Autosomal dominant myopathy caused by a novel ISCU variant

Area of Science:

• Genetics
• Biochemistry
• Mitochondrial Biology

Background:

• Hereditary myopathy with lactic acidosis is a rare energy metabolism disorder linked to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency.
• ISCU protein is crucial for assembling iron-sulfur clusters, essential for mitochondrial respiratory chain enzyme activity.

Purpose of the Study:

• To identify the genetic cause of progressive muscle weakness in a patient with suspected hereditary myopathy.
• To functionally characterize a novel heterozygous variant in the ISCU gene and determine its pathogenic role.

Main Methods:

• Whole exome sequencing to identify genetic variants.
• Bioinformatics analysis to predict variant pathogenicity.
• Functional studies in yeast (Saccharomyces cerevisiae) to assess the impact of the variant on protein function.

Main Results:

• A novel heterozygous ISCU gene variant (c.399del, p.Val134Ter) was identified in a patient and segregates with myopathy in her family.
• Bioinformatics predicted the variant to be damaging to ISCU protein function.
• Yeast functional studies confirmed the variant's pathogenicity and supported dominant inheritance.

Conclusions:

• The novel c.399del variant in the ISCU gene is pathogenic and causes hereditary myopathy with lactic acidosis.
• This finding expands the known spectrum of ISCU-related disorders and highlights dominant inheritance patterns.
• Yeast models are effective for studying the functional impact of variants in iron-sulfur cluster assembly disorders.