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

Department of Pathology, Dalhousie University Halifax, Nova Scotia, Canada.
Nature Genetics (Impact Factor: 29.35). 06/2009; 41(6):651-3. DOI: 10.1038/ng.359
Source: PubMed

ABSTRACT The sideroblastic anemias are a heterogeneous group of congenital and acquired hematological disorders whose morphological hallmark is the presence of ringed sideroblasts--bone marrow erythroid precursors containing pathologic iron deposits within mitochondria. Here, by positional cloning, we define a previously unknown form of autosomal recessive nonsyndromic congenital sideroblastic anemia, associated with mutations in the gene encoding the erythroid specific mitochondrial carrier family protein SLC25A38, and demonstrate that SLC25A38 is important for the biosynthesis of heme in eukaryotes.

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Available from: Dean R Campagna, Jan 28, 2015
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    • "205950): a homozygous mutation was found in GLRX5 in a consanguineous proband [Camaschella et al., 2007], and SLC25A38, which encodes a putative glycine transporter, was found to be mutated in the affected members of different families [Guernsey et al., 2009]. Thus, for the 13 probands without any ALAS2 mutation, and for one patient with the P520L variant, these two genes were explored and mutations were identified in SLC25A38 for four probands (manuscript submitted). "
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    • "Newly synthesized proteins subsequently translocate into the inner membranes of mitochondria, where they transport various substrates, such as metabolites, nucleotides and cofactors between the cytoplasm and the mitochondrial matrix (13). SLC25A38 belongs to the SLC25 family (13) and previous studies have found that variations in the SLC25A38 gene, which is located on chromosome 3p22, are responsible for severe pyridoxine-refractory congenital sideroblastic anemia (14–16). The gene encodes a mitochondrial carrier protein required for erythropoiesis and it may act by importing glycine into mitochondria or may act as a transporter of glycine/5-aminolevulinic acid (ALA) across the mitochondrial inner membrane (14–16). "
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    ABSTRACT: SLC25A38 is a recently identified protein that belongs to the mitochondrial solute carrier family, SLC25. Previous studies have shown that it is a pro-apoptotic protein, which regulates intrinsic caspase-dependent apoptosis. In order to clarify the effect of SLC25A38 protein expression on acute lymphoblastic leukemia (ALL) cells, we detected the expression of SLC25A38 in various cell lines (RPMI 8226, U266, Molt-4 and Jurkat) by western blot analysis. The results indicate that SLC25A38 is highly expressed in the four cell lines. Among 55 leukemia patients (adult, n=32 and infant, n=23), a high expression of SLC25A38 protein was observed in seven infant (7/23, 30.4%) and 15 adult (15/32, 46.9%) ALL patients. Two adult ALL patients that were positive for SLC25A38 were analyzed and the level of SLC25A38 significantly reduced or disappeared following combined chemotherapy, however, reappeared upon ALL recurrence. The expression level was identified to be associated with the proportion of blast cells in the bone marrow. Additionally, SLC25A38 and Notch1 were co-expressed in the four cell lines and the ALL patient samples. The present results show that expression of SLC25A38 is a common feature of ALL cells and may be a novel biomarker for diagnosis, as well as a potential therapeutic target for ALL.
    Oncology letters 05/2014; 7(5):1422-1426. DOI:10.3892/ol.2014.1947 · 1.55 Impact Factor
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    • "Interestingly, other forms of inherited sideroblastic anemias are due to mutations in genes indirectly involved in the heme biosynthetic pathway. Mutations in the gene coding for SLC25A38, the putative mitochondrial exporter of ALA, have been identified in patients with an autosomal recessive form of sideroblastic anemia (Guernsey et al., 2009). In other patients, mutations in the ATP-binding cassette transporter ABCB7 gene or in GLUTAREDOXIN5 (GLRX5) gene have been identified (Allikmets et al., 1999; Camaschella et al., 2007). "
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    ABSTRACT: Heme (iron-protoporphyrin IX) is an essential co-factor involved in multiple biological processes: oxygen transport and storage, electron transfer, drug and steroid metabolism, signal transduction, and micro RNA processing. However, excess free-heme is highly toxic due to its ability to promote oxidative stress and lipid peroxidation, thus leading to membrane injury and, ultimately, apoptosis. Thus, heme metabolism needs to be finely regulated. Intracellular heme amount is controlled at multiple levels: synthesis, utilization by hemoproteins, degradation and both intracellular and intercellular trafficking. This review focuses on recent findings highlighting the importance of controlling intracellular heme levels to counteract heme-induced oxidative stress. The contributions of heme scavenging from the extracellular environment, heme synthesis and incorporation into hemoproteins, heme catabolism and heme transport in maintaining adequate intracellular heme content are discussed. Particular attention is put on the recently described mechanisms of heme trafficking through the plasma membrane mediated by specific heme importers and exporters. Finally, the involvement of genes orchestrating heme metabolism in several pathological conditions is illustrated and new therapeutic approaches aimed at controlling heme metabolism are discussed.
    Frontiers in Pharmacology 04/2014; 5:61. DOI:10.3389/fphar.2014.00061 · 3.80 Impact Factor
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