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

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3404-3415
Number of pages12
JournalBrain
Volume135
Issue number11
DOIs
Publication statusPublished - 2012

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Mitochondrial DNA
Mutation
Chronic Progressive External Ophthalmoplegia
Mitochondrial Myopathies
deoxyguanosine kinase
Skeletal Muscle
Deoxyribonucleotides
Mitochondrial Diseases
Rhabdomyolysis
Mitochondrial Genes
Protein Stability
Motor Neurons
Age of Onset
Transplants
Phenotype
Muscles
Liver
Genes

Keywords

  • autosomal recessive progressive external ophthalmoplegia
  • DGUOK
  • mitochondrial DNA instability
  • multiple mitochondrial DNA deletions

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. / Ronchi, Dario; Garone, Caterina; Bordoni, Andreina; Gutierrez Rios, Purificacion; Calvo, Sarah E.; Ripolone, Michela; Ranieri, Michela; Rizzuti, Mafalda; Villa, Luisa; Magri, Francesca; Corti, Stefania; Bresolin, Nereo; Mootha, Vamsi K.; Moggio, Maurizio; Dimauro, Salvatore; Comi, Giacomo P.; Sciacco, Monica.

In: Brain, Vol. 135, No. 11, 2012, p. 3404-3415.

Research output: Contribution to journalArticle

Ronchi, D, Garone, C, Bordoni, A, Gutierrez Rios, P, Calvo, SE, Ripolone, M, Ranieri, M, Rizzuti, M, Villa, L, Magri, F, Corti, S, Bresolin, N, Mootha, VK, Moggio, M, Dimauro, S, Comi, GP & Sciacco, M 2012, 'Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions', Brain, vol. 135, no. 11, pp. 3404-3415. https://doi.org/10.1093/brain/aws258
Ronchi, Dario ; Garone, Caterina ; Bordoni, Andreina ; Gutierrez Rios, Purificacion ; Calvo, Sarah E. ; Ripolone, Michela ; Ranieri, Michela ; Rizzuti, Mafalda ; Villa, Luisa ; Magri, Francesca ; Corti, Stefania ; Bresolin, Nereo ; Mootha, Vamsi K. ; Moggio, Maurizio ; Dimauro, Salvatore ; Comi, Giacomo P. ; Sciacco, Monica. / Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multiple deletions. In: Brain. 2012 ; Vol. 135, No. 11. pp. 3404-3415.
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abstract = "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.",
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AU - Ronchi, Dario

AU - Garone, Caterina

AU - Bordoni, Andreina

AU - Gutierrez Rios, Purificacion

AU - Calvo, Sarah E.

AU - Ripolone, Michela

AU - Ranieri, Michela

AU - Rizzuti, Mafalda

AU - Villa, Luisa

AU - Magri, Francesca

AU - Corti, Stefania

AU - Bresolin, Nereo

AU - Mootha, Vamsi K.

AU - Moggio, Maurizio

AU - Dimauro, Salvatore

AU - Comi, Giacomo P.

AU - Sciacco, Monica

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N2 - 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.

AB - 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.

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