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Article: Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy

Charif, Majida / Chevrollier, Arnaud / Gueguen, Naïg / Kane, Selma / Bris, Céline / Goudenège, David / Desquiret-Dumas, Valerie / Meunier, Isabelle / Mochel, Fanny / Jeanjean, Luc / Varenne, Fanny / Procaccio, Vincent / Reynier, Pascal / Bonneau, Dominique / Amati-Bonneau, Patrizia / Lenaers, Guy

Genes. 2022 July 05, v. 13, no. 7

2022

Abstract: Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been ... ...

Abstract	Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an α subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients’ fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration.
Keywords	atrophy ; blindness ; cerebellum ; fibroblasts ; ganglia ; genes ; heterozygosity ; mitochondria ; nerve tissue ; physiology
Language	English
Dates of publication	2022-0705
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13071202
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.

Bobba-Alves, Natalia / Sturm, Gabriel / Lin, Jue / Ware, Sarah A / Karan, Kalpita R / Monzel, Anna S / Bris, Céline / Procaccio, Vincent / Lenaers, Guy / Higgins-Chen, Albert / Levine, Morgan / Horvath, Steve / Santhanam, Balaji S / Kaufman, Brett A / Hirano, Michio / Epel, Elissa / Picard, Martin

Psychoneuroendocrinology

2023 Volume 155, Page(s) 106322

Abstract: Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional ...

Abstract	Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by ∼60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load.
MeSH term(s)	Humans ; Allostasis/physiology ; Aging/physiology ; Adaptation, Physiological/physiology ; Cellular Senescence ; Energy Metabolism
Language	English
Publishing date	2023-06-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	197636-9
ISSN	1873-3360 ; 0306-4530
ISSN (online)	1873-3360
ISSN	0306-4530
DOI	10.1016/j.psyneuen.2023.106322
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Article ; Online: Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.

Sourty, Baptiste / Dardaud, Laure-Marie / Bris, Céline / Desquiret-Dumas, Valérie / Boisselier, Blandine / Basset, Laëtitia / Figarella-Branger, Dominique / Morel, Alain / Sanson, Marc / Procaccio, Vincent / Rousseau, Audrey

Neuro-oncology advances

2022 Volume 4, Issue 1, Page(s) vdab191

Abstract: Background: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or : Methods: mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. ... ...

Abstract	Background: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or Methods: mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. Methylation of Results: Median age at diagnosis was 56.6 years-old and median OS, 13.3 months. 153/232 GBM (66 %) displayed chr7+/chr10-/ Conclusion: mtDNA copy number may be a novel prognostic biomarker in GBM, its impact depending on age.
Language	English
Publishing date	2022-01-03
Publishing country	England
Document type	Journal Article
ZDB-ID	3009682-0
ISSN	2632-2498 ; 2632-2498
ISSN (online)	2632-2498
ISSN	2632-2498
DOI	10.1093/noajnl/vdab191
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Article ; Online: Next-generation sequencing of Tunisian Leigh syndrome patients reveals novel variations: impact for diagnosis and treatment.

Hechmi, Meriem / Charif, Majida / Kraoua, Ichraf / Fassatoui, Meriem / Dallali, Hamza / Desquiret-Dumas, Valerie / Bris, Céline / Goudenège, David / Drissi, Cyrine / Galaï, Saïd / Ouerhani, Slah / Procaccio, Vincent / Amati-Bonneau, Patrizia / Abdelhak, Sonia / Ben Youssef-Turki, Ilhem / Lenaers, Guy / Kefi, Rym

Bioscience reports

2022 Volume 42, Issue 9

Abstract: Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular ... ...

Abstract	Mitochondrial cytopathies, among which the Leigh syndrome (LS), are caused by variants either in the mitochondrial or the nuclear genome, affecting the oxidative phosphorylation process. The aim of the present study consisted in defining the molecular diagnosis of a group of Tunisian patients with LS. Six children, belonging to five Tunisian families, with clinical and imaging presentations suggestive of LS were recruited. Whole mitochondrial DNA and targeted next-generation sequencing of a panel of 281 nuclear genes involved in mitochondrial physiology were performed. Bioinformatic analyses were achieved in order to identify deleterious variations. A single m.10197G>A (p.Ala47Thr) variant was found in the mitochondrial MT-ND3 gene in one patient, while the others were related to autosomal homozygous variants: two c.1412delA (p.Gln471ArgfsTer42) and c.1264A>G (p.Thr422Ala) in SLC19A3, one c.454C>G (p.Pro152Ala) in SLC25A19 and one c.122G>A (p.Gly41Asp) in ETHE1. Our findings demonstrate the usefulness of genomic investigations to improve LS diagnosis in consanguineous populations and further allow for treating the patients harboring variants in SLC19A3 and SLC25A19 that contribute to thiamine transport, by thiamine and biotin supplementation. Considering the Tunisian genetic background, the newly identified variants could be screened in patients with similar clinical presentation in related populations.
MeSH term(s)	Biotin/genetics ; Child ; DNA, Mitochondrial/genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Leigh Disease/diagnosis ; Leigh Disease/genetics ; Leigh Disease/therapy ; Membrane Transport Proteins/genetics ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins/genetics ; Mutation ; Nucleocytoplasmic Transport Proteins/genetics ; Thiamine
Chemical Substances	DNA, Mitochondrial ; ETHE1 protein, human ; Membrane Transport Proteins ; Mitochondrial Membrane Transport Proteins ; Mitochondrial Proteins ; Nucleocytoplasmic Transport Proteins ; SLC19A3 protein, human ; SLC25A19 protein, human ; Biotin (6SO6U10H04) ; Thiamine (X66NSO3N35)
Language	English
Publishing date	2022-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20220194
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Article ; Online: Next-Generation Sequencing Identifies Novel

Genes

2022 Volume 13, Issue 7

Abstract	Dominant Optic Atrophy (DOA) is one of the most common inherited mitochondrial diseases, leading to blindness. It is caused by the chronic degeneration of the retinal ganglion cells (RGCs) and their axons forming the optic nerve. Until now, DOA has been mainly associated with genes encoding proteins involved in mitochondrial network dynamics. Using next-generation and exome sequencing, we identified for the first time heterozygous PMPCA variants having a causative role in the pathology of late-onset primary DOA in five patients. PMPCA encodes an α subunit of the mitochondrial peptidase (MPP), responsible for the cleavage and maturation of the mitochondrial precursor proteins imported from the cytoplasm into mitochondria. Recently, PMPCA has been identified as the gene responsible for Autosomal Recessive Cerebellar Ataxia type 2 (SCAR2) and another severe recessive mitochondrial disease. In this study, four PMPCA variants were identified, two are frameshifts (c.309delA and c.820delG) classified as pathogenic and two are missenses (c.1363G>A and c.1547G>A) classified with uncertain pathological significance. Functional assays on patients’ fibroblasts show a hyperconnection of the mitochondrial network and revealed that frameshift variants reduced α-MPP levels, while not significantly affecting the respiratory machinery. These results suggest that alterations in mitochondrial peptidase function can affect the fusion-fission balance, a key element in maintaining the physiology of retinal ganglion cells, and consequently lead to their progressive degeneration.
MeSH term(s)	Humans ; High-Throughput Nucleotide Sequencing ; Mitochondrial Diseases ; Mitochondrial Proteins/genetics ; Optic Atrophy, Autosomal Dominant/genetics ; Optic Atrophy, Autosomal Dominant/metabolism ; Optic Atrophy, Autosomal Dominant/pathology ; Peptide Hydrolases ; Mitochondrial Processing Peptidase
Chemical Substances	Mitochondrial Proteins ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2022-07-05
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13071202
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Article: Long-Term Persistence of Mitochondrial DNA Instability in HIV-Exposed Uninfected Children during and after Exposure to Antiretroviral Drugs and HIV.

Desquiret-Dumas, Valérie / D'Ottavi, Morgana / Monnin, Audrey / Goudenège, David / Méda, Nicolas / Vizeneux, Amélie / Kankasa, Chipepo / Tylleskar, Thorkild / Bris, Céline / Procaccio, Vincent / Nagot, Nicolas / Van de Perre, Philippe / Reynier, Pascal / Molès, Jean-Pierre

Biomedicines

2022 Volume 10, Issue 8

Abstract: HIV-exposed uninfected (HEU) children show impaired health outcomes during childhood. A high rate of mitochondrial DNA (mtDNA) instability was reported in the blood of HEU at birth. We aimed to explore the relationship between these health outcomes and ... ...

Abstract	HIV-exposed uninfected (HEU) children show impaired health outcomes during childhood. A high rate of mitochondrial DNA (mtDNA) instability was reported in the blood of HEU at birth. We aimed to explore the relationship between these health outcomes and mtDNA deletions over time in a case series of 24 HEU children. MtDNA instability was assessed by deep sequencing and analyzed by eKLIPse-v2 algorithm at three time points, namely birth, 1 year, and 6 years of age. Association between mtDNA deletion and health outcomes, including growth, clinical, and neurodevelopmental parameters, were explored using univariate statistical analyses and after stratification with relevant variables. HEU children were selected with an equal male:female ratio. An elevated number of mtDNA deletions and duplications events was observed at 7 days' post-partum. Median heteroplasmy increased at one year of life and then returned to baseline by six years of age. The mtDNA instability was acquired and was not transmitted by the mother. No risk factors were significantly associated with mtDNA instability. In this small case series, we did not detect any association between any health outcome at 6 years and mtDNA instability measures. A significant effect modification of the association between the duration of maternal prophylaxis and child growth was observed after stratification with heteroplasmy rate. Genomic instability persists over time among HEU children but, despite its extension, stays subclinical at six years.
Language	English
Publishing date	2022-07-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10081786
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Article ; Online: A multi-omics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations.

Sturm, Gabriel / Monzel, Anna S / Karan, Kalpita R / Michelson, Jeremy / Ware, Sarah A / Cardenas, Andres / Lin, Jue / Bris, Céline / Santhanam, Balaji / Murphy, Michael P / Levine, Morgan E / Horvath, Steve / Belsky, Daniel W / Wang, Shuang / Procaccio, Vincent / Kaufman, Brett A / Hirano, Michio / Picard, Martin

Scientific data

2022 Volume 9, Issue 1, Page(s) 751

Abstract: Aging is a process of progressive change. To develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omics longitudinal dataset for cultured primary human fibroblasts measured across ... ...

Abstract	Aging is a process of progressive change. To develop biological models of aging, longitudinal datasets with high temporal resolution are needed. Here we report a multi-omics longitudinal dataset for cultured primary human fibroblasts measured across their replicative lifespans. Fibroblasts were sourced from both healthy donors (n = 6) and individuals with lifespan-shortening mitochondrial disease (n = 3). The dataset includes cytological, bioenergetic, DNA methylation, gene expression, secreted proteins, mitochondrial DNA copy number and mutations, cell-free DNA, telomere length, and whole-genome sequencing data. This dataset enables the bridging of mechanistic processes of aging as outlined by the "hallmarks of aging", with the descriptive characterization of aging such as epigenetic age clocks. Here we focus on bridging the gap for the hallmark mitochondrial metabolism. Our dataset includes measurement of healthy cells, and cells subjected to over a dozen experimental manipulations targeting oxidative phosphorylation (OxPhos), glycolysis, and glucocorticoid signaling, among others. These experiments provide opportunities to test how cellular energetics affect the biology of cellular aging. All data are publicly available at our webtool: https://columbia-picard.shinyapps.io/shinyapp-Lifespan_Study/.
MeSH term(s)	Humans ; Aging ; Fibroblasts ; Longevity ; Cellular Senescence ; Glycolysis
Language	English
Publishing date	2022-12-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2775191-0
ISSN	2052-4463 ; 2052-4463
ISSN (online)	2052-4463
ISSN	2052-4463
DOI	10.1038/s41597-022-01852-y
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Article: Mitochondrial DNA Instability Is Common in HIV-Exposed Uninfected Newborns.

Monnin, Audrey / Desquiret-Dumas, Valérie / Méda, Nicolas / Goudenège, David / Bris, Céline / Kankasa, Chipepo / Singata-Madliki, Mandisa / Tylleskar, Thorkild / Procaccio, Vincent / Nagot, Nicolas / Van de Perre, Philippe / Reynier, Pascal / Molès, Jean-Pierre

Journal of clinical medicine

2021 Volume 10, Issue 11

Abstract: Worldwide, one million HIV-exposed uninfected (HEU) children are born yearly, and chronic health impairments have been reported in these children. Mitochondrial DNA (mtDNA) instability and altered mtDNA content have been evidenced in these children, but ... ...

Abstract	Worldwide, one million HIV-exposed uninfected (HEU) children are born yearly, and chronic health impairments have been reported in these children. Mitochondrial DNA (mtDNA) instability and altered mtDNA content have been evidenced in these children, but an exhaustive characterization of altered mitochondrial genomes has never been reported. We applied deep mtDNA sequencing coupled to the deletion identification algorithm eKLIPse to the blood of HEU neonates (
Language	English
Publishing date	2021-05-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm10112399
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Article: Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy.

Charif, Majida / Bris, Céline / Goudenège, David / Desquiret-Dumas, Valérie / Colin, Estelle / Ziegler, Alban / Procaccio, Vincent / Reynier, Pascal / Bonneau, Dominique / Lenaers, Guy / Amati-Bonneau, Patrizia

Frontiers in neurology

2021 Volume 12, Page(s) 602979

Abstract: Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we ... ...

Abstract	Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that
Language	English
Publishing date	2021-03-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2564214-5
ISSN	1664-2295
ISSN	1664-2295
DOI	10.3389/fneur.2021.602979
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Article ; Online: Prenatal diagnosis of Desbuquois dysplasia type 1 by whole exome sequencing before the occurrence of specific ultrasound signs.

Houdayer, Clara / Ziegler, Alban / Boussion, Françoise / Blesson, Sophie / Bris, Céline / Toutain, Annick / Biquard, Florence / Guichet, Agnès / Bonneau, Dominique / Colin, Estelle

The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians

2019 Volume 34, Issue 13, Page(s) 2217–2220

Abstract: Desbuquois dysplasia is a very severe and sometimes lethal form of osteochondrodysplasia characterized by prenatal onset of severe micromelic short stature, joint laxity with multiple joint dislocations, specific radiographic features, and facial ... ...

Abstract	Desbuquois dysplasia is a very severe and sometimes lethal form of osteochondrodysplasia characterized by prenatal onset of severe micromelic short stature, joint laxity with multiple joint dislocations, specific radiographic features, and facial dysmorphism. Here, we report a case for which whole exome sequencing allowed early prenatal diagnosis of Desbuquois dysplasia before the detection of characteristic ultrasound signs of the disease.
MeSH term(s)	Craniofacial Abnormalities ; Dwarfism ; Female ; Humans ; Joint Instability ; Ossification, Heterotopic ; Polydactyly ; Pregnancy ; Prenatal Diagnosis ; Whole Exome Sequencing
Language	English
Publishing date	2019-09-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2077261-0
ISSN	1476-4954 ; 1057-0802 ; 1476-7058
ISSN (online)	1476-4954
ISSN	1057-0802 ; 1476-7058
DOI	10.1080/14767058.2019.1657084
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