Expanding the phenotype of the 8344 transfer RNA
            <sup>lysine</sup>
            mitochondrial DNA mutation

Austin, Sara; Vriesendorp, Francine J.; Thandroyen, Francis T.; Hecht, JacquelineT; Jones, Owen; Johns, Donald R.

doi:10.1212/wnl.51.5.1447

Cited by 55 publications

(36 citation statements)

References 2 publications

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“…These features are neither common nor specific to mitochondrial diseases, but they may both have been overlooked to date, because they are frequent in the general population and difficult to relate to mitochondrial dysfunction 40, 41, 42, 43. However, the striking similarity of both probands from each family (III:7 in Family 1 and III:1 in Family 2) and further recurrence of these features in other individuals suggest that both hypertension and anxiety disorder may be underestimated features in mitochondrial diseases.…”

Section: Discussionmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

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ObjectiveMounting evidence links neurodegenerative disorders such as Parkinson disease and Alzheimer disease with mitochondrial dysfunction, and recent emphasis has focused on mitochondrial dynamics and quality control. Mitochondrial dynamics and mtDNA maintenance is another link recently emerged, implicating mutations in the mitochondrial fusion genes OPA1 and MFN2 in the pathogenesis of multisystem syndromes characterized by neurodegeneration and accumulation of mtDNA multiple deletions in postmitotic tissues. Here, we report 2 Italian families affected by dominant chronic progressive external ophthalmoplegia (CPEO) complicated by parkinsonism and dementia.MethodsPatients were extensively studied by optical coherence tomography (OCT) to assess retinal nerve fibers, and underwent muscle and brain magnetic resonance spectroscopy (MRS), and muscle biopsy and fibroblasts were analyzed. Candidate genes were sequenced, and mtDNA was analyzed for rearrangements.ResultsAffected individuals displayed a slowly progressive syndrome characterized by CPEO, mitochondrial myopathy, sensorineural deafness, peripheral neuropathy, parkinsonism, and/or cognitive impairment, in most cases without visual complains, but with subclinical loss of retinal nerve fibers at OCT. Muscle biopsies showed cytochrome c oxidase‐negative fibers and mtDNA multiple deletions, and MRS displayed defective oxidative metabolism in muscle and brain. We found 2 heterozygous OPA1 missense mutations affecting highly conserved amino acid positions (p.G488R, p.A495V) in the guanosine triphosphatase domain, each segregating with affected individuals. Fibroblast studies showed a reduced amount of OPA1 protein with normal mRNA expression, fragmented mitochondria, impaired bioenergetics, increased autophagy and mitophagy.InterpretationThe association of CPEO and parkinsonism/dementia with subclinical optic neuropathy widens the phenotypic spectrum of OPA1 mutations, highlighting the association of defective mitochondrial dynamics, mtDNA multiple deletions, and altered mitophagy with parkinsonism. Ann Neurol 2015;78:21–38

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Section: Discussionmentioning

confidence: 99%

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Carelli

Musumeci

Caporali

et al. 2015

Annals of Neurology

160

106

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“…It has been reported that synapsis of homozygous chromosomes in the mammalian spermatogenic meiotic process begins at the zygotene stage through chromosome movement and attachment [6,24] and that several factors for synaptonemal complexes of homozygous chromosomes, such as RAD51, DMC1, and cohesin, contain functional ATP binding domains [1,30,43]. Actually, abnormal and incomplete attachment of homozygous chromosomes occurred only in mito-mice∆ with a high load of ∆mtDNA.…”

Section: Male Infertility In Mito-mice∆mentioning

confidence: 99%

“…Dementia and ataxia are sometime found in patients with traditional mitochondrial diseases caused by accumulation of mutated mtDNAs, such as MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes), MERRF (myoclonic epilepsy and ragged red fibers), KSS (Kearns-Sayre Syndrome), CPeO (chronic progressive external ophthalmoplegia), and NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) [1,6,13,24,30,43], and the same mutated mtDNAs have been identified in patients with dementia, ataxia, and Alzheimer's disease [31,42]. Moreover, there appears to be a relationship between mtDNA polymorphisms and cognitive function in humans [38].…”

Section: Abnormalities Of Spatial Remote Memory In Mito-mice∆mentioning

confidence: 99%

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Nakada

Hayashi

2011

Exp. Anim.

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Mitochondrial genome (mtDNA) mutations and the resultant mitochondrial respiratory abnormalities are associated with a wide variety of disorders, such as mitochondrial diseases, neurodegenerative diseases, diabetes, and cancer, as well as aging. Generation of model animals carrying mutant mtDNAs is important for understanding the pathophysiological mechanisms of the mtDNA-based diseases. We have succeeded in generating three kinds of mice with pathogenic mutant mtDNAs, named "mito-mice," by the introduction of mitochondria carrying pathogenic mutant mtDNAs into mouse zygotes and mouse embryonic stem (ES) cells. In the case of mito-mice possessing the heteroplasmic state of wild-type mtDNA and pathogenic mtDNA with a large-scale deletion (∆mtDNA, mito-mice∆), a high load of ∆mtDNA induced mitochondrial respiration defects in various tissues, resulting in mitochondrial disease phenotypes, such as low body weight, lactic acidosis, ischemia, myopathy, heart block, deafness, male infertility, long-term memory defects, and renal failure. In this review, we summarize generation and clinical phenotypes of three types of mito-mice and we introduce several treatment trials for mitochondrial diseases using mito-mice∆.

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“…We could speculate that if this polymorphism really exerts a large effect on BP this should have been reflected by an augmented incidence of CV events, as for other polymorphisms we tested in the same cohort [310,32]. Finally, since Goring and colleagues, using a genome-wide transcriptional profiles of lymphocyte samples, identified the cis-regulated VNN1 as harbouring sequence variants that influence HDL-cholesterol concentrations, in an exploratory analysis we evaluated also a possible Fava et al 12 effect of the T26I SNP on HDL-cholesterol and other components of the metabolic syndrome but without any evidence of association in both cohorts.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, subjects with genetic and acquired forms of mitochondriopathy have an impaired respiratory chain with subsequent production of ROS and a tendency to higher levels of BP [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes

Fava

Montagnana

Danese

et al. 2013

Nutrition, Metabolism and Cardiovascular Diseases

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Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes.Fava, Cristiano; Montagnana, Martina; Danese, E; Sjögren, Marketa; Almgren, Peter; Engström, Gunnar; Hedblad, Bo; Guidi, G C; Minuz, P; Melander, Olle Link to publication Citation for published version (APA): Fava, C., Montagnana, M., Danese, E., Sjögren, M., Almgren, P., Engström, G., ... Melander, O. (2011). Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes. Nutrition Metabolism and Cardiovascular Diseases. DOI: 10.1016DOI: 10. /j.numecd.2011 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ABSTRACT Background: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of redox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. Methods:The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP.Results: Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females.However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in MDC-CVA was not significantly different in carriers of different genotypes. Conclusions:Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events.

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Expanding the phenotype of the 8344 transfer RNA ^lysine mitochondrial DNA mutation

Cited by 55 publications

References 2 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes

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Expanding the phenotype of the 8344 transfer RNA lysine mitochondrial DNA mutation

Cited by 55 publications

References 2 publications

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes

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Expanding the phenotype of the 8344 transfer RNA ^lysine mitochondrial DNA mutation