Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA389402 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.
2021-11-01 | GSE183871 | GEO
Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.
2021-11-01 | GSE183870 | GEO
Project description:Pontocerebellar Hypoplasia Type 10 (PCH10) is a childhood neurodegenerative disease caused by bi-allelic p.R140H variants in CLP1, a multifunctional RNA kinase, by unknown pathophysiological mechanisms. Here, we combine novel patient data with mutation-specific in vivo and in vitro models to define motor neuron dysfunction as a penetrant, prominent feature of PCH10 and uncover a previously unrecognized mRNA misprocessing signature in motor neurons that likely contributes to pathology.
2021-11-01 | GSE183869 | GEO
Project description:Molecular Characterization of Pontocerebellar Hypoplasia
| PRJNA1062912 | ENA
Project description:Molecular Characterization of Pontocerebellar Hypoplasia
| PRJNA1062911 | ENA
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Purine biosynthesis and metabolism, conserved in all living organisms, is essential for cellular energy homeostasis and nucleic acids synthesis. The de novo synthesis of purine precursors is under tight negative feedback regulation mediated by adenine and guanine nucleotides. We describe a new early-onset distinct neurodegenerative condition resulting from mutations in the adenosine monophosphate deaminase 2 gene (AMPD2). Patients have characteristic brain imaging features of pontocerebellar hypoplasia (PCH), due to loss of brainstem and cerebellar parenchyma. We found that AMPD2 plays an evolutionary conserved role in the maintenance of cellular guanine nucleotide pools by regulating the feedback inhibition of adenosine derivatives on de novo purine synthesis. AMPD2 deficiency results in defective GTP-dependent initiation of protein translation, which can be rescued by administration of purine precursors. These data suggest AMPD2-related PCH as a new potentially treatable early-onset neurodegenerative disease. An 18 chip study, that compares iPSC derived neural progenitor cells from two individuals: a patient with pontocerebellar hypoplasia and an unaffected parent. Samples are run as either non-treated, treated with Adenosine, or treated with Adenosine and AICAr. Three replicates are included for every individuals in every treatment condition.
2013-12-01 | E-GEOD-46615 | biostudies-arrayexpress
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature