المؤلفون: Morad Khayat, Alessandra Torraco, M. Eileen McCormick, Klaas J. Wierenga, Holger Hengel, Rosalba Carrozzo, Stavit A. Shalev, Camilla Ceccatelli Berti, Muhammad Mahajnah, Paola Goffrini, Amit Kessel, Rajech Sharkia, Ronen Spiegel, Ludger Schöls, Andrea Klein, Abdussalam Azem, Barbara Plecko, Lucia Abela, Enrico Bertini

المصدر: Journal of inherited metabolic disease 42(2), 264-275 (2019). doi:10.1002/jimd.12022

مصطلحات موضوعية: Male, Retinal degeneration, Microcephaly, Pathology, Internationality, Compound heterozygosity, genetics [Optic Atrophy], Cerebellum, pathology [Cerebellum], genetics [Exome], Missense mutation, Exome, 610 Medicine & health, Child, Genetics (clinical), Aconitate Hydratase, 0303 health sciences, Homozygote, 030305 genetics & heredity, High-Throughput Nucleotide Sequencing, Neurodegenerative Diseases, ACO2, Syndrome, genetics [Ataxia], Magnetic Resonance Imaging, genetics [Retinal Dystrophies], Child, Preschool, Female, diagnosis [Retinal Dystrophies], medicine.medical_specialty, Adolescent, genetics [Aconitate Hydratase], Citric Acid Cycle, diagnosis [Neurodegenerative Diseases], Mutation, Missense, Aconitase, Young Adult, 03 medical and health sciences, Atrophy, genetics [Microcephaly], Retinal Dystrophies, Genetics, medicine, Humans, ddc:610, 030304 developmental biology, business.industry, diagnosis [Optic Atrophy], medicine.disease, Optic Atrophy, genetics [Neurodegenerative Diseases], deficiency [Aconitate Hydratase], Ataxia, business, Truncal ataxia

الوصف: Mitochondrial aconitase is the second enzyme in the tricarboxylic acid (TCA) cycle catalyzing the interconversion of citrate into isocitrate and encoded by the nuclear gene ACO2. A homozygous pathogenic variant in the ACO2 gene was initially described in 2012 resulting in a novel disorder termed "infantile cerebellar retinal degeneration" (ICRD, OMIM#614559). Subsequently, additional studies reported patients with pathogenic ACO2 variants, further expanding the genetic and clinical spectrum of this disorder to include milder and later onset manifestations. Here, we report an international multicenter cohort of 16 patients (of whom 7 are newly diagnosed) with biallelic pathogenic variants in ACO2 gene. Most patients present in early infancy with severe truncal hypotonia, truncal ataxia, variable seizures, evolving microcephaly, and ophthalmological abnormalities of which the most dominant are esotropia and optic atrophy with later development of retinal dystrophy. Most patients remain nonambulatory and do no acquire any language, but a subgroup of patients share a more favorable course. Brain magnetic resonance imaging (MRI) is typically normal within the first months but global atrophy gradually develops affecting predominantly the cerebellum. Ten of our patients were homozygous to the previously reported c.336C>G founder mutation while the other six patients were all compound heterozygotes displaying 10 novel mutations of whom 2 were nonsense predicting a deleterious effect on enzyme function. Structural protein modeling predicted significant impairment in aconitase substrate binding in the additional missense mutations. This study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a10635375098a53dd82a5972086f8668Test
https://doi.org/10.1002/jimd.12022Test

المؤلفون: Dana Dayan, Dajana Grossmann, Jill Bohler, Simone Schimpf-Linzenbold, Sylvie Delcambre, Bernd Wissinger, Rejko Krüger, François Massart, Anne Grünewald, Amit Kessel, Katarina Stingl, Jenny Ghelfi, Ludger Schöls, Reut Ben-Menachem, Abdussalam Azem, Tim M. Strom, Ophry Pines, Marie Anne-Catherine Neumann

المصدر: Scientific reports 10(1), 16736 (2020). doi:10.1038/s41598-020-73557-4
Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020)
Sci. Rep. 10:16736 (2020)
Scientific Reports
info:eu-repo/grantAgreement/EC/H2020/692320

مصطلحات موضوعية: 0301 basic medicine, Male, pathology [Optic Atrophy], lcsh:Medicine, Haploinsufficiency, Biochemistry, biophysics & molecular biology [F05] [Life sciences], medicine.disease_cause, pathology [Mitochondria], genetics [Optic Atrophy], 0302 clinical medicine, metabolism [Aconitate Hydratase], Exome, Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant], lcsh:Science, Sequence Deletion, Aconitate Hydratase, Multidisciplinary, ACO2, Hypotonia, Mitochondria, Neurology, Cerebellar atrophy, Female, medicine.symptom, pathology [Fibroblasts], metabolism [Fibroblasts], Mitochondrial DNA, Programmed cell death, genetics [Aconitate Hydratase], Biology, DNA, Mitochondrial, Article, 03 medical and health sciences, Atrophy, Genetics, medicine, Humans, lcsh:R, Optic Nerve, Fibroblasts, medicine.disease, metabolism [Mitochondria], Molecular biology, Optic Atrophy, 030104 developmental biology, metabolism [Optic Atrophy], lcsh:Q, genetics [Mitochondria], pathology [Optic Nerve], ddc:600, 030217 neurology & neurosurgery, Oxidative stress, Neuroscience, metabolism [Optic Nerve]

الوصف: ACO2 is a mitochondrial protein, which is critically involved in the function of the tricarboxylic acid cycle (TCA), the maintenance of iron homeostasis, oxidative stress defense and the integrity of mitochondrial DNA (mtDNA). Mutations in the ACO2 gene were identified in patients suffering from a broad range of symptoms, including optic nerve atrophy, cortical atrophy, cerebellar atrophy, hypotonia, seizures and intellectual disabilities. In the present study, we identified a heterozygous 51 bp deletion (c.1699_1749del51) in ACO2 in a family with autosomal dominant inherited isolated optic atrophy. A complementation assay using aco1-deficient yeast revealed a growth defect for the mutant ACO2 variant substantiating a pathogenic effect of the deletion. We used patient-derived fibroblasts to characterize cellular phenotypes and found a decrease of ACO2 protein levels, while ACO2 enzyme activity was not affected compared to two age- and gender-matched control lines. Several parameters of mitochondrial function, including mitochondrial morphology, mitochondrial membrane potential or mitochondrial superoxide production, were not changed under baseline conditions. However, basal respiration, maximal respiration, and spare respiratory capacity were reduced in mutant cells. Furthermore, we observed a reduction of mtDNA copy number and reduced mtDNA transcription levels in ACO2-mutant fibroblasts. Inducing oxidative stress led to an increased susceptibility for cell death in ACO2-mutant fibroblasts compared to controls. Our study reveals that a monoallelic mutation in ACO2 is sufficient to promote mitochondrial dysfunction and increased vulnerability to oxidative stress as main drivers of cell death related to optic nerve atrophy.

وصف الملف: application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0ac65a56ebb9891b00c0f4e96fae0214Test

المؤلفون: Volker F. Wendisch, Andreas Krug, Michael Bott

المصدر: The journal of biological chemistry 585-595 (2005). doi:10.1074/jbc.M408271200

مصطلحات موضوعية: Transcriptional Activation, acetate metabolism, metabolism [Bacterial Proteins], genetics [Aconitate Hydratase], Molecular Sequence Data, Repressor, binding protein, posttranscriptional regulation, Biology, Biochemistry, Aconitase, nucleotide-sequence, Corynebacterium glutamicum, chemistry.chemical_compound, Species Specificity, Bacterial Proteins, ddc:570, RNA polymerase, Genes, Regulator, Transcriptional regulation, molecular analysis, TetR, Amino Acid Sequence, Molecular Biology, Gene, metabolism [Repressor Proteins], DNA microarray analyses, Aconitate Hydratase, enzymology [Corynebacterium glutamicum], respiratory-chain, genetics [Corynebacterium glutamicum], antagonists & inhibitors [Aconitate Hydratase], Gene Expression Regulation, Bacterial, Cell Biology, gel-electrophoresis, Molecular biology, Repressor Proteins, Citric acid cycle, genetics [Repressor Proteins], escherichia-coli aconitases, chemistry, Genes, Bacterial, bacillus-subtilis aconitase, Sequence Alignment, genetics [Bacterial Proteins]

الوصف: In Corynebacterium glutamicum, the activity of aconitase is 2.5-4-fold higher on propionate, citrate, or acetate than on glucose. Here we show that this variation is caused by transcriptional regulation. In search for putative regulators, a gene (acnR) encoding a TetR-type transcriptional regulator was found to be encoded immediately downstream of the aconitase gene (acn) in C. glutamicum. Deletion of the acnR gene led to a 5-fold increased acn-mRNA level and a 5-fold increased aconitase activity, suggesting that AcnR functions as repressor of acn expression. DNA microarray analyses indicated that acn is the primary target gene of AcnR in the C. glutamicum genome. Purified AcnR was shown to be a homodimer, which binds to the acn promoter in the region from -11 to -28 relative to the transcription start. It thus presumably acts by interfering with the binding of RNA polymerase. The acn-acnR organization is conserved in all corynebacteria and mycobacteria with known genome sequence and a putative AcnR consensus binding motif (CAGNACnnncGTACTG) was identified in the corresponding acn upstream regions. Mutations within this motif inhibited AcnR binding. Because the activities of citrate synthase and isocitrate dehydrogenase were previously reported not to be increased during growth on acetate, our data indicate that aconitase is a major control point of tricarboxylic acid cycle activity in C. glutamicum, and they identify AcnR as the first transcriptional regulator of a tricarboxylic acid cycle gene in the Corynebacterianeae.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::826b681b2a8d90478580768226c7a189Test
https://doi.org/10.1074/jbc.m408271200Test

المؤلفون: Andreas Krug, Michael Bott, Meike Baumgart, Nurije Mustafi

المصدر: Journal of bacteriology 193, 6864-6873 (2011). doi:10.1128/JB.05465-11

مصطلحات موضوعية: metabolism [Bacterial Proteins], genetics [Aconitate Hydratase], Physiology and Metabolism, Mutant, Citrate (si)-Synthase, medicine.disease_cause, Microbiology, Aconitase, Corynebacterium glutamicum, Bacterial Proteins, ddc:570, medicine, Citrate synthase, Gene Silencing, Molecular Biology, Gene, genetics [Citrate (si)-Synthase], Aconitate Hydratase, Mutation, biology, enzymology [Corynebacterium glutamicum], Point mutation, genetics [Corynebacterium glutamicum], Gene Expression Regulation, Bacterial, Molecular biology, metabolism [Citrate (si)-Synthase], Biochemistry, biology.protein, Gene Deletion, genetics [Bacterial Proteins]

الوصف: The aconitase gene acn of Corynebacterium glutamicum is regulated by four transcriptional regulators, indicating that the synthesis of this enzyme is carefully controlled. To understand the causes for this elaborate regulation, the properties of the Δ acn -1 deletion mutant were analyzed in detail. The mutant was glutamate auxotrophic in glucose minimal medium, showed a strong growth defect, and secreted large amounts of acetate. None of these phenotypes could be complemented by plasmid-encoded aconitase, suggesting the presence of a secondary mutation. In fact, a point mutation within the gltA gene encoding citrate synthase was identified that caused the instability of the protein and an almost complete lack of its enzymatic activity. Subsequently, 27 further, independent Δ acn clones were isolated, and 15 of them were found to contain distinct mutations in gltA , causing the loss of citrate synthase activity. A similar result was observed for mutants lacking the isocitrate dehydrogenase gene icd . In this case, 8 of 24 Δ icd clones contained additional mutations in gltA . Indirect evidence was obtained that elevated intracellular citrate concentrations could be the cause of this selection pressure. Accordingly, the careful control of aconitase synthesis might have evolved due to the necessity to avoid inhibitory cytoplasmic citrate levels on the one hand and to prevent the excessive synthesis of an oxygen-sensitive protein requiring both iron and sulfur on the other hand.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5a5d39cda0ace073e34fa0df5130402eTest
https://europepmc.org/articles/PMC3232852Test/

المؤلفون: Andreas Krug, Julia Wennerhold, Michael Bott

المصدر: The journal of biological chemistry 280, 40500-40508 (2005). doi:10.1074/jbc.M508693200

مصطلحات موضوعية: pharmacology [Bacterial Proteins], Operon, genetics [Aconitate Hydratase], Iron, Mutant, AraC Transcription Factor, DtxR protein, Corynebacterium diphtheriae, Repressor, drug effects [Gene Expression Regulation], Biology, Nitrate reductase, Biochemistry, Aconitase, Nonheme Iron Proteins, Corynebacterium glutamicum, analysis [RNA, Messenger], Bacterial Proteins, ddc:570, pharmacology [AraC Transcription Factor], pharmacology [DNA-Binding Proteins], metabolism [Aconitate Hydratase], Escherichia coli, RNA, Messenger, Promoter Regions, Genetic, Molecular Biology, Aconitate Hydratase, Binding Sites, enzymology [Corynebacterium glutamicum], Wild type, Cell Biology, genetics [Catalase], DNA, genetics [AraC Transcription Factor], Catalase, Molecular biology, pharmacology [Iron], Recombinant Proteins, DNA-Binding Proteins, Gene Expression Regulation, Dehydratase, genetics [Promoter Regions, Genetic], chemistry [Corynebacterium glutamicum], Mutation, metabolism [DNA], genetics [Nonheme Iron Proteins]

الوصف: The mRNA level of the aconitase gene acn of Corynebacterium glutamicum is reduced under iron limitation. Here we show that an AraC-type regulator, termed RipA for "regulator of iron proteins A," is involved in this type of regulation. A C. glutamicum DeltaripA mutant has a 2-fold higher aconitase activity than the wild type under iron limitation, but not under iron excess. Comparison of the mRNA profiles of the DeltaripA mutant and the wild type revealed that the acn mRNA level was increased in the DeltaripA mutant under iron limitation, but not under iron excess, indicating a repressor function of RipA. Besides acn, some other genes showed increased mRNA levels in the DeltaripA mutant under iron starvation (i.e. those encoding succinate dehydrogenase (sdhCAB), nitrate/nitrite transporter and nitrate reductase (narKGHJI), isopropylmalate dehydratase (leuCD), catechol 1,2-dioxygenase (catA), and phosphotransacetylase (pta)). Most of these proteins contain iron. Purified RipA binds to the upstream regions of all operons mentioned above and in addition to that of the catalase gene (katA). From 13 identified binding sites, the RipA consensus binding motif RRGCGN(4)RYGAC was deduced. Expression of ripA itself is repressed under iron excess by DtxR, since purified DtxR binds to a well conserved binding site upstream of ripA. Thus, repression of acn and the other target genes indicated above under iron limitation involves a regulatory cascade of two repressors, DtxR and its target RipA. The modulation of the intracellular iron usage by RipA supplements mechanisms for iron acquisition that are directly regulated by DtxR.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4fb629e479dd2cb71f77fd64d6582286Test
https://juser.fz-juelich.de/record/48587Test