Alternative titles; symbols
HGNC Approved Gene Symbol: ABCB7
Cytogenetic location: Xq13.3 Genomic coordinates (GRCh38) : X:75,051,048-75,156,283 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq13.3 | Anemia, sideroblastic, with ataxia | 301310 | X-linked | 3 |
The ABCB7 gene encodes a member of the large, highly conserved ATP-binding cassette (ABC) transporter family, which transport a variety of substrates across cell and organelle membranes. ABCB7 localizes to the inner mitochondrial membrane and is involved in iron homeostasis (summary by Allikmets et al., 1999; D'Hooghe et al., 2012). For background information on ABC transporters, see 300135.
Savary et al. (1997) isolated a 2,684-bp mouse cDNA of a novel ABC transporter, Abc7, from a macrophage cDNA library. Beginning with the first ATG at 196, the Abc7 cDNA is predicted to encode a 629-amino acid protein with 6 transmembrane segments followed by a canonical ATP-binding cassette, features typical of a half-transporter. A search of the human EST databases identified a 1,109-bp clone from a fetal liver spleen cDNA library that showed 92% nucleotide sequence identity to mouse Abc7. The putative protein product encoded by this clone is 94% identical to the C-terminal 340 amino acids of mouse Abc7. These high sequence identities led Savary et al. (1997) to conclude that the EST clone is the human ortholog of Abc7. Northern blot analysis detected an approximately 3-kb ABC7 transcript in human heart, skeletal muscle, pancreas, lung, liver, placenta, and several cell lines, but not in brain. Northern blot analysis performed on mouse embryos showed that Abc7 was expressed through all the developmental stages examined, beginning at embryonic day 6.5. A search of sequence databases revealed that ABC7 has the highest homology with 2 yeast ABC transporters. Since one of these, S. Pombe Htm1, is required for heavy-metal tolerance in yeast, Savary et al. (1997) speculated that ABC7 may be involved in metal homeostasis. Furthermore, Savary et al. (1997) noted that diseases due to altered
Shimada et al. (1998) identified a human EST showing high sequence similarity to the mouse Abc7 gene and the yeast ATM1 gene, which encodes an ABC half-transporter located in the mitochondrial inner membrane. To obtain the complete human ABC7 cDNA sequence, they isolated additional cDNAs from a human fetal brain cDNA library. The predicted 752-amino acid ABC7 protein contains 4 transmembrane domains and an N-terminal mitochondrial targeting sequence. Human ABC7 has 92% and 49% amino acid sequence identity with mouse Abc7 and yeast ATM1, respectively. Northern blot analysis of human tissues detected a single 2.6-kb ABC7 transcript that was strongly expressed in skeletal muscle and heart. Shimada et al. (1998) suggested that ABC7 is a half-transporter involved in the transport of heme from the mitochondria to the cytosol.
Allikmets et al. (1999) cloned the full-length ABC7 cDNA.
Bekri et al. (2000) determined that the ABCB7 gene contains 16 exons.
By in situ hybridization, Savary et al. (1997) mapped the human and mouse ABC7 genes to chromosomes Xq12-q13 and XC-XD, respectively, regions that show homology of synteny.
By fluorescence in situ hybridization, Shimada et al. (1998) refined the localization of the human ABC7 gene to chromosome Xq13.1-q13.3.
In affected males from a family with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310), originally reported by Pagon et al. (1985), Allikmets et al. (1999) identified a hemizygous missense mutation in the ABCB7 gene (I400M; 300135.0001). The mutation, which occurred in a predicted transmembrane segment of the protein, was found to segregate with the disease in the family. Introduction of the corresponding mutation into the orthologous Saccharomyces cerevisiae gene resulted in a partial loss of function of the yeast ATM1 protein. In addition, the human wildtype ABCB7 protein was able to complement ATM1 deletion in yeast. The data indicated that ABCB7 is the causal gene of SCAX6 and that SCAX6 is a mitochondrial disease caused by mutation in the nuclear genome.
Bekri et al. (2000) identified a second missense mutation in the ABCB7 gene (E433K; 300135.0002) as the cause of SCAX6 in a family.
In 2 brothers with SCAX6, originally reported by Hellier et al. (2001), Maguire et al. (2001) identified a hemizygous missense mutation in the ABCB7 gene (V411L; 300135.0003). The mother was heterozygous for the mutation, and a maternal uncle with ataxia was hemizygous for the mutation. Functional studies of the variant were not performed.
In a 5-year-old boy with SCAX6, D'Hooghe et al. (2012) identified a hemizygous missense mutation in the ABCB7 gene (E209D; 300135.0004). Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old Chinese boy with SCAX6, Xiong et al. (2021) identified a hemizygous missense mutation in the ABCB7 gene (D675G; 300135.0005). The mutation, which was found by whole-exome sequencing, was inherited from the mother, who had only subtle anemia. The variant was not present in the gnomAD database. Functional studies of the variant were not performed.
Pondarre et al. (2006) found that mouse embryonic stem cells and male mouse embryos expressing a conditionally deleted Abcb7 allele were not viable. Maternally-inherited Abcb7 deletion was lethal to female embryos. By breeding a series of conditionally deleted transgenic lines, Pondarre et al. (2006) demonstrated that lethality was due to a defect in extraembryonic visceral endoderm, which, like all other extraembryonic tissue, preferentially maintains the female X chromosome as the active allele. X-inactivation assays and tissue-specific deletion showed that Abcb7 was essential in all tissues except hepatocytes and endothelial cells. In liver, loss of Abcb7 resulted in mild mitochondrial injury, impaired cytosolic Fe-S cluster assembly, and altered iron sensing by Irp1 (ACO1; 100880), which contributed to dysregulation of hepatocyte iron metabolism and increased total liver iron.
In affected males from a family with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310), originally reported by Pagon et al. (1985), Allikmets et al. (1999) identified a hemizygous ile400-to-met (I400M) mutation in the ABCB7 gene. The mutation, which occurred in a predicted transmembrane segment of the protein, was found to segregate with the disease in the family. The mutation was not detected in at least 600 chromosomes of general population controls. Introduction of the corresponding mutation into the orthologous Saccharomyces cerevisiae gene resulted in a partial loss of function of the yeast ATM1 protein. In addition, the human wildtype ABCB7 protein was able to complement ATM1 deletion in yeast.
Bekri et al. (2000) described a family in which affected males with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310) had a hemizygous missense mutation in exon 10 of the ABC7 gene: a c.1305G-A transition, resulting in a glu433-to-lys (E433K) substitution located C-terminal to the putative sixth transmembrane domain of ABCB7. In the older brother, congenital ataxia had been diagnosed at the age of 4. The ataxia was nonprogressive, and computed tomography of the brain at age 18 showed striking, selective cerebellar hypoplasia. The mother's blood film showed dimorphism, consistent with an X-linked defect. The anemia was refractory to treatment with pyridoxine.
In 2 brothers with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310) originally reported by Hellier et al. (2001), Maguire et al. (2001) identified a hemizygous c.1299G-C transversion in the ABCB7 gene, resulting in a val411-to-leu (V411L) substitution at the beginning of the last of 6 putative transmembrane regions of the protein. The mother was heterozygous for the mutation, and a maternal uncle with ataxia was hemizygous for the mutation. The patients had ataxia and hypochromic red cells with 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. Functional studies of the variant were not performed.
In a 5-year-old boy with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310), D'Hooghe et al. (2012) identified a hemizygous c.627A-T transition in the ABCB7 gene, predicted to result in a glu209-to-asp (E209D) substitution at a conserved residue adjacent to the second transmembrane domain at the mitochondrial side, which may affect protein folding. The mutation was present in the heterozygous state in the mother, who had no symptoms, but showed mild hematologic abnormalities on peripheral blood smear. Functional studies of the variant and studies of patient cells were not performed.
In a 5-year-old Chinese boy with X-linked spinocerebellar ataxia-6 with sideroblastic anemia (SCAX6; 301310), Xiong et al. (2021) identified a hemizygous c.2024A-G transition (c.2024A-G, NM_004299) in the ABCB7 gene, resulting in an asp675-to-gly (D675G) substitution. The mutation, which was found by whole-exome sequencing, was inherited from the mother, who had only subtle anemia. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. In addition to ataxia and mild anemia, the patient had global developmental delay and early-onset seizures.
Allikmets, R., Raskind, W. H., Hutchinson, A., Schueck, N. D., Dean, M., Koeller, D. M. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A). Hum. Molec. Genet. 8: 743-749, 1999. [PubMed: 10196363] [Full Text: https://doi.org/10.1093/hmg/8.5.743]
Bekri, S., Kispal, G., Lange, H., Fitzsimons, E., Tolmie, J., Lill, R., Bishop, D. F. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation. Blood 96: 3256-3264, 2000. [PubMed: 11050011]
D'Hooghe, M., Selleslag, D., Mortier, G., Van Coster, R., Vermeersch, P., Billiet, J., Bekri, S. X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation. Europ. J. Paediat. Neurol. 16: 730-735, 2012. [PubMed: 22398176] [Full Text: https://doi.org/10.1016/j.ejpn.2012.02.003]
Hellier, K. D., Hatchwell, E., Duncombe, A. S., Kew, J., Hammans, S. R. X-linked sideroblastic anaemia with ataxia: another mitochondrial disease? J. Neurol. Neurosurg. Psychiat. 70: 65-69, 2001. [PubMed: 11118249] [Full Text: https://doi.org/10.1136/jnnp.70.1.65]
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. Brit. J. Haemat. 115: 910-917, 2001. [PubMed: 11843825] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.03015.x]
Pagon, R. A., Bird, T. D., Detter, J. C., Pierce, I. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder. J. Med. Genet. 22: 267-273, 1985. [PubMed: 4045952] [Full Text: https://doi.org/10.1136/jmg.22.4.267]
Pondarre, C., Antiochos, B. B., Campagna, D. R., Clarke, S. L., Greer, E. L., Deck, K. M., McDonald, A., Han, A.-P., Medlock, A., Kutok, J. L., Anderson, S. A., Eisenstein, R. S., Fleming, M. D. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulfur cluster biogenesis. Hum. Molec. Genet. 15: 953-964, 2006. [PubMed: 16467350] [Full Text: https://doi.org/10.1093/hmg/ddl012]
Savary, S., Allikmets, R., Denizot, F., Luciani, M.-F., Mattei, M.-G., Dean, M., Chimini, G. Isolation and chromosomal mapping of a novel ATP-binding cassette transporter conserved in mouse and human. Genomics 41: 275-278, 1997. [PubMed: 9143506] [Full Text: https://doi.org/10.1006/geno.1997.4658]
Shimada, Y., Okuno, S., Kawai, A., Shinomiya, H., Saito, A., Suzuki, M., Omori, Y., Nishino, N., Kanemoto, N., Fujiwara, T., Horie, M., Takahashi, E. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia. J. Hum. Genet. 43: 115-122, 1998. [PubMed: 9621516] [Full Text: https://doi.org/10.1007/s100380050051]
Xiong, S., Jia, Y., Li, S., Huang, P., Xiong, J., Mao, D., He, Q., Liu, L. The first case report of X-linked sideroblastic anemia with ataxia of Chinese origin and literature review. Front. Pediat. 9: 692459, 2021. [PubMed: 34354969] [Full Text: https://doi.org/10.3389/fped.2021.692459]