ABCMdb

ABCB7 p.Ile400Met

Predicted by SNAP2:	A: N (53%), C: N (72%), D: D (71%), E: D (71%), F: D (53%), G: D (71%), H: D (66%), K: D (75%), L: N (57%), M: N (57%), N: D (71%), P: D (66%), Q: D (66%), R: D (71%), S: D (59%), T: D (59%), V: N (97%), W: N (61%), Y: D (63%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, K: D, L: N, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[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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20 Two of these are missense mutations, which cause the substitution of residues within the ABCB7 transmembrane domains: V411L (4) and I400M (2). Login to comment

[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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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). Login to comment

[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. Login to comment
13 (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. Login to comment

[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. Login to comment

[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
206 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. Login to comment
202 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. Login to comment

[hide] Mutation of a putative mitochondrial iron transpor... Hum Mol Genet. 1999 May;8(5):743-9. Allikmets R, Raskind WH, Hutchinson A, Schueck ND, Dean M, Koeller DM
Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A).
Hum Mol Genet. 1999 May;8(5):743-9., [PMID:10196363]

Abstract [show]
X-linked sideroblastic anemia and ataxia (XLSA/A) is a recessive disorder characterized by an infantile to early childhood onset of non-progressive cerebellar ataxia and mild anemia with hypochromia and microcytosis. A gene encoding an ATP-binding cassette (ABC) transporter was mapped to Xq13, a region previously shown by linkage analysis to harbor the XLSA/A gene. This gene, ABC7, is an ortholog of the yeast ATM1 gene whose product localizes to the mitochondrial inner membrane and is involved in iron homeostasis. The full-length ABC7 cDNA was cloned and the entire coding region screened for mutations in a kindred in which five male members manifested XLSA/A. An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. The mutation was shown to segregate with the disease in the family and was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the Saccharomyces cerevisiae ATM1 gene resulted in a partial loss of function of the yeast Atm1 protein. In addition, the human wild-type ABC7 protein was able to complement ATM1 deletion in yeast. These data indicate that ABC7 is the causal gene of XLSA/A and that XLSA/A is a mitochondrial disease caused by a mutation in the nuclear genome.

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No. Sentence Comment
4 An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. Login to comment
43 A sequence variant was detected (T1200G) that changes the amino acid sequence from Ile (ATT) to Met (ATG) at position 400 (I400M). Login to comment
46 The I400M substitution was found to segregate in the family and was detected in all affected individuals and, in the heterozygous state, in female obligate carriers (Fig. 3). Login to comment
47 The I400M allele was also found in individuals III-4, II-3 and II-4. Login to comment
48 Although we cannot completely rule out the possibility that this is a rare neutral variant, the I400M mutation was not detected in any of the 600 chromosomes from racially matched (European American) general population controls. Login to comment
49 To evaluate the functional consequences of the observed I400M substitution in the ABC7 protein, the corresponding V365M mutation was made in the yeast ATM1 gene. Login to comment
76 The location of the I400M missense mutation is shown above the sequence. Login to comment
86 Segregation of SSCP variants of the I400M mutation in the ABC7 genein kindredwith XLSA/A.Sequence analysisofSSCPbands(shownbelow the pedigree) revealed the existence of wild-type sequence (band 2) and mutant sequence (band 1). Login to comment
87 DNA sequencing revealed a T1200G (I400M) substitution in band 2. Login to comment
88 Female carriers are heterozygous for the T1200G (I400M) substitution (reveal both bands 1 and 2), while the affected male offspring (individuals II-1, III-3, III-8 and III-9) harbor the mutant ABC7 allele only. Login to comment
90 The first is the accumulation of mitochondrial iron in the bone marrow cells of patients with the I400M mutation in ABC7 and in the ∆atm1 yeast strain (6,7,18). Login to comment
5 An I400M variant was identified in a predicted transmembrane segment of the ABC7 gene in patients with XLSA/A. Login to comment
45 A sequence variant was detected (T1200G) that changes the amino acid sequence from Ile (ATT) to Met (ATG) at position 400 (I400M). Login to comment
50 Although we cannot completely rule out the possibility that this is a rare neutral variant, the I400M mutation was not detected in any of the 600 chromosomes from racially matched (European American) general population controls. Login to comment
51 To evaluate the functional consequences of the observed I400M substitution in the ABC7 protein, the corresponding V365M mutation was made in the yeast ATM1 gene. Login to comment
78 The location of the I400M missense mutation is shown above the sequence. Login to comment
89 DNA sequencing revealed a T1200G (I400M) substitution in band 2. Login to comment
92 The first is the accumulation of mitochondrial iron in the bone marrow cells of patients with the I400M mutation in ABC7 and in the ࢞atm1 yeast strain (6,7,18). Login to comment

[hide] Crystal structures of nucleotide-free and glutathi... Science. 2014 Mar 7;343(6175):1137-40. doi: 10.1126/science.1246729. Srinivasan V, Pierik AJ, Lill R
Crystal structures of nucleotide-free and glutathione-bound mitochondrial ABC transporter Atm1.
Science. 2014 Mar 7;343(6175):1137-40. doi: 10.1126/science.1246729., [PMID:24604199]

Abstract [show]
The yeast mitochondrial ABC transporter Atm1, in concert with glutathione, functions in the export of a substrate required for cytosolic-nuclear iron-sulfur protein biogenesis and cellular iron regulation. Defects in the human ortholog ABCB7 cause the sideroblastic anemia XLSA/A. Here, we report the crystal structures of free and glutathione-bound Atm1 in inward-facing, open conformations at 3.06- and 3.38-angstrom resolution, respectively. The glutathione binding site includes a residue mutated in XLSA/A and is located close to the inner membrane surface in a large cavity. The two nucleotide-free adenosine 5'-triphosphate binding domains do not interact yet are kept in close vicinity through tight interaction of the two C-terminal alpha-helices of the Atm1 dimer. The resulting protein stabilization may be a common structural feature of all ABC exporters.

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No. Sentence Comment
91 Three of the XLSA/A patient mutations are located in the membrane domain either on the matrix [E208D in long TM2 helix; yeast E173 (29)] or intermembrane space sides (I400M between TM5 and TM6, yeast V365 (26); V411L in TM6, yeast V376 (28)] (Fig. 2A and fig. S1A). Login to comment

[hide] The role of mitochondria and the CIA machinery in ... Eur J Cell Biol. 2015 Jul-Sep;94(7-9):280-91. doi: 10.1016/j.ejcb.2015.05.002. Epub 2015 May 31. Lill R, Dutkiewicz R, Freibert SA, Heidenreich T, Mascarenhas J, Netz DJ, Paul VD, Pierik AJ, Richter N, Stumpfig M, Srinivasan V, Stehling O, Muhlenhoff U
The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron-sulfur proteins.
Eur J Cell Biol. 2015 Jul-Sep;94(7-9):280-91. doi: 10.1016/j.ejcb.2015.05.002. Epub 2015 May 31., [PMID:26099175]

Abstract [show]
Mitochondria have been derived from alpha-bacterial endosymbionts during the evolution of eukaryotes. Numerous bacterial functions have been maintained inside the organelles including fatty acid degradation, citric acid cycle, oxidative phosphorylation, and the synthesis of heme or lipoic acid cofactors. Additionally, mitochondria have inherited the bacterial iron-sulfur cluster assembly (ISC) machinery. Many of the ISC components are essential for cell viability because they generate a still unknown, sulfur-containing compound for the assembly of cytosolic and nuclear Fe/S proteins that perform important functions in, e.g., protein translation, DNA synthesis and repair, and chromosome segregation. The sulfur-containing compound is exported by the mitochondrial ABC transporter Atm1 (human ABCB7) and utilized by components of the cytosolic iron-sulfur protein assembly (CIA) machinery. An appealing minimal model for the striking compartmentation of eukaryotic Fe/S protein biogenesis is provided by organisms that contain mitosomes instead of mitochondria. Mitosomes have been derived from mitochondria by reductive evolution, during which they have lost virtually all classical mitochondrial tasks. Nevertheless, mitosomes harbor all core ISC components which presumably have been maintained for assisting the maturation of cytosolic-nuclear Fe/S proteins. The current review is centered around the Atm1 export process. We present an overview on the mitochondrial requirements for the export reaction, summarize recent insights into the 3D structure and potential mechanism of Atm1, and explain how the CIA machinery uses the mitochondrial export product for the assembly of cytosolic and nuclear Fe/S proteins.

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301 All mutated residues are located in the membrane domain either on the matrix (E208D in long TM2 helix; yeast E173 D`Hooghe et al., 2012) or intermembrane space sides (I400M between TM5-TM6, yeast V365 (Allikmets et al., 1999); V411L in TM6, yeast V376 (Maguire et al., 2001) (Fig. 4). Login to comment