Disease severity and thin filament regulation in M9R TPM3 nemaline myopathy.

Journal of Neuropathology and Experimental Neurology
Biljana IlkovskiSandra T Cooper

Abstract

The mechanism of muscle weakness was investigated in an Australian family with an M9R mutation in TPM3 (alpha-tropomyosin(slow)). Detailed protein analyses of 5 muscle samples from 2 patients showed that nemaline bodies are restricted to atrophied Type 1 (slow) fibers in which the TPM3 gene is expressed. Developmental expression studies showed that alpha-tropomyosin(slow) is not expressed at significant levels until after birth, thereby likely explaining the childhood (rather than congenital) disease onset in TPM3 nemaline myopathy. Isoelectric focusing demonstrated that alpha-tropomyosin(slow) dimers, composed of equal ratios of wild-type and M9R-alpha-tropomyosin(slow), are the dominant tropomyosin species in 3 separate muscle groups from an affected patient. These findings suggest that myopathy-related slow fiber predominance likely contributes to the severity of weakness in TPM3 nemaline myopathy because of increased proportions of fibers that express the mutant protein. Using recombinant proteins and far Western blot, we demonstrated a higher affinity of tropomodulin for alpha-tropomyosin(slow) compared with beta-tropomyosin; the M9R substitution within alpha-tropomyosin(slow) greatly reduced this interaction. Finally, tra...Continue Reading

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Citations

Nov 10, 2009·DNA and Cell Biology·Zongwu ZhangYaosheng Chen
Apr 7, 2010·The Journal of Cell Biology·David S GokhinVelia M Fowler
Oct 20, 2009·Arquivos de neuro-psiquiatria·Nazah Cherif Mohamad YoussefLineu César Werneck
Mar 20, 2014·The Journal of Biological Chemistry·Sawako YamashiroVelia M Fowler
Aug 17, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alexander M MatyushenkoDmitrii I Levitsky
Oct 18, 2020·International Journal of Molecular Sciences·Olga E KarpichevaYurii S Borovikov
Oct 7, 2020·The Journal of Biological Chemistry·Alice Ward RaccaJeffrey R Moore
Jan 18, 2021·The Journal of Biological Chemistry·Alice Ward RaccaJeffrey R Moore

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