Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA

M. Mancuso, L. Salviati, S. Sacconi, D. Otaegui, P. Camaño, A. Marina, S. Bacman, Carlos T Moraes, J. R. Carlo, M. Garcia, M. Garcia-Alvarez, L. Monzon, A. B. Naini, M. Hirano, E. Bonilla, A. L. Taratuto, S. DiMauro, T. H. Vu

Research output: Contribution to journalArticle

132 Citations (Scopus)

Abstract

Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls). Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.

Original languageEnglish
Pages (from-to)1197-1202
Number of pages6
JournalNeurology
Volume59
Issue number8
StatePublished - Oct 22 2002

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Thymidine Kinase
Muscular Diseases
Mitochondrial DNA
Mutation
deoxyguanosine kinase
Genes
Siblings
Deoxyribonucleotides
Motor Neuron Disease
Virulence
thymidine kinase 2

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mancuso, M., Salviati, L., Sacconi, S., Otaegui, D., Camaño, P., Marina, A., ... Vu, T. H. (2002). Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA. Neurology, 59(8), 1197-1202.

Mitochondrial DNA depletion : Mutations in thymidine kinase gene with myopathy and SMA. / Mancuso, M.; Salviati, L.; Sacconi, S.; Otaegui, D.; Camaño, P.; Marina, A.; Bacman, S.; Moraes, Carlos T; Carlo, J. R.; Garcia, M.; Garcia-Alvarez, M.; Monzon, L.; Naini, A. B.; Hirano, M.; Bonilla, E.; Taratuto, A. L.; DiMauro, S.; Vu, T. H.

In: Neurology, Vol. 59, No. 8, 22.10.2002, p. 1197-1202.

Research output: Contribution to journalArticle

Mancuso, M, Salviati, L, Sacconi, S, Otaegui, D, Camaño, P, Marina, A, Bacman, S, Moraes, CT, Carlo, JR, Garcia, M, Garcia-Alvarez, M, Monzon, L, Naini, AB, Hirano, M, Bonilla, E, Taratuto, AL, DiMauro, S & Vu, TH 2002, 'Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA' Neurology, vol. 59, no. 8, pp. 1197-1202.
Mancuso M, Salviati L, Sacconi S, Otaegui D, Camaño P, Marina A et al. Mitochondrial DNA depletion: Mutations in thymidine kinase gene with myopathy and SMA. Neurology. 2002 Oct 22;59(8):1197-1202.
Mancuso, M. ; Salviati, L. ; Sacconi, S. ; Otaegui, D. ; Camaño, P. ; Marina, A. ; Bacman, S. ; Moraes, Carlos T ; Carlo, J. R. ; Garcia, M. ; Garcia-Alvarez, M. ; Monzon, L. ; Naini, A. B. ; Hirano, M. ; Bonilla, E. ; Taratuto, A. L. ; DiMauro, S. ; Vu, T. H. / Mitochondrial DNA depletion : Mutations in thymidine kinase gene with myopathy and SMA. In: Neurology. 2002 ; Vol. 59, No. 8. pp. 1197-1202.
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abstract = "Background: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. Objectives: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. Results: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28{\%} to 37{\%} of controls). Conclusions: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.",
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