Evidence for a dominant negative disease mechanism in cap myopathy due to TPM3.
We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.
Waddell
Leigh B
LB
Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, Australia.
Kreissl
Michaela
M
Kornberg
Andrew
A
Kennedy
Paul
P
McLean
Catriona
C
Labarre-Vila
Annick
A
Monnier
Nicole
N
North
Kathryn N
KN
Clarke
Nigel F
NF
D000293:Adolescent; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D003545:Cysteine / Q000235:genetics; D006801:Humans; D008297:Male; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D014335:Tropomyosin / Q000235:genetics* / Q000378:metabolism
C498783:TPM3 protein, human; D014335:Tropomyosin; D001120:Arginine; D003545:Cysteine