Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A4
Cytogenetic location: 4q35.1 Genomic coordinates (GRCh38): 4:185,143,266-185,150,382 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q35.1 | Mitochondrial DNA depletion syndrome 12A (cardiomyopathic type) AD | 617184 | Autosomal dominant | 3 |
| Mitochondrial DNA depletion syndrome 12B (cardiomyopathic type) AR | 615418 | Autosomal recessive | 3 | |
| Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 2 | 609283 | Autosomal dominant | 3 |
The SLC25A4 gene encodes the mitochondrial ADP/ATP, or adenine nucleotide, translocator, which is a homodimer of 30-kD subunits embedded in the mitochondrial inner membrane. The dimer forms a gated pore through which ADP is moved across the inner membrane into the mitochondrial matrix and ATP is moved from the matrix into the cytoplasm (summary by Neckelmann et al., 1987).
Neckelmann et al. (1987) characterized a 1,400-nucleotide cDNA for human skeletal muscle ANT. They compared the sequence with that of the human fibroblast ANT cognate as reported by Battini et al. (1987). This showed that the 2 distinct ANTs diverged about 275 million years ago. The skeletal muscle ANT is expressed in heart, kidney, liver, skeletal muscle, and HeLa cells. The rate of evolution of the skeletal muscle ANT is 10 to 12 times slower than that of the mitochondrial Ox/Phos genes. Mitochondrial energy production varies greatly among human tissues. Because the ANT determines the rate of ADP/ATP flux between the mitochondrion and the cytosol, it is a logical candidate for regulator of cellular dependence on oxidative energy metabolism.
Li et al. (1989, 1989) reported the cloning of the human ANT1 locus. The mRNA is 1.4 kb and most abundant in heart and skeletal muscle, but barely detectable in liver, kidney, or brain. A second full-length ANT cDNA, ANT2 (300150), derived from fibroblasts is present in all of the above-mentioned tissues at relatively constant levels. A third cDNA, ANT3 (300151), has been cloned from human liver (Houldsworth and Attardi, 1988). ANT1, ANT2, and ANT3 are approximately 90% homologous at the amino acid level.
Crystal Structure
Pebay-Peyroula et al. (2003) solved the bovine ADP/ATP carrier structure at a resolution of 2.2 angstroms by X-ray crystallography in complex with an inhibitor, carboxyatractyloside. Six alpha helices form a compact transmembrane domain, which, at the surface toward the space between inner and outer mitochondrial membranes, reveals a deep depression. At its bottom, a hexapeptide carrying the signature of nucleotide carriers (RRRMMM) is located. Pebay-Peyroula et al. (2003) concluded that their structure, together with earlier biochemical results, suggested that transport substrates bind to the bottom of the cavity and that translocation results from a transient transition from a 'pit' to a 'channel' conformation.
Li et al. (1989) determined that the ANT1 gene is 5.8 kb long and contains 4 exons.
Minoshima et al. (1989) used hybridization to flow-sorted human chromosomes and Southern blot hybridization to mouse/human somatic cell hybrids to demonstrate that the ANT1 gene localizes to human chromosome 4. Fan et al. (1992) regionalized the ANT1 gene to 4q35 by fluorescence in situ hybridization. Haraguchi et al. (1993) mapped the ANT1 gene to 4q35-qter using somatic cell hybrids containing various deletions of chromosome 4. The regional location was further refined through family studies using ANT1 intron and promoter nucleotide polymorphisms recognized by 3 different restriction endonucleases. Family studies suggested that ANT1 is located centromeric to D4S139 which in turn is centromeric to the locus for FSHD. Wijmenga et al. (1993) likewise mapped the ANT1 gene to 4q35 to a site proximal to the FSHD gene. Studies using a polymorphic CA-repeat 5 kb upstream of the ANT1 gene as a marker in FSHD and CEPH families suggested that the ANT1 gene is centromeric to FSHD and is separated from it by several markers, including the factor XI gene (264900).
Mills et al. (1996) demonstrated that the murine homolog Ant1 is located on chromosome 8 by studies of an interspecific cross. The gene had been previously localized to chromosome 8 by PCR of a somatic cell hybrid mapping panel with primers from the cDNA sequence. Only a single recombination event in 227 chromosomes was observed between Ant1 and the plasma kallikrein gene Klk3 (KLKB1; 229000) which in the human maps to 4q35 as does also ANT1.
Almost all patients with facioscapulohumeral muscular dystrophy (FSHD; 158900) carry deletions of an integral number of tandem 3.3-kb repeats, termed D4Z4, on chromosome 4q35. Gabellini et al. (2002) found that in FSHD muscle, genes located upstream of D4Z4 on 4q35, including FRG1 (601278), FRG2 (609032), and ANT1, are inappropriately overexpressed. They showed that an element within D4Z4 specifically binds a multiprotein complex that mediates transcriptional repression of 4q35 genes. Gabellini et al. (2002) proposed that deletion of D4Z4 leads to the inappropriate transcriptional derepression of 4q35 genes, resulting in disease.
Forlani et al. (2010) showed that MeCP2 (300005) cooperates with YY1 (600013) in repressing the ANT1 gene, encoding a mitochondrial adenine nucleotide translocase. Importantly, ANT1 mRNA levels are increased in human and mouse cell lines devoid of MeCP2, in Rett syndrome (312750) patient fibroblast, and in the brain of MeCP2-null mice. Forlani et al. (2010) further demonstrated that ANT1 protein levels are upregulated in MeCP2-null mice.
Hoshino et al. (2019) developed a multidimensional CRISPR-Cas9 genetic screen, using multiple mitophagy reporter systems and promitophagy triggers, and identified numerous components of parkin (PARK2; 602544)-dependent mitophagy. Unexpectedly, they found that the ANT complex was required for mitophagy in several cell types. Whereas pharmacologic inhibition of ANT-mediated ADP/ATP exchange promoted mitophagy, genetic ablation of ANT paradoxically suppressed mitophagy. Notably, ANT promoted mitophagy independently of its nucleotide translocase catalytic activity. Instead, the ANT complex was required for inhibition of the presequence translocase TIM23 (605034), which led to stabilization of PINK1 (608309), in response to bioenergetic collapse. ANT modulated TIM23 indirectly via interaction with TIM44 (605058), which regulated peptide import through TIM23. Mice that lacked ANT1 showed blunted mitophagy and consequent profound accumulation of aberrant mitochondria. Disease-causing human mutations in ANT1 abrogated binding to TIM44 and TIM23 and inhibited mitophagy.
Autosomal Dominant Progressive External Ophthalmoplegia 2
Kaukonen et al. (2000) identified a missense mutation in the ANT1 gene (A114P; 103220.0001) in 5 families with autosomal dominant progressive external ophthalmoplegia (PEOA2; 609283). The analogous mutation in yeast caused a respiratory defect. Kaukonen et al. (2000) also identified a mutations in the ANT1 gene (V289M; 103220.0002) in a sporadic case of PEO. The A114P mutation is likely to be located either in the third transmembrane domain of ANT1 or just adjacent to it in the loop joining the second and third transmembrane domains in the intermembrane space. The V289M mutation affects the sixth transmembrane domain. A simulation analysis of the secondary structure of human ANT1 suggested that the adenine-to-proline substitution would cause an additional bend in the polypeptide, disrupting the local alpha helix. Because patients with dominant PEO carry 1 wildtype and 1 mutant allele, defective ANT1 dimers would form in 2 out of 3 dimerization events.
Chen (2002) determined that the A128P mutation of the S. cerevisiae Aac2 protein, equivalent to A114P (103220.0001) in human ANT1, does not always affect respiratory growth. Rather, expression of A128P resulted in depolarization, structural swelling, and disintegration of mitochondria, and ultimately an arrest of cell growth in a dominant-negative manner. Chen (2002) proposed that the A128P mutation may induce an unregulated channel, allowing free passage of solutes across the inner membrane, rather than interfere specifically with ATP/ADP exchange.
Fontanesi et al. (2004) introduced dominant-acting missense mutations associated with PEO into AAC2, the yeast ortholog of human ANT1. Expression of the equivalent mutations in aac2-defective haploid strains of Saccharomyces cerevisiae resulted in a marked growth defect on nonfermentable carbon sources, and a concurrent reduction of the amount of mitochondrial cytochromes, cytochrome c oxidase activity, and cellular respiration. The AAC2 pathogenic mutants showed a significant defect in ADP versus ATP transport compared with wildtype AAC2. The aac2 mutant alleles were also inserted in combination with the endogenous wildtype AAC2 gene. The heteroallelic strains behaved as recessive for oxidative growth and petite-negative phenotype. In contrast, reduction in cytochrome content and increased mtDNA instability appeared to behave as dominant traits in heteroallelic strains.
Autosomal Dominant Mitochondrial DNA Depletion Syndrome 12A
In 7 children from 6 unrelated families with autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A; 617184), Thompson et al. (2016) identified 1 of 2 recurrent de novo heterozygous missense mutations in the SLC25A4 gene (R80H, 103220.0009 and R235G, 103220.0010). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that each mutation significantly impaired SLC25A4 transporter activity. Thompson et al. (2016) concluded that the highly reduced capacity for ADP/ATP transport in mitochondria probably affects mitochondrial DNA maintenance and negatively impacts respiration, causing severe energy depletion. The patients had severe hypotonia apparent from birth; 5 died in early infancy.
Autosomal Recessive Mitochondrial DNA Depletion Syndrome 12B
In a 25-year-old Slovenian man with autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418), manifest as hypertrophic cardiomyopathy and exercise intolerance, Palmieri et al. (2005) identified homozygosity for a mutation in the ANT1 gene (A123D; 103220.0005). The clinical and biochemical features were different from those found in dominant ANT1 mutations, resembling those described in ANT1-knockout mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe oxidative phosphorylation phenotype displayed by WB-12, an AAC1/AAC2-defective yeast strain.
In a 21-year-old Portuguese girl with MTDPS12, Echaniz-Laguna et al. (2012) identified a homozygous splice site mutation in the ANT1 gene (103220.0006). The mutant transcript was undetectable in patient cells, consistent with complete loss of protein expression and function. The clinically unaffected mother, who was heterozygous for the mutation, had low levels (less than 2%) of mtDNA rearrangements in skeletal muscle. The deceased father was reportedly unaffected. The patient had hypertrophic cardiomyopathy, exercise intolerance with muscle weakness and atrophy, congenital cataracts, and lactic acidosis. Muscle biopsy showed ragged-red fibers and multiple mtDNA deletions.
In a 28-year-old man with a mitochondrial myopathy, originally reported by Bakker et al. (1993, 1993), Korver-Keularts et al. (2015) identified compound heterozygous mutations in the SLC25A4 gene (103220.0007 and 103220.0008): a frameshift mutation demonstrated to result in nonsense-mediated mRNA decay, and a missense mutation (R236P; 103220.0008). Functional studies of the missense variant were not performed.
Thompson et al. (2016) suggested that residual SLC25A4 transport activities broadly fall into 3 groups that segregate with the clinical phenotypes. Heterozygous mutations associated with PEOA2 manifest higher residual transport activities (24-56%) than MTDPS12A heterozygous de novo mutations (3-24%), which could explain the less severe phenotype in PEOA2. Mutations in PEOA2 do not affect functional parts of the protein, whereas those in MTDPS12B affect functional residues. Mutations in MTDPS12A result in an energy crisis that affects key mitochondrial functions leading to the severe, early-onset, and often fatal clinical presentation. Mutations in autosomal recessive MTDPS12B are completely null (less than 1% transport activity), which likely triggers a compensatory mechanism to upregulate expression of other ADP/ATP carrier isoforms, resulting in an intermediate phenotype.
Mutations in mitochondrial DNA (mtDNA) involving rearrangements and point mutations in tRNAs (e.g., 590050, 590045, 590035.0001) are associated with mitochondrial disease in which myopathy associated with ragged-red fibers and hypertrophic cardiomyopathy are common features. Graham et al. (1997) hypothesized that these clinical manifestations may derive from severe defects in oxidative phosphorylation, resulting in marked mitochondrial energy deficiency and a compensatory induction of mitochondrial proliferation. To test this hypothesis, they took advantage of the presence of tissue-specific isoforms of ANT. They reasoned that if ATP deficiency were the cause of mitochondrial myopathy and cardiomyopathy, inactivation of ANT1 would starve the skeletal muscle and the heart of mitochondrial ATP, resulting in the pathology. They generated 'knockout' mice deficient in the heart/muscle isoform of ANT. Histologic and ultrastructural examination of skeletal muscle from Ant1-null mutants revealed ragged-red muscle fibers a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1-mutant adults also had a resting serum lactate level 4-fold higher than that of controls, indicative of metabolic acidosis. Significantly, mutant adults manifested severe exercise intolerance.
The mitochondrial permeability transition pore (mtPTP), a protein complex that includes the ANTs, mediates the sudden increase in inner mitochondrial membrane permeability that is a common feature of apoptosis. Kokoszka et al. (2004) confirmed that the mouse genome contains only 2 Ant genes, Ant1 and Ant2. They inactivated both Ant genes in mouse liver and analyzed mtPTP activation in isolated mitochondria and the induction of cell death in hepatocytes. Mitochondria lacking Ant could still undergo inner membrane permeability transition and release cytochrome c (123970). However, more Ca(2+) than usual was required to activate mtPTP, and the pore could not be regulated by Ant ligands, including adenine nucleotides. Hepatocytes without Ant remained competent to respond to various initiators of cell death. In addition, mutant mouse liver mitochondria showed respiration rates that were almost twice that of controls and that were nonresponsive to the addition of ADP. The mitochondrial membrane potential was higher than that of controls. The increased respiration rate was associated with upregulated Cox1 (176805) protein levels.
Halestrap (2004) commented on the observations of Kokoszka et al. (2004).
In 5 Italian families with progressive external ophthalmoplegia with mitochondrial DNA deletions (PEOA2; 609283), Kaukonen et al. (2000) identified a G-to-C transversion in exon 2 of the ANT1 gene, resulting in an ala114-to-pro (A114P) substitution. The nucleotide change was present in all affected family members, but not in 860 Finnish or 150 Italian control individuals. Alanine-114 and its flanking sequences are strictly conserved among species. A common disease haplotype with identical markers was shared by all patients in 3 Italian families, suggesting that there is 1 founder mutation and common ancestry, although this could not be genealogically confirmed. Three families had been reported by Kaukonen et al. (1996, 1999).
In a sporadic patient with PEOA2 (609283) and multiple mitochondrial DNA deletions, Kaukonen et al. (2000) identified a missense mutation, a G-to-A transition in exon 4 of the ANT1 gene resulting in a val289-to-met (V289M) substitution.
In 3 members of a Greek family with PEOA2 (609283), Napoli et al. (2001) identified a heterozygous 293T-C transition in the ANT1 gene, resulting in a leu98-to-pro (L98P) substitution. The mutation was absent in several unaffected family members and in Italian and Greek controls.
In 4 affected members of a Japanese family with PEOA2 (609283), Komaki et al. (2002) identified a 311A-G heterozygous mutation in exon 2 of the ANT1 gene, resulting in an asp104-to-gly (D104G) substitution. The mutation was not detected in 2 unaffected family members or 120 normal individuals. The authors noted that the mutation converted a highly conserved aspartic acid into a nonpolar glycine in a side chain.
In a 25-year-old Slovenian man with autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418), Palmieri et al. (2005) identified homozygosity for a 368C-A transversion in the ANT1 gene, resulting in an ala123-to-asp (A123D) substitution in a conserved residue. The unaffected mother was heterozygous for the mutation, and the father was unavailable for testing. The mutation was absent in 500 control individuals. The patient presented with hypertrophic cardiomyopathy, mild myopathy with exercise intolerance, and lactic acidosis but no ophthalmoplegia. Muscle biopsy revealed numerous ragged-red fibers, and Southern blot analysis disclosed multiple deletions of muscle mitochondrial DNA. Muscle tissue was unavailable from the patient's mother, so the presence of subclinical amounts of multiple deletions could not be ruled out. The clinical and biochemical features were different from those found in dominant ANT1 mutations, resembling those described in ANT1-knockout mice. No ATP uptake was measured in proteoliposomes reconstituted with protein extracts from the patient's muscle. The equivalent mutation in AAC2, the yeast ortholog of human ANT1, resulted in a complete loss of transport activity and in the inability to rescue the severe oxidative phosphorylation phenotype displayed by WB-12, an AAC1/AAC2-defective yeast strain.
In a patient, born of consanguineous Portuguese parents, with autosomal recessive MTDPS12B (615418), Echaniz-Laguna et al. (2012) identified a homozygous G-to-A transition in intron 1 of the SLC25A4 gene (c.111+1G-A). The mutant transcript was undetectable in patient cells, consistent with complete loss of protein expression and function. The clinically unaffected mother, who was heterozygous for the mutation, had low levels (less than 2%) of mtDNA rearrangements in skeletal muscle. The deceased father was reportedly unaffected. The patient had hypertrophic cardiomyopathy, exercise intolerance with muscle weakness and atrophy, congenital cataracts, and lactic acidosis. Muscle biopsy showed ragged-red fibers and multiple mtDNA deletions.
In a 28-year-old man with autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418), previously reported by Bakker et al. (1993, 1993), Korver-Keularts et al. (2015) identified compound heterozygous mutations in the SLC25A4 gene: a 22-bp deletion (c.116_137del) in exon 2, resulting in a frameshift and premature termination (Gln39LeufsTer14), and a 707G-C transversion in exon 3, resulting in an arg236-to-pro (R236P; 103220.0008) substitution at a highly conserved residue in the predicted transmembrane region. Neither mutation was found in the dbSNP, 1000 Genomes Project, or ExAC databases, or in 114 ethnically matched controls. The patient's unaffected father and brother were heterozygous for the R236P mutation; DNA from the deceased mother was not available for study. Cellular studies indicated that the frameshift mutation resulted in nonsense-mediated mRNA decay. Functional studies of the missense mutation were not performed.
For discussion of the c.707G-C transversion in exon 3 of the SLC25A4 gene, resulting in an arg236-to-pro (R236P) substitution that was found in compound heterozygous state in a patient with autosomal recessive mitochondrial DNA depletion syndrome-12B (MTDPS12B; 615418) by Korver-Keularts et al. (2015), see 103220.0007.
In 4 unrelated children with autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A; 617184), Thompson et al. (2016) identified a recurrent de novo heterozygous c.239G-A transition (c.239G-A, NM_001151.3) in the SLC25A4 gene, resulting in an arg80-to-his (R80H) substitution at a highly conserved residue within the phosphate substrate binding site. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against various public databases, including dbSNP, 1000 Genomes Project, and ExAC. Western blot analysis of patient muscle samples showed decreased levels of ANT1 and decreased levels of components of several mitochondrial respiratory complexes compared to controls. In vitro functional expression studies showed that the R80H mutant had only about 24% residual transporter activity. Complementation and transport studies in yeast confirmed that the mutant protein was functionally defective: it was unable to complement an oxidative phosphorylation defect and caused decreased transport activity, but it did not act in a dominant-negative manner.
In 3 patients from 2 unrelated families, including a pair of monozygotic twins, with autosomal dominant mitochondrial DNA depletion syndrome-12A (MTDPS12A; 617184), Thompson et al. (2016) identified a recurrent de novo heterozygous c.703C-G transversion (c.703C-G, NM_001151.3) in the SLC25A4 gene, resulting in an arg235-to-gly (R235G) substitution at a highly conserved residue affecting a salt bridge required for formation of the matrix network. Western blot analysis of patient muscle samples showed decreased levels of ANT1 and decreased levels of components of several mitochondrial respiratory complexes compared to controls. In vitro functional expression studies showed that the R235G mutant had only about 3% residual transporter activity. Complementation and transport studies in yeast confirmed that the mutant protein was functionally defective: it was unable to complement an oxidative phosphorylation defect and caused decreased transport activity, but it did not act in a dominant-negative manner.
Bakker, H. D., Scholte, H. R., Van den Bogert, C., Jeneson, J. A. L., Ruitenbeek, W., Wanders, R. J. A., Abeling, N. G. G. M., van Gennip, A. H. Adenine nucleotide translocator deficiency in muscle: potential therapeutic value of vitamin E. J. Inherit. Metab. Dis. 16: 548-552, 1993. [PubMed: 7609449] [Full Text: https://doi.org/10.1007/BF00711678]
Bakker, H. D., Scholte, H. R., Van den Bogert, C., Ruitenbeek, W., Jeneson, J. A. L., Wanders, R. J. A., Abeling, N. G. G. M., Dorland, B., Sengers, R. C. A., van Gennip, A. H. Deficiency of the adenine nucleotide translocator in muscle of a patient with myopathy and lactic acidosis: a new mitochondrial defect. Pediat. Res. 33: 412-417, 1993. [PubMed: 8479824] [Full Text: https://doi.org/10.1203/00006450-199304000-00019]
Battini, R., Ferrari, S., Kaczmarek, L., Calabretta, B., Chen, S., Baserga, R. Molecular cloning of a cDNA for a human ADP/ATP carrier which is growth-regulated. J. Biol. Chem. 262: 4355-4359, 1987. [PubMed: 3031073]
Chen, X. J. Induction of an unregulated channel by mutations in adenine nucleotide translocase suggests an explanation for human ophthalmoplegia. Hum. Molec. Genet. 11: 1835-1843, 2002. [PubMed: 12140186] [Full Text: https://doi.org/10.1093/hmg/11.16.1835]
Echaniz-Laguna, A., Chassagne, M., Ceresuela, J., Rouvet, I., Padet, S., Acquaviva, C., Nataf, S., Vinzio, S., Bozon, D., Mousson de Camaret, B. Complete loss of expression of the ANT1 gene causing cardiomyopathy and myopathy. J. Med. Genet. 49: 146-150, 2012. [PubMed: 22187496] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100504]
Fan, Y.-S., Yang, H.-M., Lin, C. C. Assignment of the human muscle adenine nucleotide translocator gene (ANT1) to 4q35 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 60: 29-30, 1992. [PubMed: 1582253] [Full Text: https://doi.org/10.1159/000133288]
Fontanesi, F., Palmieri, L., Scarcia, P., Lodi, T., Donnini, C., Limongelli, A., Tiranti, V., Zeviani, M., Ferrero, I., Viola, A. M. Mutations in AAC2, equivalent to human adPEO-associated ANT1 mutations, lead to defective oxidative phosphorylation in Saccharomyces cerevisiae and affect mitochondrial DNA stability. Hum. Molec. Genet. 13: 923-934, 2004. [PubMed: 15016764] [Full Text: https://doi.org/10.1093/hmg/ddh108]
Forlani, G., Giarda, E., Ala, U., Di Cunto, F., Salani, M., Tupler, R., Kilstrup-Nielsen, C., Landsberger, N. : The MeCP2/YY1 interaction regulates ANT1 expression at 4q35: novel hints for Rett syndrome pathogenesis. Hum. Molec. Genet. 19: 3114-3123, 2010. [PubMed: 20504995] [Full Text: https://doi.org/10.1093/hmg/ddq214]
Gabellini, D., Green, M. R., Tupler, R. Inappropriate gene activation in FSHD: a repressor complex binds a chromosomal repeat deleted in dystrophic muscle. Cell 110: 339-348, 2002. [PubMed: 12176321] [Full Text: https://doi.org/10.1016/s0092-8674(02)00826-7]
Graham, B. H., Waymire, K. G., Cottrell, B., Trounce, I. A., MacGregor, G. R., Wallace, D. C. A mouse model for mitochondrial myopathy and cardiomyopathy resulting from a deficiency in the heart/muscle isoform of the adenine nucleotide translocator. Nature Genet. 16: 226-234, 1997. [PubMed: 9207786] [Full Text: https://doi.org/10.1038/ng0797-226]
Halestrap, A. P. Mitochondrial permeability: dual role for the ADP/ATP translocator? Comment on 'The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore'. Nature 430: 984 only, 2004.
Haraguchi, Y., Chung, A. B., Torroni, A., Stepien, G., Shoffner, J. M., Wasmuth, J. J., Costigan, D. A., Polak, M., Altherr, M. R., Winokur, S. T., Wallace, D. C. Genetic mapping of human heart-skeletal muscle adenine nucleotide translocator and its relationship to the facioscapulohumeral muscular dystrophy locus. Genomics 16: 479-485, 1993. [PubMed: 8100217] [Full Text: https://doi.org/10.1006/geno.1993.1214]
Hoshino, A., Wang, W. J., Wada, S., McDermott-Roe, C., Evans, C. S., Gosis, B., Morley, M. P., Rathi, K. S., Li, J., Li, K., Yang, S., McManus, M. J., Bowman, C., Potluri, P., Levin, M., Damrauer, S., Wallace, D. C., Holzbaur, E. L. F., Arany, Z. The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature 575: 375-379, 2019. [PubMed: 31618756] [Full Text: https://doi.org/10.1038/s41586-019-1667-4]
Houldsworth, J., Attardi, G. Two distinct genes for ADP/ATP translocase are expressed at the mRNA level in adult human liver. Proc. Nat. Acad. Sci. 85: 377-381, 1988. [PubMed: 2829183] [Full Text: https://doi.org/10.1073/pnas.85.2.377]
Kaukonen, J. A., Amati, P., Suomalainen, A., Rotig, A., Piscaglia, M.-G., Salvi, F., Weissenbach, J., Fratta, G., Comi, G., Peltonen, L., Zeviani, M. An autosomal locus predisposing to multiple deletions of mtDNA on chromosome 3p. Am. J. Hum. Genet. 58: 763-769, 1996. [PubMed: 8644740]
Kaukonen, J., Juselius, J. K., Tiranti, V., Kyttala, A., Zeviani, M., Comi, G. P., Keranen, J., Peltonen, L., Suomalainen, A. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289: 782-785, 2000. [PubMed: 10926541] [Full Text: https://doi.org/10.1126/science.289.5480.782]
Kaukonen, J., Zeviani, M., Comi, G. P., Piscaglia, M.-G., Peltonen, L., Suomalainen, A. A third locus predisposing to multiple deletions of mtDNA in autosomal dominant progressive external ophthalmoplegia. (Letter) Am. J. Hum. Genet. 65: 256-261, 1999. [PubMed: 10364542] [Full Text: https://doi.org/10.1086/302445]
Kokoszka, J. E., Waymire, K. G., Levy, S. E., Sligh, J. E., Cai, J., Jones, D. P., MacGregor, G. R., Wallace, D. C. The ADP/ATP translocator is not essential for the mitochondrial permeability transition pore. Nature 427: 461-465, 2004. [PubMed: 14749836] [Full Text: https://doi.org/10.1038/nature02229]
Komaki, H., Fukazawa, T., Houzen, H., Yoshida, K., Nonaka, I., Goto, Y. A novel D104G mutation in the adenine nucleotide translocator 1 gene in autosomal dominant progressive external ophthalmoplegia patients with mitochondrial DNA with multiple deletions. Ann. Neurol. 51: 645-648, 2002. [PubMed: 12112115] [Full Text: https://doi.org/10.1002/ana.10172]
Korver-Keularts, I. M. L. W., de Visser, M., Bakker, H. D., Wanders, R. J. A., Vansenne, F., Scholte, H. R., Dorland, L., Nicolaes, G. A. F., Spaapen, L. M. J., Smeets, H. J. M., Hendrickx, A. T. M., van den Bosch, B. J. C. Two novel mutations in the SLC25A4 gene in a patient with mitochondrial myopathy. JIMD Rep. 22: 39-45, 2015. [PubMed: 25732997] [Full Text: https://doi.org/10.1007/8904_2015_409]
Li, K., Warner, C. K., Hodge, J. A., Minoshima, S., Kudoh, J., Fukuyama, R., Maekawa, M., Shimizu, Y., Shimizu, N., Wallace, D. C. A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed. J. Biol. Chem. 264: 13998-14004, 1989. [PubMed: 2547778]
Li, K., Warner, C. K., Hodge, J. A., Wallace, D. C. Cloning and tissue-differential expression of human heart-skeletal muscle adenine nucleotide translocator gene. (Abstract) Cytogenet. Cell Genet. 51: 1032-1033, 1989.
Mills, K. A., Ellison, J. W., Mathews, K. D. The Ant1 gene maps near Klk3 on proximal mouse chromosome 8. Mammalian Genome 7: 707 only, 1996. [PubMed: 8703133] [Full Text: https://doi.org/10.1007/s003359900296]
Minoshima, S., Kudoh, J., Fukuyama, R., Maekawa, M., Shimizu, Y., Li, K., Wallace, D. C., Shimizu, N. Mapping of the human muscle adenine nucleotide translocator gene (ANT1) to chromosome 4. (Abstract) Cytogenet. Cell Genet. 51: 1044-1045, 1989.
Napoli, L., Bordoni, A., Zeviani, M., Hadjigeorgiou, G. M., Sciacco, M., Tiranti, V., Terentiou, A., Moggio, M., Papadimitriou, A., Scarlato, G., Comi, G. P. A novel missense adenine nucleotide translocator-1 gene mutation in a Greek adPEO family. Neurology 57: 2295-2298, 2001. [PubMed: 11756613] [Full Text: https://doi.org/10.1212/wnl.57.12.2295]
Neckelmann, N., Li, K., Wade, R. P., Shuster, R., Wallace, D. C. cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc. Nat. Acad. Sci. 84: 7580-7584, 1987. [PubMed: 2823266] [Full Text: https://doi.org/10.1073/pnas.84.21.7580]
Palmieri, L., Alberio, S., Pisano, I., Lodi, T., Meznaric-Petrusa, M., Zidar, J., Santoro, A., Scarcia, P., Fontanesi, F., Lamantea, E., Ferrero, I., Zeviani, M. Complete loss-of-function of the heart/muscle-specific adenine nucleotide translocator is associated with mitochondrial myopathy and cardiomyopathy. Hum. Molec. Genet. 14: 3079-3088, 2005. [PubMed: 16155110] [Full Text: https://doi.org/10.1093/hmg/ddi341]
Pebay-Peyroula, E., Dahout-Gonzalez, C., Kahn, R., Trezeguet, V., Lauquin, G. J.-M., Brandolin, G. Structure of mitochondrial ADP/ATP carrier in complex with carboxyatractyloside. Nature 426: 39-44, 2003. [PubMed: 14603310] [Full Text: https://doi.org/10.1038/nature02056]
Thompson, K., Majd, H., Dallabona, C., Reinson, K., King, M. S., Alston, C. L., He, L., Lodi, T., Jones, S. A., Fattal-Valevski, A., Fraenkel, N. D., Saada, A., and 16 others. Recurrent de novo dominant mutations in SLC25A4 cause severe early-onset mitochondrial disease and loss of mitochondrial DNA copy number. Am. J. Hum. Genet. 99: 860-876, 2016. Note: Erratum: Am. J. Hum. Genet. 99: 1405 only, 2016. [PubMed: 27693233] [Full Text: https://doi.org/10.1016/j.ajhg.2016.08.014]
Wijmenga, C., Winokur, S. T., Padberg, G. W., Skraastad, M. I., Altherr, M. R., Wasmuth, J. J., Murray, J. C., Hofker, M. H., Frants, R. R. The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus. Hum. Genet. 92: 198-203, 1993. [PubMed: 8103757] [Full Text: https://doi.org/10.1007/BF00219692]