Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Nishigaki, Yutaka; Martí, Ramón; Copeland, William C.; Hirano, Michio

doi:10.1172/jci17828

Cited by 165 publications

(76 citation statements)

References 45 publications

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“…MNGIE is caused by defects in TYMP that result in increased levels of plasma thymidine and deoxyuridine. The imbalance of mitochondrial deoxynucleotide pools cause next-nucleotide effects leading to site-specific somatic mtDNA point mutations involving primarily T to C transitions preceded by 5 0 -AA sequences [20]. In addition to mtDNA point mutations, the nucleotide pool imbalance also causes mtDNA instability resulting in mtDNA multiple deletions and mtDNA depletion [21][22][23].…”

Section: Patientmentioning

confidence: 99%

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

et al. 2011

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The aim of the study was to determine the prevalence of MNGIE-like phenotype in patients with recessive POLG1 mutations. Mutations in the POLG1 gene, which encodes for the catalytic subunit of the mitochondrial DNA polymerase gamma essential for mitochondrial DNA replication, cause a wide spectrum of mitochondrial disorders. Common phenotypes associated with POLG1 mutations include Alpers syndrome, ataxia-neuropathy syndrome, and progressive external ophthalmoplegia (PEO). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, PEO and/or ptosis, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by TYMP mutations. Rare cases of MNGIE-like phenotype have been linked to RRM2B mutations. Recently, POLG1 mutations were identified in a family with clinical features of MNGIE but no leukoencephalopathy. The coding regions and exon-intron boundaries of POLG1 were sequence analyzed in patients suspected of POLG1 related disorders. Clinical features of 92 unrelated patients with two pathogenic POLG1 alleles were carefully reviewed. Three patients, accounting for 3.3% of all patients with two pathogenic POLG1 mutations, were found to have clinical features consistent with MNGIE but no leukoencephalopathy. Patient 1 carries p.W748S and p.R953C; patient 2 is homozygous for p.W748S, and patient 3 is homozygous for p.A467T. In addition, patient 2 has a similarly affected sibling with the same POLG1 genotype. POLG1 mutations may cause MNGIE-like syndrome, but the lack of leukoencephalopathy and the normal plasma thymidine favor POLG1 mutations as responsible molecular defect.

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Section: Patientmentioning

confidence: 99%

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

et al. 2011

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“…These may manifest as mtDNA multiple deletions, depletion, or accumulation of point mutations at specific sites, with a variable distribution in different tissues [3,4]. However, the mtDNA alterations are secondary to mutations in a nuclear gene, the thymidine phosphorylase (TP) on chromosome 22q13.32-qter [4].…”

Section: Introductionmentioning

confidence: 99%

Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report

Barboni¹,

Savini²,

Plazzi

et al. 2004

Graefe's Arch Clin Exp Ophthalmol

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“…Michio Hirano at CUMC carried the research on MNGIE full circle, from characterizing the clinical presentation (Hirano et al 1994) to mapping the locus to chromosome 22q (Hirano et al 1998), to identifying the mutant gene (TYMP, encoding thymidine phosphorylase) in collaboration with Ichizo Nishino , to defining biochemical abnormalities and mtDNA instability (Marti et al 2003;Nishigaki et al 2003;Spinazzola et al 2002), to developing an effective stem cell therapy (Hirano et al 2006).…”

Section: Mutations Of Nuclear Dna: Multiple Deletions and Depletion Omentioning

confidence: 99%

A history of mitochondrial diseases

DiMauro¹

2010

J of Inher Metab Disea

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This articles reviews the development of mitochondrial medicine from the premolecular era (1962-1988), when mitochondrial diseases were defined on the basis of clinical examination, muscle biopsy, and biochemical criteria, through the molecular era, when the full complexity of these disorders became evident. In a chronological order, I have followed the introduction of new pathogenic concepts that have shaped a rational genetic classification of these clinically heterogeneous disorders. Thus, mitochondrial DNA (mtDNA)-related diseases can be divided into two main groups: those that impair mitochondrial protein synthesis in toto, and those that affect specific respiratory chain proteins. Mutations in nuclear DNA can affect components of respiratory chain complexes (direct hits) or assembly proteins (indirect hits), but they can also impair mtDNA integrity (multiple mtDNA mutations), replication (mtDNA depletion), or mtDNA translation. Besides these disorders that affect the respiratory chain directly, defects in other mitochondrial functions may also affect oxidative phosphorylation, including problems in mitochondrial protein import, alterations of the inner mitochondrial membrane lipid composition, and defects of mitochondrial dynamics. The enormous and still ongoing progress in our understanding of mitochondrial medicine was made possible by the intense collaboration of an international cadre of "mitochondriacs." Having published my first paper on a patient with mitochondrial myopathy 37 years ago (DiMauro et al., 1973), I feel qualified to write a history of the mitochondrial diseases, a fascinating, still evolving, and continuously puzzling area of medicine. In each section, I follow a chronological order of the salient discoveries and I show only the portraits of distinguished deceased mitochondriacs and those whose names became eponyms of mitochondrial diseases.

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Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency

Cited by 165 publications

References 45 publications

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype: an expanded clinical spectrum of POLG1 mutations

Ocular findings in mitochondrial neurogastrointestinal encephalomyopathy: a case report

A history of mitochondrial diseases

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