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Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions

Dario Ronchi, Caterina Garone, Andreina Bordoni, Purificacion Gutierrez Rios, Sarah E. Calvo, Michela Ripolone, Michela Ranieri, Mafalda Rizzuti, Luisa Villa, Francesca Magri, Stefania Corti, Nereo Bresolin, Vamsi K. Mootha, Maurizio Moggio, Salvatore DiMauro, Giacomo P. Comi, Monica Sciacco
DOI: http://dx.doi.org/10.1093/brain/aws258 3404-3415 First published online: 5 October 2012

Summary

The molecular diagnosis of mitochondrial disorders still remains elusive in a large proportion of patients, but advances in next generation sequencing are significantly improving our chances to detect mutations even in sporadic patients. Syndromes associated with mitochondrial DNA multiple deletions are caused by different molecular defects resulting in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia to multi-systemic disorders of variable severity. The mutations underlying these conditions remain undisclosed in half of the affected subjects. We applied next-generation sequencing of known mitochondrial targets (MitoExome) to probands presenting with adult-onset mitochondrial myopathy and harbouring mitochondrial DNA multiple deletions in skeletal muscle. We identified autosomal recessive mutations in the DGUOK gene (encoding mitochondrial deoxyguanosine kinase), which has previously been associated with an infantile hepatocerebral form of mitochondrial DNA depletion. Mutations in DGUOK occurred in five independent subjects, representing 5.6% of our cohort of patients with mitochondrial DNA multiple deletions, and impaired both muscle DGUOK activity and protein stability. Clinical presentations were variable, including mitochondrial myopathy with or without progressive external ophthalmoplegia, recurrent rhabdomyolysis in a young female who had received a liver transplant at 9 months of age and adult-onset lower motor neuron syndrome with mild cognitive impairment. These findings reinforce the concept that mutations in genes involved in deoxyribonucleotide metabolism can cause diverse clinical phenotypes and suggest that DGUOK should be screened in patients harbouring mitochondrial DNA deletions in skeletal muscle.

  • DGUOK
  • mitochondrial DNA instability
  • autosomal recessive progressive external ophthalmoplegia
  • multiple mitochondrial DNA deletions
  • Abbreviations
    COX
    cytochrome c oxidase
    SDH
    succinate dehydrogenase
    mtDNA
    mitochondrial DNA
    PCR
    polymerase chain reaction
    dNTP
    deoxyribonucleotide triphosphate
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