Decreased mRNA expression of malonyl-CoA decarboxylase emerges from an inborn error-like defect in the Mlycd gene of DBA/2J mice
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ABSTRACT:
PROVIDER: PRJNA777062 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16693312.fastq.gz | Fastqsanger.gz | |||
| SRR16693313.fastq.gz | Fastqsanger.gz | |||
| SRR16693314.fastq.gz | Fastqsanger.gz | |||
| SRR16693315.fastq.gz | Fastqsanger.gz |
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Project description:Mlycd encodes malonyl-CoA decarboxylase (MCD), which is an enzyme that localizes in the cytosolic, mitochondrial, and peroxisomal compartments and catalyzes the conversion of malonyl-CoA into acetyl-CoA. Malonyl-CoA can be converted into malonylcarnitine (C3DC). Patients with an autosomal recessive defect of MCD and MCD KO mice have pronounced elevations of C3DC. Analysis of plasma C3DC levels in the BxD genetic reference population revealed increased levels in BxD strains that harbor the DBA/2J haplotype at the site of the Mlycd gene. RNA sequencing was performed on two samples of DBA/2J mouse livers and two C57BL/6J mouse livers. Decreased expression of Mlycd gene as well as intronic reads in intron 2 were observed in DBA/2J livers. Long-read sequecing of DBA/2J livers in the Mlycd region confirmed an intracisternal A-particle (IAP) retrotransposon in intron 2 of the DBA/2J Mlycd sequence. To confirm the causal nature of the variant, DBA/2J mice with and without the C57BL/6J variant of Mlycd spliced in were tested for products of MCD enzymatic activity, and the C57BL/6J variant was able to rescue the phenotype seen in the DBA/2J mice.
2024-10-26 | GSE186973 | GEO
Project description:CblX is a recently described X-linked variant of combined methylmalonic acidemia and homocystinuria, cblC type, which is the most common inborn error of intracellular cobalamin metabolism. While cblC is due to mutations in MMACHC, which is in the cobalamin metabolic pathway, cblX is caused by mutations in the transcriptional cofactor HCFC1 and its obligate transcription factor partner RONIN . Since HCFC1 and RONIN jointly regulate MMACHC transcription, cblX patients suffer from low levels of MMACHC during development and thus develop a disease highly similar to cblC. Beyond this finding, there is little else known about the other genes de-regulated in cblX and the resulting pathophysiology. Therefore, we have generated the first mouse models of this disease (Hcfc1A115V/Y and RoninF80L/F80L). We show that our cblX models exhibit the expected metabolic perturbations, along with CNS, hematopoietic and cardiac developmental defects, typically observed in cblC patients. We also uncovered a large cohort of target genes that encode ribosome protein subunits as well as unexpected phenotypes that we ascribe to deregulation of ribosome biogenesis impacting normal translation during development. In addition to identifying RONIN and HCFC1 as new transcriptional regulators of ribosome biogenesis, we establish cblX as a complex syndrome exhibiting aspects of cblC and a ribosomopathy.
2021-11-15 | GSE161763 | GEO
Project description:PHARC is a neurodegenerative disease comprising early onset cataract and hearing loss, retinitis pigmentosa, and involvement of both the central and peripheral nervous systems; including demyelinating sensorimotor polyneuropathy and cerebellar ataxia. Previously, we mapped this Refsum-like disorder to a 16 Mb region on chromosome 20. Here we report that mutations in the ABHD12 gene cause PHARC disease and we describe the clinical manifestations in a total of 19 patients from four different countries. The ABHD12 enzyme was recently shown to hydrolyse 2-arachidonoyl glycerol (2-AG), the main endocannabinoid lipid transmitter that acts on cannabinoid receptors CB1 and CB2. Our data therefore represent an example of an inherited disorder related to endocannabinoid metabolism. The endocannabinoid system is involved in a wide range of physiological processes including neurotransmission, mood, appetite, pain appreciation, addiction behaviour and inflammation, and several potential drugs targeting these pathways are in development for clinical applications. Our findings show that ABHD12 performs essential functions in both the central and peripheral nervous systems and the eye. Any future drug-mediated interference with this enzyme should consider the potential risk of long-term adverse effects. Homozygosity mapping using Affymetrix 250K SNP arrays were performed according to the manufacturer's directions on DNA extracted from peripheral blood samples. This accession number contains the data for families 1-5 plus 7 in the article. Supplementary files linked below. The region of interest on chromosome 20 was found using families 1 and 2. The patients in families 3,4 and 5 were then recruited and the patients were homozygous for the same region on chromosome 20 as those in families 1 and 2, showing that all these patients are distantly related. All affected are homozygous for the same mutation. The rest of the chromosomes fall outside the scope of our study. Mutations in ABHD12 Cause the Neurodegenerative Disease PHARC: An Inborn Error of Endocannabinoid Metabolism, Fiskerstrand et al. The American Journal of Human Genetics, 26 August 2010 http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B8JDD-50W2K9M-3&_user=6129429&_coverDate=08%2F26%2F2010&_rdoc=1&_fmt=high&_orig=search&_sort=d&_docanchor=&view=c&_acct=C000000150&_version=1&_urlVersion=0&_userid=6129429&md5=234296648f66debd3e2b08e795f2179f
2010-08-26 | E-GEOD-23151 | biostudies-arrayexpress
Project description:CblX disease is both an inborn error of cobalamin metabolism and a ribosomopathy
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2016-06-03 | GSE82179 | GEO
Project description:Ever since Garrod deduced the existence of inborn errors in 1901, a vast array of metabolic diseases has been identified and characterized in molecular terms. In 2018 it is difficult to imagine that there is any uncharted backyard left in the metabolic disease landscape. Nevertheless, it took until 2013 to identify the cause of a relatively frequent inborn error, pseudoxanthoma elasticum (PXE), a disorder resulting in aberrant calcification. The mechanism found was not only biochemically interesting but also points to possible new treatments for PXE, a disease that has remained untreatable. In this review we sketch the tortuous road that led to the biochemical understanding of PXE and to new ideas for treatment. We also discuss some of the controversies still haunting the field.
| S-EPMC6340748 | biostudies-literature
Project description:Genome sequencing of the DBA/2J strain of mouse
| PRJNA33589 | ENA
Project description:Purpose: The DBA/2J mouse is a model for secondary angle-closure glaucoma due to iris atrophy and pigment dispersion, which ultimately leads to increased intraocular pressure (IOP). We sought to correlate changes in retinal gene expression with glaucoma-like pathology by performing microarray analysis of retinal RNA from DBA/2J mice at 3 months before disease onset, and at 8 months, after IOP elevation. Methods: IOP was monitored monthly in DBA/2J animals by Tono-Pen and animals with normal (3 months) or elevated IOP (8 months) were identified. RNA was prepared from 3 individual retinas at each age, and the RNA was amplified and used to generate biotin-labeled probe for high density mouse Affymetrix arrays (U430.2). A subset of genes was selected for confirmation by quantitative RT-PCR using independent retina samples from DBA/2J animals at 3, 5 and 8 months of age, and compared to retinas from C57BL/6J control animals at 3 and 8 months. Results: There were changes in expression of 68 genes, with 32 genes increasing and 36 genes decreasing at 8 months versus 3 months. Upregulated genes were associated with immune response, glial activation, signaling and gene expression, while down-regulated genes included multiple crystallin genes. Significant changes in 9 upregulated genes and 2 downregulated genes were confirmed by quantitative RT-PCR, with some showing changes in expression by 5 months. Conclusions: DBA/2J retina shows evidence for glial activation and an immune-related response following IOP elevation, similar to what has been reported following acute elevation of IOP in other models. Keywords: retina, glaucoma, DBA/2J, elevated intraocular pressure
2005-11-04 | GSE3554 | GEO