Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins
Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we di...
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doaj-7dd8055e8c754e3c9397ed672fce876a2020-11-25T00:27:53ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-08-01910.3389/fgene.2018.00338385287Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic TwinsEleonora Napoli0Andrea Schneider1Andrea Schneider2Randi Hagerman3Randi Hagerman4Gyu Song5Sarah Wong6Flora Tassone7Flora Tassone8Cecilia Giulivi9Cecilia Giulivi10Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesUC Davis MIND Institute, UC Davis Health, Sacramento, CA, United StatesDepartment of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA, United StatesUC Davis MIND Institute, UC Davis Health, Sacramento, CA, United StatesDepartment of Pediatrics, School of Medicine, University of California, Davis, Sacramento, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesUC Davis MIND Institute, UC Davis Health, Sacramento, CA, United StatesDepartment of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, United StatesDepartment of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United StatesUC Davis MIND Institute, UC Davis Health, Sacramento, CA, United StatesMitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150–180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother’s ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention.https://www.frontiersin.org/article/10.3389/fgene.2018.00338/fullbioenergeticsFXTASmitochondrial dysfunctionoxidative stresspremutation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Eleonora Napoli Andrea Schneider Andrea Schneider Randi Hagerman Randi Hagerman Gyu Song Sarah Wong Flora Tassone Flora Tassone Cecilia Giulivi Cecilia Giulivi |
spellingShingle |
Eleonora Napoli Andrea Schneider Andrea Schneider Randi Hagerman Randi Hagerman Gyu Song Sarah Wong Flora Tassone Flora Tassone Cecilia Giulivi Cecilia Giulivi Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins Frontiers in Genetics bioenergetics FXTAS mitochondrial dysfunction oxidative stress premutation |
author_facet |
Eleonora Napoli Andrea Schneider Andrea Schneider Randi Hagerman Randi Hagerman Gyu Song Sarah Wong Flora Tassone Flora Tassone Cecilia Giulivi Cecilia Giulivi |
author_sort |
Eleonora Napoli |
title |
Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins |
title_short |
Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins |
title_full |
Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins |
title_fullStr |
Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins |
title_full_unstemmed |
Impact of FMR1 Premutation on Neurobehavior and Bioenergetics in Young Monozygotic Twins |
title_sort |
impact of fmr1 premutation on neurobehavior and bioenergetics in young monozygotic twins |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Genetics |
issn |
1664-8021 |
publishDate |
2018-08-01 |
description |
Mitochondrial dysfunction (MD) has been identified in lymphocytes, fibroblasts and brain samples from adults carrying a 55–200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene (premutation; PM); however, limited data are available on the bioenergetics of pediatric carriers. Here we discuss a case report of three PM carriers: two monozygotic twins (aged 8 years) harboring an FMR1 allele with 150–180 CGG repeats, with no cognitive or intellectual issues but diagnosed with depression, mood instability and ADHD, and their mother (asymptomatic carrier with 78 CGG repeats). Fibroblasts and lymphocytes from the twins presented a generalized OXPHOS deficit, altered mitochondrial network, accumulation of depolarized mitochondria, and increased mitochondrial ROS production, outcomes distinct and more severe than the mother’s ones, suggesting the involvement of modulatory effects mediated by CGG expansion, X-activation ratio, sex hormones and epigenetic factors (chronic inflammation, consequence of Lyme disease). The degree of the severity of MD appeared to segregate with the morbidity of the phenotype. The mitochondrial ROS-mediated HIF-1α stabilization was identified as a key player at contributing to the MD, pointing it as a novel target for future therapeutical intervention. |
topic |
bioenergetics FXTAS mitochondrial dysfunction oxidative stress premutation |
url |
https://www.frontiersin.org/article/10.3389/fgene.2018.00338/full |
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