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A novel de novo dominant mutation in ISCU associated with mitochondrial myopathy

Published version
Peer-reviewed

Type

Article

Change log

Authors

Legati, Andrea 
Reyes, Aurelio 
Ceccatelli Berti, Camilla 
Stehling, Oliver 
Marchet, Silvia 

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.

Description

Keywords

De Novo Mutation, Fe-s Cluster, iscu, mitochondrial myopathy

Journal Title

Journal of Medical Genetics

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

54

Publisher

BMJ Publishing Group
Sponsorship
Medical Research Council (MC_UP_1002/1)
Medical Research Council (MC_U105674181)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_UU_00015/7)
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.