Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia

Guernsey, Duane L.; Jiang, Haiyan; Campagna, Dean R.; Evans, Susan C.; Ferguson, Meghan; Kellogg, Mark D.; Lachance, Mathieu; Matsuoka, Makoto; Nightingale, Mathew; Rideout, Andrea L.; Saint-Amant, Louis; Schmidt, Paul; Orr, Andrew; Bottomley, Sylvia S.; Fleming, Mark D.; Ludman, Mark D.; Dyack, Sarah; Fernandez, Conrad V.; Samuels, Mark E.

doi:10.1038/ng.359

Cited by 213 publications

(238 citation statements)

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“…Missense mutations in SLC25A38, which encodes a mitochondrial solute carrier, lead to congenital sideroblastic anemia characterized by defective erythropoiesis and mitochondrial iron overload. 78 The function of SLC25A38 in adipose tissue remains unclear. The signal observed at this locus might represent cell types other than adipocytes in light of the cellular heterogeneity of adipose tissue.…”

Section: à5mentioning

confidence: 99%

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Civelek

Pan

et al. 2017

The American Journal of Human Genetics

148

211

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Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 3 10 À8 ) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.

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Section: à5mentioning

confidence: 99%

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits

Civelek

Pan

et al. 2017

The American Journal of Human Genetics

148

211

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“…It belongs to the mitochondrial solute carrier family (SLC25), which is encoded by nuclear genes located on chromosome 3p22.1, synthesized in the cytosol and located in the inner mitochondrial membrane. Appoptosin acts as a transporter that shuttles glycine into mitochondria and 5-aminolevulinic acid out of mitochondria [10,11] . Further research has found that appoptosin regulates intrinsic caspasedependent apoptosis by governing heme biosynthesis, hence inducing ROS overproduction, impairing mitochondrial www.chinaphar.com Zheng KM et al Acta Pharmacologica Sinica npg membrane potential, promoting cytochrome c release, and activating caspase 9 and caspase 3 [9] .…”

Section: Introductionmentioning

confidence: 99%

Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells

Zheng

Zhang

et al. 2015

Acta Pharmacol Sin

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Aim: Appoptosin (SLC25A38) is a pro-apoptotic protein, which is upregulated in Alzheimer's disease (AD) brains and plays an important role in promoting the pathological progress of AD. The aim of this study was to investigate the effects of curcumin from the rhizome of Curcuma longa on appoptosin-induced apoptosis in SH-SY5Y cells. Methods: SH-SY5Y cells were pretreated with curcumin, then transfected with appoptosin or vector. The apoptotic cells were detected with Annexin V staining analysis by flow cytometry. The expression of cleaved caspase-3, appoptosin, heme oxygenase-1 (HO-1) was examined using Western blotting. Intracellular level of ROS was measured with DCFH-DA staining by flow cytometry analysis. Mitochondrial membrane potential (ΔΨm) was detected with JC-1 staining under a fluorescence microscope and quantified by fluorescence ratio detection. Results: Overexpression of appoptosin in SH-SY5Y cells markedly increased cell apoptosis accompanied by reduced HO-1 expression, increased intracellular heme level, ROS overproduction and ΔΨm impairment. Treatment of SH-SY5Y cells with curcumin (2.5-20 μmol/L) for 24 h did not significantly affect their viability. However, pretreatment with curcumin (2.5-20 μmol/L) dose-dependently attenuated all above-mentioned pathological changes in appoptosin-transfected SH-SY5Y cells. Conclusion: Curcumin inhibits appoptosin-induced apoptosis in SH-SY5Y cells by upregulating the expression of HO-1, reducing the production of intracellular heme and ROS, and preventing the ΔΨm loss.

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“…Although there is extensive evidence implicating abnormal expression of genes involved in heme biosynthesis, iron processing and altered mitochondrial function in the pathogenesis of RARS, none have been translated to targeted and improved therapies for these diseases. 15,16 It is possible that the role of the spliceosome in RARS and related diseases is not restricted to SF3B1, and may involve other components of the splicing machinery. This prompted us to also perform genomic sequencing of two other spliceosome components associated with SF3B1: SF3B14 and SF3B4.…”

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confidence: 99%