Differential isoform expression and selective muscle involvement in muscular dystrophies.
Despite the expression of the mutated gene in all muscles, selective muscles are involved in genetic muscular dystrophies. Different muscular dystrophies show characteristic patterns of fatty degenerative changes by muscle imaging, even to the extent that the patterns have been used for diagnostic purposes. However, the underlying molecular mechanisms explaining the selective involvement of muscles are not known. To test the hypothesis that different muscles may express variable amounts of different isoforms of muscle genes, we applied a custom-designed exon microarray containing probes for 57 muscle-specific genes to assay the transcriptional profiles in sets of human adult lower limb skeletal muscles. Quantitative real-time PCR and whole transcriptome sequencing were used to further analyze the results. Our results demonstrate significant variations in isoform and gene expression levels in anatomically different muscles. Comparison of the known patterns of selective involvement of certain muscles in two autosomal dominant titinopathies and one autosomal dominant myosinopathy, with the isoform and gene expression results, shows a correlation between the specific muscles involved and significant differences in the level of expression of the affected gene and exons in these same muscles compared with some other selected muscles. Our results suggest that differential expression levels of muscle genes and isoforms are one determinant in the selectivity of muscle involvement in muscular dystrophies.
Department of Pathology, Fimlab Laboratories, Tampere University Hospital, Tampere, Finland; Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland. Electronic address: sanna.huovinen@fimlab.fi.
Sanna
S
Huovinen
Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
Sini
S
Penttilä
The Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Panu
P
Somervuo
The Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Joni
J
Keto
The Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
Petri
P
Auvinen
Department of Medical Genetics, Folkhälsan Institute of Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
Anna
A
Vihola
Department of Electrical Engineering, University of Oulu, Oulu, Finland.
Sami
S
Huovinen
Department of Biosciences, Division of Genetics, University of Helsinki, Helsinki, Finland.
Katarina
K
Pelin
Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
Olayinka
O
Raheem
Division of Vascular Surgery, Department of Surgery, Tampere University Hospital and University of Tampere, Tampere, Finland.
Juha
J
Salenius
Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland.
Tiina
T
Suominen
Department of Medical Genetics, Folkhälsan Institute of Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
Peter
P
Hackman
Neuromuscular Research Center, Tampere University Hospital and University of Tampere, Tampere, Finland; Department of Medical Genetics, Folkhälsan Institute of Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; Department of Neurology, Vaasa Central Hospital, Vaasa, Finland.
Bjarne
B
Udd
D000368:Aged; D000369:Aged, 80 and over; D005091:Exons; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D020033:Protein Isoforms