku-Otsuji A, Setou M, Miyajima H.
Title Dominant-negative effects of a novel mutation in the filamin myopathy.
Journal Neurology
Abstract BACKGROUND:Filamin myopathy is associated with mutations in the filamin C gene (FLNC) and is a myofibrillar myopathy characterized by focal myofibrillar destruction and cytoplasmic aggregates containing several Z-disk-related proteins.
METHODS:This study investigated 6 Japanese patients with dominantly inherited myofibrillar myopathy manifested by adult-onset, slow and progressive muscle weakness and atrophy in the distal extremities.
RESULTS:The abundantly expressed proteins in the affected muscles were identified as filamin C by nano liquid chromatography-tandem mass spectrometry. A genetic analysis of FLNC identified a heterozygous c.8107delG mutation that was localized to the dimerization domain of filamin C. A biochemical crosslinking analysis of bacterially expressed recombinant wild-type and mutant filamin C fragments demonstrated that the mutant monomer disturbed the proper dimerization of the wild-type filamin dimer, resulting in formation of a heterotrimer with the wild-type filamin dimer. The expression study in C2C12 myoblasts showed that the mutant filamin fragments formed cytoplasmic aggregates with endogenous wild-type filamin C.
CONCLUSIONS:This study provides evidence for the dominant-negative effects of the FLNC mutation. These effects may be mutation-specific and likely result in the variation in the clinical phenotypes seen in patients with filamin myopathy.
Volume 75(6)
Pages 547-54
Published 2010-8-10
DOI 10.1212/WNL.0b013e3181ec7fbd
PII 75/6/547
PMID 20697107
MeSH Adult Aged Amino Acid Sequence Animals Cell Line Contractile Proteins / genetics* Female Filamins Gene Deletion* Genes, Dominant / genetics* Genetic Carrier Screening Humans Male Mice Microfilament Proteins / genetics* Middle Aged Molecular Sequence Data Muscular Diseases / diagnosis* Muscular Diseases / genetics* Muscular Diseases / pathology Myoblasts / pathology Pedigree Phenotype
IF 8.77
Times Cited 6
Human and Animal Cells C2C12(RCB0987)