Article

In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.

National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-9404, USA.
European journal of human genetics: EJHG (impact factor: 3.56). 01/2009; 17(5):656-63. DOI:10.1038/ejhg.2008.226 pp.656-63
Source: PubMed

ABSTRACT Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val930_Thr933del) in the seventh repeat of filamin C was identified. Both affected family members, mother and daughter, but not unrelated control individuals, carried the p.Val930_Thr933del mutation. The mutation is transcribed and, based on myopathological features and immunoblot analysis, it leads to an accumulation of dysfunctional filamin C in the myocytes. The study results suggest that the novel p.Val930_Thr933del mutation in filamin C is the cause of MFM but also indicate that filamin C mutations are a comparatively rare cause of MFM.

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Keywords

24th immunoglobulin-like repeat
 
39 families
 
46 patients
 
distinct type
 
dysfunctional filamin C
 
family members
 
filamin C
 
filamin C mutations
 
German families
 
immunoblot analysis
 
International cohort
 
latest gene
 
mutations
 
Myofibrillar myopathies
 
myopathological features
 
neuromuscular disorders
 
predicted in-frame four-residue deletion
 
seventh repeat
 
unrelated control individuals
 
ZASP mutations