Differences in RNA processing underlie the tissue specific phenotype of ISCU myopathy

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• Hereditary myopathy with lactic acidosis (Swedish type) is linked to mutations in the iron-sulfur cluster scaffold (ISCU) gene.
• A specific g.7044G>C mutation in ISCU causes splicing errors, leading to mRNA and protein loss, yet results in a pure myopathy.

Observation:

• Studied the first non-Swedish case using muscle, myoblasts, fibroblasts, and blood cells.
• Found abnormal respiratory chain complex activities in patient muscle, consistent with ISCU's role.
• Observed varying ratios of normally and abnormally spliced ISCU mRNA across tissues, with mature muscle most affected.

Findings:

• Splicing abnormalities and normal mRNA variants coexist in all tissues studied.
• Mature skeletal muscle exhibits the highest proportion of abnormal splicing and lowest ISCU mRNA levels.
• Skeletal muscle and myoblasts show increased mtDNA copy number, suggesting a compensatory response.

Implications:

• Tissue specificity in ISCU myopathy is influenced by initial ISCU mRNA levels.
• The amount of functional, normally spliced ISCU RNA and compensatory mechanisms determine disease presentation.
• Understanding these factors is crucial for elucidating the disease mechanism and potential therapeutic strategies.