Dominant-negative effects of a novel mutation in the filamin myopathy
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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.
Footnotes
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Supplemental data at www.neurology.org
Disclosure: The authors report no disclosures.
Received November 20, 2009. Accepted in final form April 28, 2010.
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Letters: Rapid online correspondence
- Dominant-negative effects of a novel mutation in the filamin myopathy
- Peter F.M. van der Ven, Bonn, Germanypvdven@uni-bonn.de
- Zagaa Odgerel (Bethesda, MD; odgerelz@ninds.nih.gov), Dieter O. Fürst (Bonn, Germany; dfuerst@uni-bonn.de) Lev G Goldfarb (Bethesda, MD; goldfarbl@ninds.nih.gov )
Submitted October 20, 2010 - Reply from the authors
- Satoshi Kono, First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hmamatsu, Japansatokono@hama-med.ac.jp
- Hiroaki Miyajima (Japan; miyajima@hama-med.ac.jp)
Submitted October 20, 2010
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