Article Text
Abstract
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.
- Iscu
- Mitochondrial Myopathy
- De Novo Mutation
- Fe-s Cluster
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Footnotes
AL and AR contributed equally.
Contributors AL carried out the molecular biology experiments; AR carried out WES; CCB performed yeast studies under the supervision of PG; OS performed experiments in patient’s fibroblasts; SM carried out the histochemical analysis; CL provided the clinical report; AF performed structural analysis; AJR provided bioinformatics management of the WES data; UM performed yeast studies under the supervision of RL; RL, MZ, PG and DG organized the experimental set-up and wrote the manuscript; all authors read and approved the manuscript.
Funding This work was supported by the TelethonItaly [GrantGGP15041]; the Pierfranco and Luisa Mariani Foundation; the MRC7QQR [201572020] grant; the ERC advanced grant [FP77322424]; the NRJ Foundation7Institut de France; the E7Rare project GENOMIT. RL acknowledges generous financial support from Deutsche Forschungsgemeinschaft [SFB 987 and SPP 1927] and the LOEWE program of state Hessen.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethical Committee of the Fondazione IRCCS Istituto Neurologico ‘Carlo Besta’, Milan, Italy.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Values of the biochemical activities reported in the graphs are available upon request.Images of the histochemical stainings are available upon request. The complete list of the variants found by WES in the proband is available upon request.
Correction notice This article has been corrected since it was published Online First. The affiliation of Massimo Zeviani has been updated.