Desmin myopathy is a hereditary or sporadic cardiac and skeletal
myopathy characterised by intracytoplasmic accumulation of
desmin reactive deposits in muscle cells. We have characterised novel splice site mutations in the gene
desmin resulting in deletion of the entire exon 3 during the
pre-mRNA splicing. Sequencing of
cDNA and genomic
DNA identified a heterozygous de novo A to G change at the +3 position of the
splice donor site of intron 3 (IVS3+3A-->G) in a patient with sporadic skeletal and cardiac
myopathy. A G to A transition at the highly conserved -1
nucleotide position of intron 2 affecting the
splice acceptor site (IVS2-1G-->A) was found in an unrelated patient with a similar phenotype. Expression of genomic
DNA fragments carrying the IVS3+3A-->G and IVS2-1G-->A mutations confirmed that these mutations cause exon 3 deletion. Aberrant splicing leads to an in frame deletion of 32 complete
codons and is predicted to result in mutant
desmin lacking 32
amino acids from the 1B segment of the alpha helical rod. Functional analysis of the mutant
desmin in SW13 (vim-) cells showed aggregation of abnormal coarse clumps of
desmin positive material dispersed throughout the cytoplasm. This is the first report on the pathogenic potentials of splice site mutations in the
desmin gene.