In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.
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.
Shatunov
Alexey
A
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-9404, USA.
Olivé
Montse
M
Odgerel
Zagaa
Z
Stadelmann-Nessler
Christine
C
Irlbacher
Kerstin
K
van Landeghem
Frank
F
Bayarsaikhan
Munkhuu
M
Lee
Hee-Suk
HS
Goudeau
Bertrand
B
Chinnery
Patrick F
PF
Straub
Volker
V
Hilton-Jones
David
D
Damian
Maxwell S
MS
Kaminska
Anna
A
Vicart
Patrick
P
Bushby
Kate
K
Dalakas
Marinos C
MC
Sambuughin
Nyamkhishig
N
Ferrer
Isidro
I
Goebel
Hans H
HH
Goldfarb
Lev G
LG
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
D003285:Contractile Proteins; C578661:FLNC protein, human; D064448:Filamins; D007136:Immunoglobulins; D008840:Microfilament Proteins