Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice

Anderson, Sarah; Lee, Inyoul; Ebeling, Christine; Stephenson, Dennis A.; Schweitzer, Kelsey M.; Baxter, David; Moon, Tara M.; LaPierre, Sarah; Jaques, Benjamin; Silvius, Derek; Wegner, Michael; Hood, Leroy; Carlson, George A.; Gunn, Teresa M.

doi:10.1007/s00335-014-9548-5

Cited by 4 publications

(3 citation statements)

References 52 publications

(57 reference statements)

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“…SOX10 has been associated with multiple brain conditions, including demyelination disorders (52), and NFIX, a factor unexplored in oligodendrocytes, has been linked to agenesis of the corpus callosum (53). Lastly, we found motifs for transcription factors potentially important for astrocyte identity, such as SOX9 (54,55).…”

Section: Inference Of Cell Type-specific Lineage-determining Transcrmentioning

confidence: 65%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

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Identification of cell type-specific regulatory elements in the human brain enables interpretation of non-coding GWAS risk variants. AbstractUnique cell type-specific patterns of activated enhancers can be leveraged to interpret non-coding genetic variation associated with complex traits and diseases such as neurological and psychiatric disorders. Here, we have defined active promoters and enhancers for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with regulatory regions in neurons, idiopathic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting GWAS variants in cell type-specific enhancers to gene promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring ADrisk variants ablated BIN1 expression in microglia but not in neurons or astrocytes. These findings revise and expand the genes likely to be influenced by non-coding variants in AD and suggest the probable brain cell types in which they function. of neurons, microglia, astrocytes, oligodendrocytes and other cell types that reside within the brain (1-4). In contrast, transcriptional mechanisms that control their developmental and functional properties in health and disease remain less well understood. Studies in animal models have provided deep insights into conserved processes, but significant differences between species often limit the translatability of findings in model systems to humans (5).Genome-wide association studies (GWASs) provide a genetic approach to identifying molecular pathways involved in complex traits and diseases by defining associations between genetic variants and phenotypes of interest (6, 7). Large-scale GWASs have discovered hundreds of single nucleotide polymorphisms (SNPs) that are associated with the risk of neurological and psychiatric disorders. The vast majority of disease-risk genetic variants are located in non-coding regions of the genome (7) and the specific cell type (s) in which the disease-risk variants are active is often unclear. Furthermore, linkagedisequilibrium between disease-risk variants at GWAS significant loci complicates the identification of causal variants. Collectively, these limitations have hindered the assignment and interpretation of disease-risk genes.GWAS-identified risk variants that are located in non-coding regions of the genome can exert phenotypic effects through several mechanisms, including perturbation of transcriptional enhancers and promoters (6). While promoters provide the essential sites of transcriptional initiation of mRNAs, they are frequently not sufficient to direct appropriate developmental and signal-dependent levels of gene expression (8,9). This additional information is provided by enhancers, short regions of DNA that, when bound by transcription factors, enhance mRNA expression from target promoters. Enhancers can reside hundreds of thousands of base pairs away from their target gene and their function is generally consid...

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Section: Inference Of Cell Type-specific Lineage-determining Transcrmentioning

confidence: 65%

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Nott¹,

Holtman²,

Coufal

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Many genes are known to regulate eumelanin synthesis or the switch between eumelanin and pheomelanin [65], but only a few have been identified that specifically affect pheomelanin synthesis. Mutations in Slc7a11, Ggt1, Mfsd12, Clcn7, Ostm1, Sox10, and several as yet undefined genes have all been shown to reduce pheomelanin pigmentation in mouse with no or modest impact on eumelanin production [10,[66][67][68][69][70][71][72]. Several of these genes (Slc7a11, Mfsd12, and Ggt1) impact cysteine uptake, intracellular transport, or incorporation into glutathione [10,73,74], and thus might share a mechanistic basis with Comtd1 for their impact on pheomelanin synthesis.…”

Section: Plos Geneticsmentioning

confidence: 99%

A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken

Tranell

Harper

et al. 2023

PLoS Genet

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The biochemical pathway regulating the synthesis of yellow/red pheomelanin is less well characterized than the synthesis of black/brown eumelanin. Inhibitor of gold (IG phenotype) is a plumage colour variant in chicken that provides an opportunity to further explore this pathway since the recessive allele (IG) at this locus is associated with a defect in the production of pheomelanin. IG/IG homozygotes display a marked dilution of red pheomelanin pigmentation, whilst black pigmentation (eumelanin) is only slightly affected. Here we show that a 2-base pair insertion (frame-shift mutation) in the 5th exon of the Catechol-O-methyltransferase containing domain 1 gene (COMTD1), expected to cause a complete or partial loss-of-function of the COMTD1 enzyme, shows complete concordance with the IG phenotype within and across breeds. We show that the COMTD1 protein is localized to mitochondria in pigment cells. Knockout of Comtd1 in a mouse melanocytic cell line results in a reduction in pheomelanin metabolites and significant alterations in metabolites of glutamate/glutathione, riboflavin, and the tricarboxylic acid cycle. Furthermore, COMTD1 overexpression enhanced cellular proliferation following chemical-induced transfection, a potential inducer of oxidative stress. These observations suggest that COMTD1 plays a protective role for melanocytes against oxidative stress and that this supports their ability to produce pheomelanin.

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“…In recent years, with the continuous development of molecular biology, a variety of genes have been found to be associated with HD pathogenesis (6). Although some studies (7) have reported that the abnormalities of these genes may be responsible for the pathogenesis of HD, subsequent studies have found that the mutations of these genes have certain limitations, and the etiology of all HD cases cannot be explained.…”

Section: Introductionmentioning

confidence: 99%

Expression of BMP‑4 and Smad1 in patients with Hirschsprung disease and its clinical significance

Zhang

Liu²

2019

Exp Ther Med

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Expression and clinical significance of bone morphogenetic protein (BMP)-4 and Smad1 in patients with Hirschsprung disease (HD) were investigated. A retrospective analysis of 96 HD patients (experimental group) admitted to Xuzhou Children's Hospital, Xuzhou Medical University from June 2015 to June 2017 was performed. According to the samples, the experimental group was divided into the stenosis group, the transition group and the expansion group. Forty-seven children with colostomy due to intestinal obstruction were selected as the control group. The expression levels of BMP-4 and Smad1 proteins were detected by immunohistochemical staining. The expression levels of BMP-4 and Smad mRNA were detected by real-time quantitative PCR (RT-qPCR), and were quantified and compared. Via immunohistochemistry, BMP-4 and Smad1 proteins were detected in the samples of different parts of HD patients and children with intestinal obstruction. The positive expression levels of BMP-4 and Smad1 proteins in the transition group were decreased compared with those in the expansion and control groups (P<0.05), and the positive expression levels of BMP-4 and Smad1 proteins in the stenosis group were decreased compared with those in the transition, expansion, and control groups (P<0.05). Also, the gene expression levels of BMP-4 and Smad1 in the transition and stenosis groups were successively decreased, and the differences were statistically significant (P<0.05). In conclusion, the expression of BMP-4 and Smad1 in the intestinal plexus of HD lesions was significantly reduced, indicating that BMP-4 and Smad1 are closely related to the occurrence of HD, and it is suspected that they have a certain influence on the intestinal development of congenital digestive tract malformations.

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Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice

Cited by 4 publications

References 52 publications

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

Cell type-specific enhancer-promoter connectivity maps in the human brain and disease risk association

A frame-shift mutation in COMTD1 is associated with impaired pheomelanin pigmentation in chicken

Expression of BMP‑4 and Smad1 in patients with Hirschsprung disease and its clinical significance

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