Dominant-negative effects of a novel mutation in the filamin myopathy.
Neurology
; 75(6): 547-54, 2010 Aug 10.
Article
in En
| MEDLINE
| ID: mdl-20697107
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Deletion
/
Contractile Proteins
/
Genes, Dominant
/
Microfilament Proteins
/
Muscular Diseases
Type of study:
Prognostic_studies
Limits:
Adult
/
Aged
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Neurology
Year:
2010
Document type:
Article
Affiliation country:
Japan