ABCB7 p.Glu433Lys
Predicted by SNAP2: | A: D (66%), C: D (71%), D: N (57%), F: D (80%), G: D (75%), H: D (80%), I: D (80%), K: D (85%), L: D (80%), M: D (59%), N: D (80%), P: D (91%), Q: D (71%), R: D (85%), S: D (71%), T: D (71%), V: D (75%), W: D (85%), Y: D (80%), |
Predicted by PROVEAN: | A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Mitochondrial ABC transporters function: the role ... Biochim Biophys Acta. 2012 Oct;1823(10):1945-57. doi: 10.1016/j.bbamcr.2012.07.013. Epub 2012 Aug 3. Liesa M, Qiu W, Shirihai OS
Mitochondrial ABC transporters function: the role of ABCB10 (ABC-me) as a novel player in cellular handling of reactive oxygen species.
Biochim Biophys Acta. 2012 Oct;1823(10):1945-57. doi: 10.1016/j.bbamcr.2012.07.013. Epub 2012 Aug 3., [PMID:22884976]
Abstract [show]
Mitochondria are one of the major sources of reactive oxygen species (ROS) in the cell. When exceeding the capacity of antioxidant mechanisms, ROS production may lead to different pathologies, such as ischemia-reperfusion injury, neurodegeneration, anemia and ageing. As a consequence of the endosymbiotic origin of mitochondria, eukaryotic cells have developed different transport mechanisms that coordinate mitochondrial function with other cellular compartments. Four mitochondrial ATP-binding cassette (ABC) transporters have been described to date in mammals: ABCB6, ABCB8, ABCB7 and ABCB10. ABCB10 is located in the inner mitochondrial membrane forming homodimers, with the ATP binding domain facing the mitochondrial matrix. ABCB10 expression is highly induced during erythroid differentiation and its overexpression increases hemoglobin synthesis in erythroid cells. However, ABCB10 is also expressed in nonerythroid tissues, suggesting a role not directly related to hemoglobin synthesis. Recent evidence points toward ABCB10 as an important player in the protection from oxidative stress in mammals. In this regard, ABCB10 is required for normal erythropoiesis and cardiac recovery after ischemia-reperfusion, processes intimately related to mitochondrial ROS generation. Here, we review the current knowledge on mitochondrial ABC transporters and ABCB10 and discuss the potential mechanisms by which ABCB10 and its transport activity may regulate oxidative stress. We discuss ABCB10 as a potential therapeutic target for diseases in which increased mitochondrial ROS production and oxidative stress play a major role.
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No. Sentence Comment
96 The heritage family study shows that the amino acid change of E433K at the C-terminal of the sixth TMD [9,70] or V411L at the beginning of the sixth TMD in ABCB7 is sufficient to cause XLSA/A [56].
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ABCB7 p.Glu433Lys 22884976:96:62
status: NEW[hide] Disruption of the ATP-binding cassette B7 (ABTM-1/... J Biol Chem. 2011 Jun 17;286(24):21304-14. Epub 2011 Apr 4. Gonzalez-Cabo P, Bolinches-Amoros A, Cabello J, Ros S, Moreno S, Baylis HA, Palau F, Vazquez-Manrique RP
Disruption of the ATP-binding cassette B7 (ABTM-1/ABCB7) induces oxidative stress and premature cell death in Caenorhabditis elegans.
J Biol Chem. 2011 Jun 17;286(24):21304-14. Epub 2011 Apr 4., [PMID:21464130]
Abstract [show]
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare inherited disorder characterized by mild anemia and ataxia. XLSA/A is caused by mutations in the ABCB7 gene, which encodes a member of the ATP-binding cassette transporter family. Studies in yeast, mammalian cells, and mice have shown that ABCB7 functions in the transport of iron-sulfur (Fe-S) clusters into the cytoplasm. To further investigate the mechanism of this disease, we have identified and characterized the Caenorhabditis elegans homologue of the ABCB7 gene, abtm-1. We have studied the function of abtm-1 using mutants and RNAi. abtm-1-depleted animals produce arrested embryos that have morphogenetic defects and unusual premature, putative apoptotic events. abtm-1(RNAi) animals also show accumulation of ferric iron and increased oxidative stress. Despite the increased level of oxidative stress in abtm-1(RNAi) animals, they have an increased life span. We observed accumulation of DAF-16/FOXO in the nuclei of affected animals and elevation of the expression of SOD-3, a well established target of DAF-16, which may explain the increased life span extension of these animals. abtm-1 is strongly expressed in tissues with a high energy demand, and abtm-1(RNAi) animals have phenotypes that reflect the need for abtm-1 in these tissues. Finally, we show that reducing the function of other genes involved in Fe-S cluster production produces similar phenotypic consequences to abtm-1 loss of function. Therefore, ablation of abtm-1 in C. elegans provides a model in which to investigate the mechanism underlying XLSA/A.
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No. Sentence Comment
21 The third mutation produces a more substantial amino acid change E433K (5).
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ABCB7 p.Glu433Lys 21464130:21:65
status: NEW22 A human cDNA containing the E433K change is able to partially rescue yeast carrying a mutation in ATM1, the homologue of ABCB7, suggesting that this change does not cause a complete loss of function (5).
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ABCB7 p.Glu433Lys 21464130:22:28
status: NEW[hide] Human iron-sulfur cluster assembly, cellular iron ... Biochemistry. 2010 Jun 22;49(24):4945-56. Ye H, Rouault TA
Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease.
Biochemistry. 2010 Jun 22;49(24):4945-56., [PMID:20481466]
Abstract [show]
Iron-sulfur (Fe-S) proteins contain prosthetic groups consisting of two or more iron atoms bridged by sulfur ligands, which facilitate multiple functions, including redox activity, enzymatic function, and maintenance of structural integrity. More than 20 proteins are involved in the biosynthesis of iron-sulfur clusters in eukaryotes. Defective Fe-S cluster synthesis not only affects activities of many iron-sulfur enzymes, such as aconitase and succinate dehydrogenase, but also alters the regulation of cellular iron homeostasis, causing both mitochondrial iron overload and cytosolic iron deficiency. In this work, we review human Fe-S cluster biogenesis and human diseases that are caused by defective Fe-S cluster biogenesis. Fe-S cluster biogenesis takes place essentially in every tissue of humans, and products of human disease genes, including frataxin, GLRX5, ISCU, and ABCB7, have important roles in the process. However, the human diseases, Friedreich ataxia, glutaredoxin 5-deficient sideroblastic anemia, ISCU myopathy, and ABCB7 sideroblastic anemia/ataxia syndrome, affect specific tissues, while sparing others. Here we discuss the phenotypes caused by mutations in these different disease genes, and we compare the underlying pathophysiology and discuss the possible explanations for tissue-specific pathology in these diseases caused by defective Fe-S cluster biogenesis.
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227 In the second family, a single missense mutation is found in exon 10 of the ABCB7 gene in two affected brothers, and the mutation is a G-to-A transition at nucleotide 1305, resulting in a Glu-to-Lys substitution at residue 433 (E433K) in the putative sixth transmembrane domain of ABCB7 (72).
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ABCB7 p.Glu433Lys 20481466:227:188
status: NEWX
ABCB7 p.Glu433Lys 20481466:227:228
status: NEW228 In the third family, the affected brothers have a G-to-C transition at position 1299, which predicts a V411L substitution in the sixth putative transmembrane domain (86).
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ABCB7 p.Glu433Lys 20481466:228:188
status: NEWX
ABCB7 p.Glu433Lys 20481466:228:228
status: NEW[hide] Recent advances in the understanding of inherited ... Br J Haematol. 2008 Oct;143(1):27-38. Epub 2008 Jul 14. Camaschella C
Recent advances in the understanding of inherited sideroblastic anaemia.
Br J Haematol. 2008 Oct;143(1):27-38. Epub 2008 Jul 14., [PMID:18637800]
Abstract [show]
Sideroblastic anaemia includes a heterogeneous group of rare conditions, characterized by decreased haem synthesis and mitochondrial iron overload, which are diagnosed by the presence of ringed sideroblasts in the bone marrow aspirate. The most frequent form is X-linked sideroblastic anaemia, caused by mutations of delta-aminolevulinic acid synthase 2 (ALAS2), the enzyme that catalyses the first and regulatory step of haem synthesis in erythroid precursors and is post-transcriptionally controlled by the iron regulatory proteins. Impaired haem production causes variable degrees of anaemia and mitochondrial iron accumulation as ringed sideroblasts. The heterogeneity and complexity of sideroblastic anaemia is explained by an increasing number of recognized molecular defects. New forms have been recognized as being linked to the deficient function of mitochondrial proteins involved in iron-sulphur cluster biogenesis, such as ABCB7 and GLRX5, which are extremely rare but represent important biological models. Local mitochondrial iron overload is present in all sideroblastic anaemias, whereas systemic iron overload occurs only in the forms because of primary or secondary deficiency of ALAS2.
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No. Sentence Comment
132 The missense mutations (Ile400 Met Glu 433Lys, Val 411Leu) reported in patients are unable to rescue the Atm1p-deficient phenotype, indicating that they are partial loss of function mutations (reviewed in Fleming, 2002).
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ABCB7 p.Glu433Lys 18637800:132:35
status: NEW[hide] Abcb7, the gene responsible for X-linked siderobla... Blood. 2007 Apr 15;109(8):3567-9. Epub 2006 Dec 27. Pondarre C, Campagna DR, Antiochos B, Sikorski L, Mulhern H, Fleming MD
Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis.
Blood. 2007 Apr 15;109(8):3567-9. Epub 2006 Dec 27., [PMID:17192398]
Abstract [show]
X-linked sideroblastic anemia with ataxia (XLSA/A) is a rare syndromic form of inherited sideroblastic anemia associated with spinocerebellar ataxia, and is due to mutations in the mitochondrial ATP-binding cassette transporter Abcb7. Here, we show that Abcb7 is essential for hematopoiesis and formally demonstrate that XLSA/A is due to partial loss of function mutations in Abcb7 that directly or indirectly inhibit heme biosynthesis.
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7 Materials and methods The generation of a conditionally targeted ("floxed") allele of Abcb7 (Abcb7fl) has been described previously.10 A targeted point mutant allele was made by site-directed mutagenesis (QuickChange; Stratagene, La Jolla, CA) of the original gene targeting construct to create a glutamic acid-to- lysine mutation at position 433 (E433K) of the mouse protein corresponding to the hematologically most severe, E433K, human allele.2 All exons and intron/exon boundaries were resequenced in the mutagenized targeting construct.
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ABCB7 p.Glu433Lys 17192398:7:348
status: NEWX
ABCB7 p.Glu433Lys 17192398:7:426
status: NEW37 In order to circumvent the bone marrow-dependent lethality, we created a targeted point mutant allele corresponding to the hematologically most severe human E433K mutation.2 Male chimeras were, however, infertile due to testicular atrophy and incomplete spermatogenesis associated with interstitial iron deposition (not shown), which is a phenotype not reported in human subjects with XLSA/A.
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ABCB7 p.Glu433Lys 17192398:37:157
status: NEW6 Materials and methods The generation of a conditionally targeted ("floxed") allele of Abcb7 (Abcb7fl) has been described previously.10 A targeted point mutant allele was made by site-directed mutagenesis (QuickChange; Stratagene, La Jolla, CA) of the original gene targeting construct to create a glutamic acid-to- lysine mutation at position 433 (E433K) of the mouse protein corresponding to the hematologically most severe, E433K, human allele.2 All exons and intron/exon boundaries were resequenced in the mutagenized targeting construct.
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ABCB7 p.Glu433Lys 17192398:6:348
status: NEWX
ABCB7 p.Glu433Lys 17192398:6:426
status: NEW36 In order to circumvent the bone marrow-dependent lethality, we created a targeted point mutant allele corresponding to the hematologically most severe human E433K mutation.2 Male chimeras were, however, infertile due to testicular atrophy and incomplete spermatogenesis associated with interstitial iron deposition (not shown), which is a phenotype not reported in human subjects with XLSA/A.
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ABCB7 p.Glu433Lys 17192398:36:157
status: NEW[hide] RNA silencing of the mitochondrial ABCB7 transport... Blood. 2007 Apr 15;109(8):3552-9. Epub 2006 Dec 27. Cavadini P, Biasiotto G, Poli M, Levi S, Verardi R, Zanella I, Derosas M, Ingrassia R, Corrado M, Arosio P
RNA silencing of the mitochondrial ABCB7 transporter in HeLa cells causes an iron-deficient phenotype with mitochondrial iron overload.
Blood. 2007 Apr 15;109(8):3552-9. Epub 2006 Dec 27., [PMID:17192393]
Abstract [show]
X-linked sideroblastic anemia with ataxia (XLSA/A) is caused by defects of the transporter ABCB7 and is characterized by mitochondrial iron deposition and excess of protoporphyrin in erythroid cells. We describe ABCB7 silencing in HeLa cells by performing sequential transfections with siRNAs. The phenotype of the ABCB7-deficient cells was characterized by a strong reduction in proliferation rate that was not rescued by iron supplementation, by evident signs of iron deficiency, and by a large approximately 6-fold increase of iron accumulation in the mitochondria that was poorly available to mitochondrial ferritin. The cells showed an increase of protoporphyrin IX, a higher sensitivity to H(2)O(2) toxicity, and a reduced activity of mitochondrial superoxide dismutase 2 (SOD2), while the activity of mitochondrial enzymes, such as citrate synthase or succinate dehydrogenase, and ATP content were not decreased. In contrast, aconitase activity, particularly that of the cytosolic, IRP1 form, was reduced. The results support the hypothesis that ABCB7 is involved in the transfer of iron from mitochondria to cytosol, and in the maturation of cytosolic Fe/S enzymes. In addition, the results indicate that anemia in XLSA/A is caused by the accumulation of iron in a form that is not readily usable for heme synthesis.
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15 They consist of missense mutations (I400M, E433K, and V411L) at the border of putative transmembrane domains of the protein and were found to rescue only partially the defects of Atm1p-deficient yeasts.6 A study on erythroid cells showed that ABCB7 expression increases the activity of ferrochelatase by binding to its C-terminus.21 The recent study of mice deficient in ABCB7 showed that the protein is essential in early gestation.
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ABCB7 p.Glu433Lys 17192393:15:43
status: NEW13 (c) 2007 by The American Society of Hematology 3552 They consist of missense mutations (I400M, E433K, and V411L) at the border of putative transmembrane domains of the protein and were found to rescue only partially the defects of Atm1p-deficient yeasts.6 A study on erythroid cells showed that ABCB7 expression increases the activity of ferrochelatase by binding to its C-terminus.21 The recent study of mice deficient in ABCB7 showed that the protein is essential in early gestation.
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ABCB7 p.Glu433Lys 17192393:13:96
status: NEW[hide] X-linked cerebellar ataxia and sideroblastic anaem... Br J Haematol. 2001 Dec;115(4):910-7. Maguire A, Hellier K, Hammans S, May A
X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L.
Br J Haematol. 2001 Dec;115(4):910-7., [PMID:11843825]
Abstract [show]
Two brothers with X-linked ataxia (XLA) were found to have hypochromic red cells and increased erythrocyte protoporphyrin despite normal iron stores. The mother was unaffected by ataxia and had normal iron stores but showed evidence of some red cell hypochromia with heavy basophilic stippling that stained positive for iron. Bone marrow biopsy confirmed the presence of ring sideroblasts in one of the brothers. The absence of mutations in the ALAS2 gene and the predominance of zinc over free protoporphyrin led to a search using a combination of DNA and cDNA analysis for the presence of mutations in the ABC7 gene. ABC7 encodes a mitochondrial half-type ATP Binding Cassette transporter involved in iron homeostasis. The published cDNA sequence was used to search databases for the genomic sequence of which 12 exons spanning 23.4 kb were mapped leaving the most 5' nucleotides unaccounted for. The identified exons and their exon-intron boundaries were amplified from DNA while the most 5' sequence including the initiation codon was amplified from cDNA of peripheral blood cells. Direct sequencing revealed hemizygosity in the brothers and heterozygosity in the mother for a G-->C transversion at position 1299 of the published cDNA. This predicts a V411L substitution at the beginning of the last of six putative transmembrane regions of the protein. Restriction enzyme digestion confirmed the presence of this mutation in the three family members but could not detect it in 200 normal alleles. An uncle affected by ataxia also carried this mutation. This study supports the recently hypothesized involvement of the ABC7 gene in XLSA/A and highlights a protein structure region of importance to this syndrome.
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137 Furthermore, the predicted amino acid substitutions arising from previously reported mutations I400M (Allikmets et al, 1999) and E433K (Bekri et al, 2000) and that reported here at residue 411 highlight the importance of this region of the protein in iron homeostasis and ataxia.
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ABCB7 p.Glu433Lys 11843825:137:129
status: NEW[hide] Human ABC7 transporter: gene structure and mutatio... Blood. 2000 Nov 1;96(9):3256-64. Bekri S, Kispal G, Lange H, Fitzsimons E, Tolmie J, Lill R, Bishop DF
Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.
Blood. 2000 Nov 1;96(9):3256-64., [PMID:11050011]
Abstract [show]
The human protein ABC7 belongs to the adenosine triphosphate-binding cassette transporter superfamily, and its yeast orthologue, Atm1p, plays a central role in the maturation of cytosolic iron-sulfur (Fe/S) cluster-containing proteins. Previously, a missense mutation in the human ABC7 gene was shown to be the defect in members of a family affected with X-linked sideroblastic anemia with cerebellar ataxia (XLSA/A). Here, the promoter region and the intron/exon structure of the human ABC7 gene were characterized, and the function of wild-type and mutant ABC7 in cytosolic Fe/S protein maturation was analyzed. The gene contains 16 exons, all with intron/exon boundaries following the AG/GT rule. A single missense mutation was found in exon 10 of the ABC7 gene in 2 affected brothers with XLSA/A. The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7. Expression of normal ABC7 almost fully complemented the defect in the maturation of cytosolic Fe/S proteins in a yeast strain in which the ATM1 gene had been deleted (Deltaatm1 cells). Thus, ABC7 is a functional orthologue of Atm1p. In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in Deltaatm1 cells led to a low efficiency of cytosolic Fe/S protein maturation. These data demonstrate that both the molecular defect in XLSA/A and the impaired maturation of a cytosolic Fe/S protein result from an ABC7 mutation in the reported family.
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No. Sentence Comment
6 The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7.
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ABCB7 p.Glu433Lys 11050011:6:143
status: NEW9 In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in ⌬atm1 cells led to a low efficiency of cytosolic Fe/S protein maturation.
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ABCB7 p.Glu433Lys 11050011:9:45
status: NEW164 The mutation resulted in a substitution of lysine for the wild-type glutamate at amino acid 433 (E433K) of the ABC7 protein and abolished a BsmAI restriction site (Figure 1D).
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ABCB7 p.Glu433Lys 11050011:164:97
status: NEW169 In addition, we performed similar studies with Atm1p into which the mutation corresponding to the human ABC7 mutant (E433K) was introduced (Atm1p D398K).
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ABCB7 p.Glu433Lys 11050011:169:117
status: NEW170 Wild-type Atm1p and, to a slightly lesser extent, ABC7 complemented the growth defect of ⌬atm1 cells and the defect leading to mitochondrial iron accumulation.12 Similarly, both the Atm1p D398K and the ABC7 E433K mutant proteins restored growth of ⌬atm1 cells to a similar extent as the corresponding wild-type proteins (data not shown).
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ABCB7 p.Glu433Lys 11050011:170:214
status: NEW177 Finally, we investigated the consequences of the XLSA/A mutation E433K in ABC7 and the corresponding mutation in Atm1p (D398K) for the function of these proteins in cytosolic Fe/S protein maturation.
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ABCB7 p.Glu433Lys 11050011:177:65
status: NEW206 These results represent the second mutation in the human ABC7 gene and therefore confirm and extend the previous identification of an ABC7 mutation (1208T3G) that substituted a methionine for an isoleucine at codon 400 in exon 9 as the cause of XLSA/A.
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ABCB7 p.Glu433Lys 11050011:206:4
status: NEW210 The E433K mutation in ABC7 identified in this XLSA/A family impaired the function of the protein in cytosolic Fe/S protein assembly.
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ABCB7 p.Glu433Lys 11050011:210:4
status: NEW5 The mutation was a G-to-A transition at nucleotide 1305 of the full-length cDNA, resulting in a charge inversion caused by the substitution of lysine for glutamate at residue 433 C-terminal to the putative sixth transmembrane domain of ABC7.
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ABCB7 p.Glu433Lys 11050011:5:143
status: NEW8 In contrast, the expression of mutated ABC7 (E433K) or Atm1p (D398K) proteins in èc;atm1 cells led to a low efficiency of cytosolic Fe/S protein maturation.
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ABCB7 p.Glu433Lys 11050011:8:45
status: NEW160 The mutation resulted in a substitution of lysine for the wild-type glutamate at amino acid 433 (E433K) of the ABC7 protein and abolished a BsmAI restriction site (Figure 1D).
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ABCB7 p.Glu433Lys 11050011:160:97
status: NEW165 In addition, we performed similar studies with Atm1p into which the mutation corresponding to the human ABC7 mutant (E433K) was introduced (Atm1p D398K).
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ABCB7 p.Glu433Lys 11050011:165:117
status: NEW166 Wild-type Atm1p and, to a slightly lesser extent, ABC7 complemented the growth defect of èc;atm1 cells and the defect leading to mitochondrial iron accumulation.12 Similarly, both the Atm1p D398K and the ABC7 E433K mutant proteins restored growth of èc;atm1 cells to a similar extent as the corresponding wild-type proteins (data not shown).
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ABCB7 p.Glu433Lys 11050011:166:213
status: NEW173 Finally, we investigated the consequences of the XLSA/A mutation E433K in ABC7 and the corresponding mutation in Atm1p (D398K) for the function of these proteins in cytosolic Fe/S protein maturation.
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ABCB7 p.Glu433Lys 11050011:173:65
status: NEW