PT  - JOURNAL ARTICLE
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
TI  - A novel de novo dominant mutation in <em>ISCU</em> associated with mitochondrial myopathy
AID  - 10.1136/jmedgenet-2017-104822
DP  - 2017 Oct 27
TA  - Journal of Medical Genetics
PG  - jmedgenet-2017-104822
4099  - http://jmg.bmj.com/content/early/2017/10/27/jmedgenet-2017-104822.short
4100  - http://jmg.bmj.com/content/early/2017/10/27/jmedgenet-2017-104822.full
AB  - 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.