654 research outputs found
Multi-Omics Approach to Mitochondrial DNA Damage in Human Muscle Fibers
No full textAbstract: Mitochondrial DNA deletions affect energy metabolism at tissue-specific and cell-specific
threshold levels, but the pathophysiological mechanisms determining cell fate remain poorly understood.
Chronic progressive external ophthalmoplegia (CPEO) is caused by mtDNA deletions and
characterized by a mosaic distribution of muscle fibers with defective cytochrome oxidase (COX)
activity, interspersed among fibers with retained functional respiratory chain. We used diagnostic
histochemistry to distinguish COX-negative from COX-positive fibers in nine muscle biopsies from
CPEO patients and performed laser capture microdissection (LCM) coupled to genome-wide gene
expression analysis. To gain molecular insight into the pathogenesis, we applied network and
pathway analysis to highlight molecular differences of the COX-positive and COX-negative fiber
transcriptome. We then integrated our results with proteomics data that we previously obtained
comparing COX-positive and COX-negative fiber sections from three other patients. By virtue of
the combination of LCM and a multi-omics approach, we here provide a comprehensive resource
to tackle the pathogenic changes leading to progressive respiratory chain deficiency and disease in
mitochondrial deletion syndromes. Our data show that COX-negative fibers upregulate transcripts
involved in translational elongation and protein synthesis. Furthermore, based on functional annotation
analysis, we find that mitochondrial transcripts are the most enriched among those with
significantly different expression between COX-positive and COX-negative fibers, indicating that
our unbiased large-scale approach resolves the core of the pathogenic changes. Further enrichments
include transcripts encoding LIM domain proteins, ubiquitin ligases, proteins involved in
RNA turnover, and, interestingly, cell cycle arrest and cell death. These pathways may thus have a
functional association to the molecular pathogenesis of the disease. Overall, the transcriptome and
proteome show a low degree of correlation in CPEO patients, suggesting a relevant contribution of
post-transcriptional mechanisms in shaping this disease phenotype
Gene expression and splicing counts from the Yepez, Gusic et al study - non strand-specific
No full textFile description:
geneCounts: gene-level counts
k_j: split counts spanning from one exon to another.
k_theta: non-split counts covering a splice site
n_psi3: total split counts from a given acceptor site
n_psi5: total split counts from a given donor site
n_theta: total split and non-split counts for a given splice site
Sample annotation describing each sample from the dataset
Description file with global information from the dataset
The gene counts were originated using the GTF file from release 34 of GENCODE https://www.gencodegenes.org/human/release_34, and the split and non-split counts contain only the annotated junctions from the same release.
Use: The count matrices are intended to help researchers that are interested in using RNA-Seq data with the purpose of diagnostics. Researchers can merge their own dataset with the downloaded ones, provided the tissue, genome build, strand, and paired-end specifications match. Afterwards, the DROP can be used to compute expression and splicing outliers (https://github.com/gagneurlab/drop).
Number of samples: 154
Tissue: Fibroblast
Organism: Homo sapiens
Genome assembly: hg19
Gene annotation: gencode34
Disease (ICD-10: N): E75: 1, E79: 13, E88: 118, G31: 9, K72: 3, NONE: 10
Strand specific: FALSE
Paired end: TRUE
Protocol: poly(A) enrichment
Dataset contact: Vicente Yepez, [email protected]; Julien Gagneur, [email protected]; Holger Prokisch, [email protected]
Citation: Cite both the resource using Zenodo's citation and the publication under Reference
Gene expression and splicing counts from the Yepez, Gusic et al study - fibroblast, hg19, strand-specific, high seq depth
No full textFile description:
geneCounts: gene-level counts
k_j: split counts spanning from one exon to another.
k_theta: non-split counts covering a splice site
n_psi3: total split counts from a given acceptor site
n_psi5: total split counts from a given donor site
n_theta: total split and non-split counts for a given splice site
Sample annotation describing each sample from the dataset
Description file with global information from the dataset
The gene counts were originated using the GTF file from release 34 of GENCODE https://www.gencodegenes.org/human/release_34, and the split and non-split counts contain only the annotated junctions from the same release.
Use: The count matrices are intended to help researchers that are interested in using RNA-Seq data with the purpose of diagnostics. Researchers can merge their own dataset with the downloaded ones, provided the tissue, genome build, strand, and paired-end specifications match. Afterwards, DROP can be used to compute expression and splicing outliers (https://github.com/gagneurlab/drop).
Number of samples: 135
Tissue: Fibroblast
Organism: Homo sapiens
Genome assembly: hg19
Gene annotation: gencode34
Median mapped reads: 116 million
Disease (ICD-10: N): E88: 112, G31: 8, NONE: 5, K72: 2, G71: 2, E72: 1, G93: 1, I42: 1, F82: 1, E75: 1, F89: 1
Strand specific: True
Paired end: True
Dataset contact: Vicente Yepez, yepez at in.tum.de; Christian Mertes, mertes at in.tum.de; Julien Gagneur, gagneur at in.tum.de; Holger Prokisch, prokisch at helmholtz-muenchen.de
Citation: Cite both the resource using Zenodo's citation and the publication under Reference
Gene expression and splicing counts from the Yepez, Gusic et al study - strand-specific
No full textFile description:
geneCounts: gene-level counts
k_j: split counts spanning from one exon to another.
k_theta: non-split counts covering a splice site
n_psi3: total split counts from a given acceptor site
n_psi5: total split counts from a given donor site
n_theta: total split and non-split counts for a given splice site
Sample annotation describing each sample from the dataset
Description file with global information from the dataset
The gene counts were originated using the GTF file from release 34 of GENCODE https://www.gencodegenes.org/human/release_34, and the split and non-split counts contain only the annotated junctions from the same release.
Use: The count matrices are intended to help researchers that are interested in using RNA-Seq data with the purpose of diagnostics. Researchers can merge their own dataset with the downloaded ones, provided the tissue, genome build, strand, and paired-end specifications match. Afterwards, DROP can be used to compute expression and splicing outliers (https://github.com/gagneurlab/drop).
Number of samples: 269
Tissue: Fibroblast
Organism: Homo sapiens
Genome assembly: hg19
Gene annotation: gencode34
Disease (ICD-10: N): E72: 4, E75: 2, E77: 1, E88: 199, F82: 1, F89: 7, G31: 14, G40: 2, G71: 3, G82: 1, G93: 2, I42: 1, K72: 4, NONE: 18, P94: 2, Q02: 1, Q78: 1, R16: 2, R27: 3, R29: 1
Strand specific: TRUE
Paired end: TRUE
Protocol: poly(A) enrichment
Dataset contact: Vicente Yepez, [email protected]; Julien Gagneur, [email protected]; Holger Prokisch, [email protected]
Citation: Cite both the resource using Zenodo's citation and the publication under Reference
Gene expression and splicing counts from the Yepez, Gusic et al study - fibroblast, hg19, strand-specific, low seq depth
No full textFile description:
geneCounts: gene-level counts
k_j: split counts spanning from one exon to another.
k_theta: non-split counts covering a splice site
n_psi3: total split counts from a given acceptor site
n_psi5: total split counts from a given donor site
n_theta: total split and non-split counts for a given splice site
Sample annotation describing each sample from the dataset
Description file with global information from the dataset
The gene counts were originated using the GTF file from release 34 of GENCODE https://www.gencodegenes.org/human/release_34, and the split and non-split counts contain only the annotated junctions from the same release.
Use: The count matrices are intended to help researchers that are interested in using RNA-Seq data with the purpose of diagnostics. Researchers can merge their own dataset with the downloaded ones, provided the tissue, genome build, strand, and paired-end specifications match. Afterwards, DROP can be used to compute expression and splicing outliers (https://github.com/gagneurlab/drop).
Number of samples: 127
Tissue: Fibroblast
Organism: Homo sapiens
Genome assembly: hg19
Gene annotation: gencode34
Median mapped reads: 71 million
Disease (ICD-10: N): E88: 84, NONE: 12, F89: 6, G31: 3, R27: 3, E72: 3, G40: 2, R16: 2, K72: 2, P94: 2, E77: 1, E75: 1, G71: 1, G93: 1, Q78: 1, G82: 1, R29: 1, Q02: 1
Strand specific: True
Paired end: True
Dataset contact: Vicente Yepez, yepez at in.tum.de; Christian Mertes, mertes at in.tum.de; Julien Gagneur, gagneur at in.tum.de; Holger Prokisch, prokisch at helmholtz-muenchen.de
Citation: Cite both the resource using Zenodo's citation and the publication under Reference
Mutations of C19orf12, coding for a transmembrane glycine zipper containing mitochondrial protein, cause mis-localization of the protein, inability to respond to oxidative stress and increased mitochondrial Ca2+.
No full textMutations in C19orf12 have been identified in patients affected by Neurodegeneration with Brain Iron Accumulation (NBIA), a clinical entity characterized by iron accumulation in the basal ganglia. By using western blot analysis with specific antibody and confocal studies, we showed that wild-type C19orf12 protein was not exclusively present in mitochondria, but also in the Endoplasmic Reticulum (ER) and MAM (Mitochondria Associated Membrane), while mutant C19orf12 variants presented a different localization. Moreover, after induction of oxidative stress, a GFP-tagged C19orf12 wild-type protein was able to relocate to the cytosol. On the contrary, mutant isoforms were not able to respond to oxidative stress. High mitochondrial calcium concentration and increased H2O2 induced apoptosis were found in fibroblasts derived from one patient as compared to controls.C19orf12 protein is a 17kDa mitochondrial membrane-associated protein whose function is still unknown. Our in silico investigation suggests that, the glycine zipper motifs of C19orf12 form helical regions spanning the membrane. The N- and C-terminal regions with respect to the transmembrane portion, on the contrary, are predicted to rearrange in a structural domain, which is homologues to the N-terminal regulatory domain of the magnesium transporter MgtE, suggesting that C19orf12 may act as a regulatory protein for human MgtE transporters. The mutations here described affect respectively one glycine residue of the glycine zipper motifs, which are involved in dimerization of transmembrane helices and predicted to impair the correct localization of the protein into the membranes, and one residue present in the regulatory domain, which is important for protein-protein interaction
Cellular rescue-assay aids verification of causative DNA-variants in mitochondrial complex I deficiency.
No full textMitochondria! complex I deficiency is a frequent biochemical condition, causing about one third of respiratory chain disorders. Partly due to the large number of genes necessary for its assembly and function only a small proportion of complex I deficiencies are yet confirmed at the molecular genetic level. Now, next generation sequencing approaches are applied to close the gap between biochemical definition and molecular diagnosis. Nevertheless such approaches result in a long list of novel rare single nucleotide variants. Identifying the causative mutations still remains challenging. Here we describe the identification and functional confirmation of novel NDUFS1 mutations using a cellular rescue-assay. Patient-derived complex I-defective fibroblast cell lines were transduced with wild type and mutant NDUFS1-cDNA and subsequently analyzed on the functional and protein level. We established the pathogenic nature of identified rare variants in four out of five disease alleles. This approach is a valuable add-on in disease genetics and it allows the analysis of the functional consequences of genetic variants in metabolic disorders
Impairment of calcineurin function in Neurospora crassa reveals its essential role in hyphal growth, morphology and maintenance of the apical Ca 2+ gradient
No full textGene expression and splicing counts from the Kremer et al study
No full textFile description:
geneCounts: gene-level counts
k_j: split counts spanning from one exon to another.
k_theta: non-split counts covering a splice site
n_psi3: total split counts from a given acceptor site
n_psi5: total split counts from a given donor site
n_theta: total split and non-split counts for a given splice site
Sample annotation describing each sample from the dataset
Description file with global information from the dataset
The gene counts were originated using the GTF file from release 34 of GENCODE https://www.gencodegenes.org/human/release_34, and the split and non-split counts contain only the annonated junctions from the same release.
Use: The count matrices are intended to help researchers that are interested in using RNA-Seq data with the purpose of diagnostics. Researchers can merge their own dataset with the downloaded ones, provided the tissue, genome build, strand, and paired-end specifications match. Afterwards, the DROP pipeline can be used to compute expression and splicing outliers (https://github.com/gagneurlab/drop).
Number of samples: 119
Tissue: Fibroblast
Organism: Homo sapiens
Genome assembly: hg19
Gene annotation: gencode34
Disease (ICD-10: N): E75: 1, E79: 13, E88: 84, G31: 9, K72: 3, NONE: 9
Strand specific: FALSE
Paired end: TRUE
Protocol: poly(A) enrichment
Dataset contact: Vicente Yepez, [email protected]; Christian Mertes, [email protected]; Julien Gagneur, [email protected]; Holger Prokisch, [email protected]
Citation: Cite both the resource using Zenodo's citation and the publication under Reference
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