Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE39447 | GEO | 2012/07/18
SECONDARY ACCESSION(S): PRJNA170896
REPOSITORIES: GEO
Similar Datasets
Project description:Autism is present in 1% of the population, yet treatments are extremely limited. We identified homozygous inactivating mutations in the BCKDK gene in families presenting with autism and epilepsy. The encoded branched chain ketoacid dehydrogenase kinase protein is responsible for phosphorylation-mediated inactivation of the E1-alpha subunit of branched chain ketoacid dehydrogenase, itself mutated in Maple Syrup Urine Disease (MSUD). Patients with homozygous BCKDK mutations display reductions in BCKDK mRNA and protein, E1-alpha phosphorylation and serum branched chain amino acids (BCAAs). Bckdk knockout mice show abnormal brain amino acids profiles and neurobehavioral defects, which are largely corrected by dietary BCAA supplementation. Thus autism presenting with epilepsy due to BCKDK mutations represent a new and potentially treatable disease. A 51 chip study that includes both human and mouse samples to investigate the expression changes that result in a mutation or knockout of the BCKDK gene. Starting with human fibroblasts from three affecteds and two controls, cells were converted into IPSs, then NPCs, and finally Neurons. Each of these cell types were used to view the expression changes between a cells with a BCKDK mutation versus controls. Finally, a mouse knockout was performed to verify consistency of the expression pattern differences between the BCKCK knockout and wild-type. Samples are labeled as Affected if the sample came from a patient with a BCKDK mutation and WildType otherwise. Samples were usually replicated once.
2012-07-17 | E-GEOD-39447 | biostudies-arrayexpress
Project description:Purpose: The goals of this study are to find out the differential expression genes in the fadR mutant strain(ΔfadR) compared with wild-type (WT) and to further explore the regulation mechanisms of fadR. Methods: Shewanella oneidensis MR-1 WT and ΔfadR were collected in log phage(OD~0.6). RNA extraction was performed using the RNeasy minikit (Qiagen) and the RNA was quantified by using a NanoVue spectrophotometer (GE Healthcare). RNA seq was performed using Illumina NextSeq 500, 2×150 bp. Results: Our study represents that the expression of 146 genes were decreased and 94 genes were increased inΔfadR compared with WT. Branched-chain keto acid dehydrogenase (BKD) produces corresponding branched-chain acyl coenzyme A which further participating branchend-chain fatty acids synthesis. The expression of bkdA2 was also promoted in △fadR compared with WT. Conclusions: Combined with our expression results, it declared that FadR can suppress bkd operon in some degree,which further increase the synthesis of branched-chain fatty acids in ΔfadR.
2020-01-01 | GSE133375 | GEO
Project description:Postoperative insulin resistance refers to the phenomenon that the body’s glucose uptake stimulated by insulin is reduced due to stress effects such as trauma or the inhibitory effect of insulin on liver glucose output is weakened after surgery.
There is a clear link between postoperative insulin resistance and poor perioperative prognosis. Therefore, exploring interventions to reduce postoperative stress insulin resistance, stabilize postoperative blood glucose, and reduce postoperative complications are clinical problems that need to be solved urgently. In recent years, research on branched-chain amino acids and metabolic diseases has become a hot spot. Studies have found that in the rat model, preoperatively given a high branched-chain amino acid diet can inhibit postoperative insulin resistance and stabilize blood glucose levels. This research plan is to try to add branched-chain amino acids before surgery to observe the occurrence of postoperative insulin resistance in patients.
| 2744698 | ecrin-mdr-crc
Project description:The eukaryotic genome is transcribed by three RNA polymerases (Pol) I, II and III; each transcribing different classes of RNAs. Pol I transcribes ribosomal DNA and produces the polycistronic rRNA 47S, which releases 28S, 18S and 5.8S rRNAs. Heterozygous mutations in the Pol I subunit POLR1A have been described in three patients presenting with Acrofacial Dysostosis, Cincinnati Type (MIM 616462), while a homozygous mutation in POLR1A was identified in two siblings, presenting developmental regression and several brain anomalies. We present three patients with homozygous mutations in POLR1A. Patient 1, a Norwegian male homozygous for POLR1A p.T642N, presented severe neurodegeneration with epilepsy, and died at 16 years of age. Patient 2, a 5.4-years-old Mexican male homozygous for POLR1A p.R667H, presented with severe neurodegeneration, epilepsy, and skeletal anomalies. Patient 3, a 2-year-old Dutch girl homozygous for POLR1A p.T642N, manifested severe global developmental delay, and brain anomalies. Structure superimposition of POLR1A wild-type and POLR1A T642N or R667H suggested a possible abnormal interaction between POLR1A and POLR2H. In vitro experiments showed that POLR1A T642N has higher transcriptional activity, abnormal rRNA processing, increased autophagy, deprotected telomeres, and reduced levels of p53. Proteomics analysis of patients 1 supported these findings, identifying dysfunction of pathways related to protein synthesis, ubiquitination, phagosome activities, and cell survival. In conclusion, we expand the phenotype of this rare disease and document a transcriptional defect affecting multiple processes, which impact cell survival.
2023-10-24 | PXD017431 | Pride
Project description:In eukaryotes, pyruvate, a key metabolite produced by glycolysis, is converted by a mitochondrial pyruvate dehydrogenase complex (PDH) to acetyl-coenzyme A, which is fed into the tricarboxylic acid cycle. Two additional enzyme complexes catalyze similar oxidative decarboxylation reactions albeit using different substrates, the branched-chain ketoacid dehydrogenase (BCKDH) and the 2-oxoglutarate dehydrogenase (OGDH). In diplonemids, one of the most abundant and diverse groups of oceanic protists, comparative transcriptome analyses indicated that their PDH complex is compositionally unique, with the conventional E1 subunit replaced by an aceE protein of prokaryotic origin. Here we endogenously tagged the common E3 subunit with a protein A tag and performed immunoprecipitation experiments.
2023-07-17 | PXD035043 | Pride
Project description:Atxn2-Knock-Out mice show branched-chain amino acids and fatty acids pathway alterations
2022-01-14 | E-PROT-16 | ExpressionAtlas
Project description:Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to decreased levels of brain BCAAs, abnormal mRNA translation and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.
2016-12-22 | GSE87808 | GEO
Project description:In eukaryotes, pyruvate, a key metabolite produced by glycolysis, is converted by a mitochondrial pyruvate dehydrogenase complex (PDH) to acetyl-coenzyme A, which is fed into the tricarboxylic acid cycle. Two additional enzyme complexes catalyze similar oxidative decarboxylation reactions albeit using different substrates, the branched-chain ketoacid dehydrogenase (BCKDH) and the 2-oxoglutarate dehydrogenase (OGDH). In diplonemids, one of the most abundant and diverse groups of oceanic protists, comparative transcriptome analyses indicated that their PDH complex is compositionally unique, with the conventional E1 subunit replaced by an aceE protein of prokaryotic origin. Here we demonstrate in the model diplonemid Paradiplonema papillatum that the pyruvate dehydrogenase activity is comparable to that in other euglenozoan protists. By protein mass spectrometry we revealed that the aceE protein is twice as abundant as the E1 subunits of OGDH and enriched in the mitochondrion to the same level as the BCKDH E1 subunits, corroborating the functional relevance of the proposed aceE subunit of the PDH complex. Importantly, the acquisition of the archaeal aceE by the diplonemid ancestor led not only to the complete loss of the eukaryotic-type E1 of the PDH complex, but also its dedicated E2 and E3 subunits, still present in other euglenozoans. Hence, to reconstitute the diplonemid PDH, the aceE protein needs to partner with E2 and E3 subunits of BCKDH and/or OGDH. The diplonemid example illustrates that the acquisition and successful integration of a foreign E1p can profoundly reorganize the entire PDH complex.
2023-07-28 | PXD035104 | Pride
Project description:Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors. In order to study the effect of BCAT1 inhibitor (ERG240) on LPS-polarized macrophage transcriptome, we stimulated monocyte derived macrophages (MDMs) with LPS for 8 hours, with or without the presence of ERG240. We then performed whole-genome transcriptome sequencing by RNA-sequencing (RNA-seq).
2020-11-23 | GSE148701 | GEO
Project description:Diamond-Blackfan anemia (DBA) is a congenital disorder that results predominantly from mutations in various ribosomal protein genes. In order to determine how these mutations affect the translation of specific mRNAs, we performed microarray analysis of polysomal transcripts isolated from lymphoblast cells derived from DBA patients carrying different haploinsufficient mutations in either RPS19 or RPL11. One of the few overlapping transcripts that we found significantly decreased on the polysomes codes for branched-chain aminotransferase-1 (BCAT-1). We go on to determine that translation of BCAT-1 is especially impaired in cells carrying mutations in the small ribosomal protein genes, and provide evidence that this effect is due to its unusually long 5M-bM-^@M-^YUTR. The BCAT-1 enzyme is critical for synthesis of the branched-chain amino acids, including leucine. It is known that DBA patients respond well to orally administered leucine, and large-scale clinical trials as such are currently underway. Our results suggest that the haploinsufficient loss of ribosomal protein genes results in a decrease of BCAT-1 translation and provide an explanation for why leucine administration is beneficial for DBA patients. In this expression study duplicate mRNA samples were generated from polysomes isolated from celllines with mutations in RPS19 or RPL11 or normal controls. In each group 3 cellines were tested. Duplicate samples were analyzed in dyeswap. As common reference the commercial universal human reference RNA (Stratagene) was used.
2014-01-30 | E-GEOD-43117 | biostudies-arrayexpress