TY - JOUR T1 - A novel de novo dominant mutation in <em>ISCU</em> associated with mitochondrial myopathy JF - Journal of Medical Genetics JO - J Med Genet SP - 815 LP - 824 DO - 10.1136/jmedgenet-2017-104822 VL - 54 IS - 12 AU - Andrea Legati AU - Aurelio Reyes AU - Camilla Ceccatelli Berti AU - Oliver Stehling AU - Silvia Marchet AU - Costanza Lamperti AU - Alberto Ferrari AU - Alan J Robinson AU - Ulrich Mühlenhoff AU - Roland Lill AU - Massimo Zeviani AU - Paola Goffrini AU - Daniele Ghezzi Y1 - 2017/12/01 UR - http://jmg.bmj.com/content/54/12/815.abstract N2 - Background Hereditary myopathy with lactic acidosis and myopathy with deficiency of succinate dehydrogenase and aconitase are variants of a recessive disorder characterised by childhood-onset early fatigue, dyspnoea and palpitations on trivial exercise. The disease is non-progressive, but life-threatening episodes of widespread weakness, metabolic acidosis and rhabdomyolysis may occur. So far, this disease has been molecularly defined only in Swedish patients, all homozygous for a deep intronic splicing affecting mutation in ISCU encoding a scaffold protein for the assembly of iron–sulfur (Fe-S) clusters. A single Scandinavian family was identified with a different mutation, a missense change in compound heterozygosity with the common intronic mutation. The aim of the study was to identify the genetic defect in our proband.Methods A next-generation sequencing (NGS) approach was carried out on an Italian male who presented in childhood with ptosis, severe muscle weakness and exercise intolerance. His disease was slowly progressive, with partial recovery between episodes. Patient’s specimens and yeast models were investigated.Results Histochemical and biochemical analyses on muscle biopsy showed multiple defects affecting mitochondrial respiratory chain complexes. We identified a single heterozygous mutation p.Gly96Val in ISCU, which was absent in DNA from his parents indicating a possible de novo dominant effect in the patient. Patient fibroblasts showed normal levels of ISCU protein and a few variably affected Fe-S cluster-dependent enzymes. Yeast studies confirmed both pathogenicity and dominance of the identified missense mutation.Conclusion We describe the first heterozygous dominant mutation in ISCU which results in a phenotype reminiscent of the recessive disease previously reported. ER -