Key result
An intron mutation in the ISCU gene, which activates cryptic splice sites and leads to incorrectly spliced mRNA, was identified as the cause of hereditary myopathy with lactic acidosis.
Observational
Effect estimate: maximum lod score 5.26
Hereditary myopathy with lactic acidosis is caused by an intron mutation in the ISCU gene that leads to a splicing defect.
May support ISCU testing in suspected myopathy cases; extends splicing defect mechanisms but remains hypothesis-generating.
We describe the mapping and identification of the gene for hereditary myopathy with lactic acidosis (HML). HML is characterized by low physical performance, resulting in physical exertion that causes early exhaustion, dyspnoea and palpitations. Using an autosomal recessive mode of inheritance, we mapped the trait to chromosome 12q23.3-24.11, with a maximum lod score of 5.26. The 1.6-Mb disease-critical region contained one obvious candidate gene-ISCU-specifying a protein involved in iron-sulphur cluster assembly. IscU is produced in two isoforms; one cytosolic and one mitochondrial, coded for by different splice variants of the ISCU gene. Mutational analysis of all exon and intron sequences as well as 1000 bp of the promoter of the ISCU gene revealed one intron mutation that was specific for the disease haplotype. The mutation is located in a region with homology to the interferon-stimulated response element (ISRE), but we could not see any effect of the mutation on expression levels in vitro or in vivo. We did, however, observe a drastic difference in the splicing pattern between patients and controls. In controls the mRNA was, as expected, mainly in the mitochondrial form, while in the patients a larger mRNA transcript was predominant. Sequencing of the product revealed that the mutation activates cryptic splice sites in intron 5 resulting in aberrant mRNA containing 100 bp of the intron. To conclude, our data strongly suggest that an intron mutation in the ISCU gene, leading to incorrectly spliced mRNA, is the cause of myopathy with lactic acidosis in this family.
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Olsson et al. (2008) conducted an observational in Hereditary myopathy with lactic acidosis (HML). Intron mutation in the ISCU gene vs. Controls was evaluated on Genetic mapping and splicing defect identification (maximum lod score 5.26). An intron mutation in the ISCU gene, which activates cryptic splice sites and leads to incorrectly spliced mRNA, was identified as the cause of hereditary myopathy with lactic acidosis.
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