Mitochondrial DNA deletion in "identical" twin brothers

Blakely, EL; He, Lu; Taylor, RW; Chinnery, Patrick F.; Lightowlers, RN; Schaefer, AM; Turnbull, Doug M.

doi:10.1136/jmg.2003.011296

Cited by 59 publications

(40 citation statements)

References 19 publications

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“…In this pair, both twins had a small amount of 4115 base pair deletion in muscles, but the affected twin had much higher amount of deletion. 29 Discordant phenotypes due to uneven amount of heteroplasmic mutations were also found in DZ twins with myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) 30 and myoclonic epilepsy with ragged-red fibers (MERRF). 31 However, effects of nuclear genes could not be ruled out in these DZ twin cases.…”

Section: Mitochondrial Dna (Mtdna) Heteroplasmymentioning

confidence: 99%

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

et al. 2005

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Classical twin research focused on differentiating genetic factors from environmental factors by comparing the concordance rate between monozygotic (MZ) and dizygotic twins. On the other hand, recent twin research tries to identify genetic or epigenetic differences between MZ twins discordant for mental disorders. There are a number of reports of MZ twins discordant for genetic disorders caused by genetic or epigenetic differences of known pathogenic genes. In the case of mental disorder research, for which the causative gene has not been established yet, we are trying to identify the 'pathogenic gene' by comprehensive analysis of genetic or epigenetic difference between discordant MZ twins. To date, no compelling evidence suggesting such difference between MZ twins has been reported. However, if the genetic or epigenetic difference responsible for the discordant phenotype is found, it will have impact on the biology of mental disorder, in which few conclusive molecular genetic evidences have been obtained.

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Section: Mitochondrial Dna (Mtdna) Heteroplasmymentioning

confidence: 99%

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

et al. 2005

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“…These mutations might be skewedly distributed between the blastomeres through the 'mitochondrial bottleneck' and subsequently expand into different degrees of heteroplasmy in the fetuses (Kirches et al, 2001). Heteroplasmy is defined as the presence of two or more mtDNA populations in the same individual and different degrees of heteroplasmy have been shown to cause discordant symptoms in MZ twins with mitochondrial disorders (chronic progressive external ophthalmoplegia and Leber's hereditary optic neuropathy; Biousse et al, 1997;Blakely et al, 2004).…”

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confidence: 99%

Analysis of Mitochondrial DNA in Discordant Monozygotic Twins With Neurofibromatosis Type 1

et al. 2007

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Neurofibromatosis type 1 (NF1) is the most frequent neurocutaneous disorder with autosomal dominant inheritance. Phenotype variability is high ranging from merely several café-au-lait spots to malignant peripheral nerve sheath tumors or severe disfigurement through plexiform neurofibromas. Identification of genetic factors that modify the NF1 phenotype would contribute to the understanding of NF1 pathophysiology and improve patient counselling. As even monozygotic (MZ) twins with NF1 may differ phenotypically, we wondered whether these variations might be inherited in a non-Mendelian fashion. Mitochondrial DNA (mtDNA) is inherited extrachromosomally through the cytoplasm of the oocyte and often harbours heteroplasmic sequence variations. At the time of blastomere separation, these variants may be skewedly distributed and effect phenotypic differences. Because of their co-localization with the tumor suppressor protein neurofibromin, which is mutated in NF1, mitochondria were particular attractive candidates for investigation. MtDNA was extracted from nucleated blood cells of four pairs of discordant MZ twins with NF1 and from cutaneous neurofibromas of one twin pair. We sequenced the entire mitochondrial genome and determined the state of heteroplasmy by investigating a microsatellite region of the mitochondrial D-loop (D310-tract). The clinical diagnosis was confirmed in all patients by detection of pathogenic mutations in the NF1 gene. Monozygosity was verified by genotyping. However, we did not detect evidence for mtDNA sequence differences or for different degrees of heteroplasmy between individuals of the same twin pair. The phenotypic discordance of MZ twins with NF1 cannot be explained by skewed distribution of mtDNA mutations or polymorphisms.

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“…1C). Interestingly, the mutation was clearly absent from all tissues from the patient's mother, including skeletal muscle, suggesting that the pathogenic inversion had arisen sporadically within the oocyte, similar to single, large-scale mtDNA deletions (24).…”

Section: Resultsmentioning

confidence: 99%

Sporadic Intragenic Inversion of the Mitochondrial DNA MTND1 Gene Causing Fatal Infantile Lactic Acidosis

et al. 2006

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Mutations of mitochondrial DNA (mtDNA) are an important cause of genetic disease, yet rarely present in the neonatal period. Here we report the clinical, biochemical, and molecular genetic findings of an infant who died at the age of 1 mo with marked biventricular hypertrophy, aortic coarctation, and severe lactic acidosis due to a previously described but unusual mtDNA mutation, a 7-bp intragenic inversion within the mitochondrial gene encoding ND1 protein of complex I (MTND1). In direct contrast to the previous case, an adult with exercise intolerance who only harbored the mutation in muscle, the MTND1 inversion in our patient was present at high levels in several tissues including the heart, muscle, liver, and cultured skin fibroblasts. There was no evidence of the mutation or respiratory complex I defect in a muscle biopsy from the patient's mother. Transmitochondrial cytoplasmic hybrids (cybrids) containing high mutant loads of the inversion expressed the biochemical defect but apparently normal levels of the assembled complex. Our report highlights the enormous phenotypic diversity that exists among pathogenic mtDNA mutations and reemphasizes the need for appropriate genetic counseling for families affected by mtDNA disease. (Pediatr Res 59: 440-444, 2006)

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Mitochondrial DNA deletion in "identical" twin brothers

Cited by 59 publications

References 19 publications

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

Analysis of Mitochondrial DNA in Discordant Monozygotic Twins With Neurofibromatosis Type 1

Sporadic Intragenic Inversion of the Mitochondrial DNA MTND1 Gene Causing Fatal Infantile Lactic Acidosis

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