Hereditary myopathy with lactic acidosis, or
myopathy with exercise intolerance, Swedish type (OMIM #255125) is caused by mutations in the
iron-
sulfur cluster scaffold (
ISCU) gene. The g.7044G>C
ISCU mutation induces a splicing error in the
pre-mRNA that strengthens a weak intronic splice site leading to inclusion of a new exon and subsequent loss of
mRNA and
protein. While
ISCU is widely expressed, homozygosity for this particular intronic mutation gives rise to a pure
myopathy. In order to investigate tissue specificity and disease mechanism, we studied muscle, myoblasts, fibroblasts and blood cells from the first non-Swedish case of this disease. Consistent with the recognised role of
ISCU, we found abnormal activities of respiratory chain complexes containing
iron-
sulfur clusters in patient muscle. We confirmed that, in the presence of the g.7044G>C mutation, splicing produces both abnormally and normally spliced
mRNA in all tissues. The ratio of these products varies dramatically between tissues, being most abnormal in mature skeletal muscle that also has the lowest relative starting levels of
ISCU mRNA compared with other tissues. Myoblasts and fibroblasts have more of the normally spliced variant as well as higher starting levels of
ISCU mRNA. Up-regulation of
mtDNA copy number was found in skeletal muscle and myoblasts, but not fibroblasts, and is thought to represent a compensatory response. Tissue specificity in this disorder appears therefore to be dependent on the
mRNA starting level, the amount of remaining normally spliced
RNA, and the degree to which compensatory mechanisms can respond.