Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome

Papadimitriou, A.; Comi, Giacomo Pietro; Hadjigeorgiou, George; Bordoni, Andreina; Sciacco, Monica; Napoli, Laura; Prelle, A.; Moggio, Maurizio; Fagiolari, Gigliola; Bresolin, Nereo; Salani, Sabrina; Anastasopoulos, I.; Giassakis, G.; Divari, R.; Scarlato, G.

doi:10.1212/wnl.51.4.1086

Cited by 99 publications

(82 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mutations in the mitochondrial proteins adenine nucleotide translocator 1 (ANT1) (Kaukonen et al), Twinkle (Spelbrink et al) and polymerase γ (Van Goethem et al) have been found to cause autosomal dominant progressive external ophthalmoplegia with multiple deletion of mtDNA. Mitochondrial Neurogastrointestinal Encephalomyopathy (MINGIE) is an autosomal recessive disorder due to loss-of-function mutations in the gene encoding thymidine phosphorylase, associated with multiple deletions, depletion and site-specific point mutations of mtDNA (Hirano et al, 1994;Nishigaki et al, 2003;Papadimitriou et al, 1998). ANT1 forms a homodimeric inner mitochondrial membrane channel that translocates ADP into ATP out of the mitochondrial matrix.…”

Section: Causes For Mtdna Depletion and Deletionmentioning

confidence: 99%

Regulation of mitochondrial DNA content and cancer

Higuchi

2007

Mitochondrion

View full text Add to dashboard Cite

Enzymatic activities of the proteins encoded in nuclear genome are regulated by transcriptional, translational and post-transcriptional level. Enzymatic activities of proteins encoded in mitochondrial DNA (mtDNA) have been considered to be regulated by the same steps although detailed mechanisms might differ. However, dynamic change of the number of mtDNA, from some hundred to more than ten thousand, should be considered as another novel mechanism to regulate mtDNA-encoded proteins. Recently, we showed the connection of mtDNA depletion and deletion to cancer progression (Higuchi et al., 2006). This review focuses and describes the possible connections of the mitochondrial DNA depletion and deletion to cancer.

show abstract

Section: Causes For Mtdna Depletion and Deletionmentioning

confidence: 99%

Regulation of mitochondrial DNA content and cancer

Higuchi

2007

Mitochondrion

View full text Add to dashboard Cite

show abstract

“…Southern blot analysis, with Pvu II digestion of total DNA (5 µg), and slot blot procedure were conducted as previously described. 12,17 Quantification of the mtDNA relative amount was performed with a 18S rRNA probe as previously reported. 12 The boundaries of the mtDNA deletions were amplified with several set of primers: 2A: nt 8155 to nt 8176 and 2B: nt 14263 to nt 14246; 3A: nt 8128 to nt 8147 and 3B: nt 16125 to nt 16106; 4A: nt 4232 to nt 4251 and 4B: nt 9339 to nt 9320; 5A: nt 111 to nt 130 and 5B: nt 4970 to nt 4951.…”

Section: Molecular Analysismentioning

confidence: 99%

“…12,17 Quantification of the mtDNA relative amount was performed with a 18S rRNA probe as previously reported. 12 The boundaries of the mtDNA deletions were amplified with several set of primers: 2A: nt 8155 to nt 8176 and 2B: nt 14263 to nt 14246; 3A: nt 8128 to nt 8147 and 3B: nt 16125 to nt 16106; 4A: nt 4232 to nt 4251 and 4B: nt 9339 to nt 9320; 5A: nt 111 to nt 130 and 5B: nt 4970 to nt 4951. PCR reactions were performed under conditions depending on each primer set, with the Expand Long Template PCR System (Roche, Meylan, France).…”

Section: Molecular Analysismentioning

confidence: 99%

“…6 Nevertheless, no clinical marker is really specific and this is probably explained in part by the variable distribution of deleted molecules in the different tissues. 6,7 Multiple mtDNA deletions have also been described in recessive disorders including neurogastrointestinal encephalomyopathy (MNGIE) [11][12][13] and cardiomyopathy with ophthalmoplegia (ARCO). 14 The patients with recessive disorders have multi-organ involvement but the most striking difference from dominant forms is that they present an earlier onset.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions

et al. 2000

View full text Add to dashboard Cite

Multiple mitochondrial DNA (mtDNA) deletions have been reported in patients with autosomal dominant and recessive disorders. We studied several affected and one non-affected individuals belonging to a pedigree in which the inheritance of the pathological trait was compatible with an autosomique dominant transmission. Affected members had late-onset multisystem disorders with multiple mtDNA deletions in skeletal muscle. But this family presented a striking difference from previously described cases, because none of the patients had progressive external ophthalmoplegia (PEO). We also studied one young boy with a no contributary family history. He had a cerebellar ataxia with PEO and multiple mtDNA deletions in muscle. Molecular analysis revealed that in the first family, repeated sequences were present at the breakpoint junctions, whereas such motifs were not found in the young patient's case. In the first family, we evidenced mtDNA point mutations in clones containing breakpoint junctions and a 9-bp motif triplication in the intergenic COII/tRNA Lys region, whereas this sequence is repeated twice in the wild type mtDNA. Our results suggest that multiple deletions observed in the two pedigrees result from different molecular mechanisms and point out the role of repeated sequences in the first pedigree. No mtDNA repair system has been described in mammals so far, but the molecular abnormalities found in the first family suggest that a defect in an mtDNA repair system, homologous to the E. coli MutHLS pathway, could be responsible for such a phenotype.

show abstract

“…1 Skeletal muscle biopsies of patients have revealed abnormalities of mtDNA and mitochondrial respiratory chain enzymes. 2 The disease is caused by the thymidine phosphorylase defect. This enzyme catalyses phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate.…”

Section: Introductionmentioning

confidence: 99%

Pre‐ and post‐dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC‐ESI‐MS/MS

Marca

Malvagia

Casetta³

et al. 2006

J. Mass Spectrom.

View full text Add to dashboard Cite

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by severe gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. The disease is due to a thymidine phosphorylase defect. This enzyme catalyses the phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. For this reason, increased levels of thymidine in plasma and urine are found in MNGIE patients. Haemodialysis can reduce circulating plasma thymidine levels and can be beneficial in some MNGIE patients. We developed a fast analytical method based on HPLC-ESI-MS/MS capable of identifying pyrimidine nucleotides (thymine, cytosine, uracil) and nucleosides (thymidine, citidine, uridine) in plasma and urine after direct dilution of the samples without pre-treatment.In the patient studied, we observed a significant reduction of plasmatic and urinary thymidine levels during and after dialysis. However, we noted a progressive reduction of the initial thymidine level after some dialytic trials. This method will be useful not only for thymidine level follow-up during dialysis in MNGIE patients but also for the improvement of the diagnosis or diagnostic suspect in other pyrimidine defects such as dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinase deficiency and ureidopropionase deficiency.

show abstract

Partial depletion and multiple deletions of muscle mtDNA in familial MNGIE syndrome

Cited by 99 publications

References 9 publications

Regulation of mitochondrial DNA content and cancer

Regulation of mitochondrial DNA content and cancer

Importance of searching for associated mitochondrial DNA alterations in patients with multiple deletions

Pre‐ and post‐dialysis quantitative dosage of thymidine in urine and plasma of a MNGIE patient by using HPLC‐ESI‐MS/MS

Contact Info

Product

Resources

About