Autosomal dominant myopathy caused by a novel ISCU variant

Joanna Magdalena Rusecka^1,2*Camilla Ceccatelli Berti^3*Dominika Szczęśniak^2,4Małgorzata Bednarska -Makaruk⁴Magdalena Mroczek⁵Magdalena M Kacprzak²Agnieszka Sobczyńska -Tomaszewska²Paola Goffrini³

• ¹Maria Sklodowska-Curie Medical Academy, Warsaw, Masovian, Poland
• ²MedGen Medical Centre, Warsaw, Masovian, Poland
• ³University of Parma, Parma, Emilia-Romagna, Italy
• ⁴Institute of Psychiatry and Neurology (IPiN), Warsaw, Masovian, Poland
• ⁵University Hospital of Basel, Basel, Basel-Stadt, Switzerland

Hereditary myopathy with lactic acidosis due to Iron-Sulfur Cluster Assembly Enzyme (ISCU) deficiency is a rare disorder of energy metabolism characterized clinically by myopathy with exercise intolerance, and biochemically by deficiencies of skeletal muscle mitochondrial respiratory chain enzymes. ISCU protein plays an important role in iron-sulphur clusters (Fe-S) assembly and is therefore essential for the activity of mitochondrial Fe-S proteins such as succinate dehydrogenase and aconitase. Recessive hypomorphic ISCU alleles have been associated with hereditary myopathy with lactic acidosis, also known as Swedish-type myopathy. To date, only one heterozygous dominant variant (c.287G>T, p.Gly96Val) in the ISCU gene has been reported as pathogenic. Functional studies have shown that this variant has a detrimental, dominant effect on activity of Fe-S-dependent enzymes. Whole exome sequencing performed in an adult female patient with progressive muscle weakness led to the identification of a novel heterozygous variant c.399del (p.Val134Ter) in the ISCU. This variant is localized in the functional IscU_like domain of the protein, with bioinformatics prediction of damaging effects on protein function. Moreover, the same variant was also found in a few family members, who present signs of myopathy. This novel variant segregates with the disease and results in a phenotype reminiscent of the recessive disease. Yeast Saccharomyces cerevisiae is a widely used tool able to assess the impact of the VUS in a quick and efficient way, therefore functional studies were performed on this model system. The results obtained not only confirm the pathogenetic effect of the variant, but also support its dominant inheritance.