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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.

Original publication

DOI

10.1038/ejhg.2008.226

Type

Journal article

Journal

Eur J Hum Genet

Publication Date

05/2009

Volume

17

Pages

656 - 663

Keywords

Amino Acid Sequence, Contractile Proteins, DNA Mutational Analysis, Family Health, Female, Filamins, Humans, Immunoblotting, Immunoglobulins, Immunohistochemistry, Male, Microfilament Proteins, Microscopy, Electron, Molecular Sequence Data, Muscle, Skeletal, Muscular Diseases, Mutation, Myofibrils, Repetitive Sequences, Nucleic Acid, Sequence Deletion, Sequence Homology, Amino Acid