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P.3.13 Gene expression profiling in Welander distal myopathydoi="10.1016/j.nmd.2013.06.438" aid="2750.64"

Neuromuscular Disorders
DOI: 10.1016/j.nmd.2013.06.438
  • Biology
  • Chemistry
  • Medicine


Welander distal myopathy (WDM) is a late onset disease caused by a mutation in the C-terminal region of the TIA1 gene. The secondary molecular events resulting from the causative TIA1 mutations to the preterm death of muscle cells in WDM are mostly unknown. In order to identify downstream pathogenetic mechanisms we explored WDM biopsies genetic profile by expression profiling. We compared the changes to the expression profile of the phenotypically overlapping tibial muscular dystrophy (TMD). Six WDM patient biopsies and five healthy control muscle biopsies were used and the expression data was analyzed using Ingenuity Pathway Analysis. We identified biochemical and genetic pathway changes distinctive to WDM, such as 14-3-3 mediated apoptosis, cleavage and polyadenylation of pre-mRNA, protein trafficking and transport, and oxidative phosphorylation pathway changes. We also identified shared changes with TMD that result in the similarity seen in both these distal myopathies, such as SAP-JNK apoptosis, P70S6 mTOR signalling, mitochondrial dysfunction, and protein ubiquitination pathway changes. TIA1 is a key component of stress granules, a mechanism used to protect other cellular mechanisms during stress. The unique oxidative phosphorylation changes we identified by expression profiling may be associated with increased oxidative stress in WDM. TIA1 is also involved in polyadenylation and splicing of mRNA and the identified changes in these pathways in our study suggest mutated TIA1 affects these pathways in WDM. In addition, both WDM and TMD have common pathological changes in P70S6-mTOR signalling, SAP-JNK apoptosis and protein ubiquitination signalling pathways, which have been reported in other rimmed vacuolar myopathies.

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