title: In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.
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.
authors.affiliation: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-9404, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Shatunov
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.forename: Zagaa
authors.initials: Z
authors.lastname: Odgerel
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann-Nessler
authors.forename: Kerstin
authors.initials: K
authors.lastname: Irlbacher
authors.forename: Frank
authors.initials: F
authors.lastname: van Landeghem
authors.forename: Munkhuu
authors.initials: M
authors.lastname: Bayarsaikhan
authors.forename: Hee-Suk
authors.initials: HS
authors.lastname: Lee
authors.forename: Bertrand
authors.initials: B
authors.lastname: Goudeau
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: David
authors.initials: D
authors.lastname: Hilton-Jones
authors.forename: Maxwell S
authors.initials: MS
authors.lastname: Damian
authors.forename: Anna
authors.initials: A
authors.lastname: Kaminska
authors.forename: Patrick
authors.initials: P
authors.lastname: Vicart
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Marinos C
authors.initials: MC
authors.lastname: Dalakas
authors.forename: Nyamkhishig
authors.initials: N
authors.lastname: Sambuughin
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Hans H
authors.initials: HH
authors.lastname: Goebel
authors.forename: Lev G
authors.initials: LG
authors.lastname: Goldfarb
mesh_terms: D000595:Amino Acid Sequence; D003285:Contractile Proteins / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D064448:Filamins; D006801:Humans; D015151:Immunoblotting; D007136:Immunoglobulins / Q000235:genetics; D007150:Immunohistochemistry; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D007136:Immunoglobulins; D008840:Microfilament Proteins