Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Molecular Characterization of Pontocerebellar Hypoplasia

ABSTRACT: Molecular Characterization of Pontocerebellar Hypoplasia

PROVIDER: PRJNA1062911 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Similar Datasets

Molecular Characterization of Pontocerebellar Hypoplasia

Project description:Molecular Characterization of Pontocerebellar Hypoplasia

| PRJNA1062912 | ENA

Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia

Project description:Recessive mutations in EXOSC3, encoding a subunit of the human RNA exosome complex, cause Pontocerebellar hypoplasia type 1b (PCH1B). We report a boy with severe muscular hypotonia, psychomotor retardation, progressive microcephaly, and cerebellar atrophy. Biochemical abnormalities comprised mitochondrial Complex I and PDHc deficiency. Whole exome sequencing uncovered a known EXOSC3-mutation p.(D132A) as the underlying cause. In patient fibroblasts, >50% of the EXOSC3 protein was trapped in the cytosol. mtDNA-copy numbers in muscle were reduced to 40%, but mutations in the mtDNA and nuclear mitochondrial genes were excluded. RNA-seq of patient muscle showed highly increased mRNA-copy numbers, especially for genes encoding structural subunits of OXPHOS-complexes I, III, and IV, possibly due to reduced degradation by a dysfunctional exosome complex. This is the first case of mitochondrial dysfunction associated with an EXOSC3 mutation, which expands the phenotypic spectrum of PCH1B. We discuss the links between exosome and mitochondrial dysfunction.

2017-08-22 | GSE99715 | GEO

RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Project description:RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

| PRJNA635887 | ENA

RNA exosome mutations in pontocerebellar hypoplasia alter ribosome biogenesis and p53 levels

Project description:The eukaryotic RNA exosome is a ubiquitously expressed complex of nine core proteins (EXOSC1-9) and associated nucleases responsible for RNA processing and degradation. Autosomal recessive mutations in EXOSC3, EXOSC8, EXOSC9 and the exosome cofactor RBM7 cause pontocerebellar hypoplasia and motor neuronopathy. To understand the importance of the exosome in neurodegeneration, we investigated the consequences of exosome mutations on RNA metabolism and cellular survival in zebrafish and human cell models. We observed that levels of mRNAs encoding p53 and ribosome biogenesis factors are upregulated in zebrafish lines with homozygous mutations of exosc8 or exosc9, respectively. In addition, exosome deficiency leads to increased levels of multiple non-coding RNAs (e.g. tRNAs, snoRNAs, scaRNAs). Consistent with higher p53 levels, mutant zebrafish have a reduced head size, smaller brain and cerebellum caused by an increased number of apoptotic cells during development. Downregulation of EXOSC9 in human cells leads to p53 protein stabilisation and G2/M cell cycle arrest. The work provides explanation for the pathogenesis of exosome-related disorders and highlights the link between exosome function, ribosome biogenesis and p53-dependent signalling.

2020-05-30 | GSE151452 | GEO

A Drosophila Model of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons

Project description:A Drosophila Model of Pontocerebellar Hypoplasia Reveals a Critical Role for the RNA Exosome in Neurons

| PRJNA612828 | ENA

The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

Project description:Homozygous mutation of the RNA kinase CLP1 causes pontocerebellar hypoplasia type 10 (PCH10), a pediatric neurodegenerative disease. CLP1 is associated with the tRNA splicing endonuclease complex and the cleavage and polyadenylation machinery, but its function remains unclear. We generated two mouse models of PCH10: one homozygous for the disease-associated Clp1 mutation, R140H, and one heterozygous for this mutation and a null allele. Both models exhibit loss of lower motor neurons and neurons of the deep cerebellar nuclei. To explore whether Clp1 mutation impacts tRNA splicing, we profiled the products of intron-containing tRNA genes. While mature tRNAs were expressed at normal levels in mutant mice, numerous other products of intron-containing tRNA genes were dysregulated, with pre-tRNAs, introns, and certain tRNA fragments upregulated, and other fragments downregulated. However, the spatiotemporal patterns of dysregulation did not support a role in pathogenicity for most altered tRNA products. To elucidate the effect of Clp1 mutation on pre-mRNA cleavage, we analyzed poly(A) site (PAS) usage and gene expression in Clp1R140H/- spinal cord. PAS usage was shifted from proximal to distal sites in the mutant mouse, particularly in short and closely spaced genes. Many such genes also were expressed at lower levels in the Clp1R140H/- mouse, possibly as a result of impaired transcript maturation. These findings are consistent with the hypothesis that select genes are particularly dependent upon CLP1 for proper pre-mRNA cleavage, suggesting that the contribution of mRNA 3’ processing to pathogenesis in PCH10 merits further investigation.

2021-09-20 | GSE176183 | GEO

The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

Project description:The Clp1 R140H mutation alters tRNA metabolism and mRNA 3’ processing in mouse models of pontocerebellar hypoplasia

| PRJNA735232 | ENA

Assembly defects of the human tRNA splicing endonuclease contribute to impaired pre-tRNA splicing in pontocerebellar hypoplasia

Project description:Assembly defects of the human tRNA splicing endonuclease contribute to impaired pre-tRNA splicing in pontocerebellar hypoplasia

| PRJNA635177 | ENA

Molecular characterization of DLBCL

Project description:Molecular characterization of DLBCL

| PRJNA605794 | ENA

Molecular Characterization of Hemimegalencephaly

Project description:Molecular Characterization of Hemimegalencephaly

| PRJNA671236 | ENA