Alternative titles; symbols
HGNC Approved Gene Symbol: SLC25A32
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:103,398,638-103,415,107 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q22.3 | ?Exercise intolerance, riboflavin-responsive | 616839 | Autosomal recessive | 3 |
Folate metabolism is distributed between the cytosolic and mitochondrial compartments. SLC25A32 is a transporter that shuttles folates from the cytoplasm into mitochondria (Titus and Moran, 2000).
GlyB Chinese hamster ovary cells are auxotrophic for glycine and have a defect in their ability to accumulate folates in mitochondria. By screening a human placenta cDNA expression library for clones that complemented glycine auxotrophy in glyB cells, followed by 5-prime RACE, Titus and Moran (2000) obtained a full-length cDNA encoding SLC3A32, which they called MFT. The deduced 315-amino acid protein has a calculated molecular mass of 35.4 kD. It has 6 transmembrane domains, 3 interspersed loops facing the mitochondrial matrix, 3 repeats of an energy transfer sequence, but no ATP-binding motif, suggesting that MFT is an ATP-independent mitochondrial transporter. MFT shares highest homology with a yeast mitochondrial flavin nucleotide transporter and human and rodent carrier proteins involved in ATP/ADP exchange in mitochondria. Northern blot analysis of a human leukemia cell line detected a 1.5-kb transcript and diffuse hybridization between 2.4 and 2.6 kb.
By searching databases for SLC25 family members, Haitina et al. (2006) identified 2 splice variants of SLC25A32.
Titus and Moran (2000) determined that the SLC25A32 gene contains at least 8 exons and spans more than 7 kb.
Jones et al. (1981) mapped the human gene complementing the hamster glycine auxotroph GLY(-)B to chromosome 8. The defect in the hamster mutant appeared to involve folate metabolism, with impaired recycling of 5,10-methylenetetrahydrofolate to tetrahydrofolate and resulting decreased rate of conversion from serine to glycine (Taylor and Hanna, 1982).
Kao et al. (1984) assigned the human GLYB complementing gene to chromosome 8q21.1-qter.
By genomic sequence analysis, Titus and Moran (2000) mapped the SLC25A32 gene to chromosome 8q21.2. Haitina et al. (2006) mapped the mouse Slc25a32 gene to chromosome 15.
Titus and Moran (2000) found that MFT complemented glycine auxotrophy and reinstated folate accumulation in mitochondria of transfected glyB cells.
In a 14-year-old girl with riboflavin-responsive exercise intolerance (RREI; 616839), Schiff et al. (2016) identified compound heterozygosity for a nonsense and a missense mutation in the SLC25A32 gene (138480.0001-138480.0002).
Kim et al. (2018) found that knockout of Slc25a32 in mice caused failure of neural tube closure, resulting in embryonic lethality. RNA-sequencing analysis of Slc25a32-knockout mice at embryonic day 9.0 (E9.0) identified multiple dysregulated genes, including genes important for folate-mediated 1C metabolism. Calcium formate supplementation rescued neural tube closure in the majority of Slc25a32-knockout embryos and allowed them to remain viable until E15.5.
In a 14-year-old girl with riboflavin-responsive exercise intolerance (RREI; 616839), Schiff et al. (2016) identified compound heterozygous mutations in the SLC25A32 gene: a c.425G-A transition, resulting in a trp142-to-ter (W142X) substitution, and a c.440G-A transition, resulting in an arg147-to-his (R147H; 138480.0002) substitution. The mutations segregated with the disorder in the family. Analysis of patient cDNA suggested that the nonsense mutation resulted in nonsense-mediated mRNA decay. Introduction of the R147H mutation into the yeast FLX1 homolog resulted in a severe growth defect that could be rescued by wildtype SLC25A32, indicating a deleterious effect of the R147H variant. The patient had a beneficial response to riboflavin supplementation, which prompted the authors to study genes involved in FAD biosynthesis or transport. Patient lymphocytes showed a defect in mitochondrial fatty acid oxidation flux, and fibroblasts showed a modest effect on FAD-dependent mitochondrial enzymes.
For discussion of the c.440G-A transition in the SLC25A32 gene, resulting in an arg147-to-his (R147H) substitution, that was found in compound heterozygous state in a patient with riboflavin-responsive exercise intolerance (RREI; 616839) by Schiff et al. (2016), see 138480.0001.
Haitina, T., Lindblom, J., Renstrom, T., Fredriksson, R. Fourteen novel human members of mitochondrial solute carrier family 25 (SLC25) widely expressed in the central nervous system. Genomics 88: 779-790, 2006. [PubMed: 16949250] [Full Text: https://doi.org/10.1016/j.ygeno.2006.06.016]
Jones, C., Patterson, D., Kao, F. T. Assignment of the gene coding for phosphoribosylglycineamide formyltransferase to human chromosome 14. Somat. Cell Genet. 7: 399-409, 1981. [PubMed: 7197058] [Full Text: https://doi.org/10.1007/BF01542985]
Kao, F. T., Zhang, X., Law, M. L., Jones, C. Regional mapping of GLYB (gly-B) to 8q21.1-qter and PGFT (phosphoribosyl glycinamide formyltransferase) to 14q22-qter. (Abstract) Cytogenet. Cell Genet. 37: 504-505, 1984.
Kim, J., Lei, Y., Guo, J., Kim, S.-E., Wlodarczyk, B. J., Cabrera, R. M., Lin, Y. L., Nilsson, T. K., Zhang, T., Ren, A., Wang, L., Yuan, Z., Zheng, Y.-F., Wang, H.-Y., Finnell, R. H. Formate rescues neural tube defects caused by mutations in Slc25a32. Proc. Nat. Acad. Sci. 115: 4690-4695, 2018. [PubMed: 29666258] [Full Text: https://doi.org/10.1073/pnas.1800138115]
Schiff, M., Veauville-Merllie, A., Acquaviva-Bourdain, C. SLC25A32 mutations and riboflavin-responsive exercise intolerance. (Letter) New Eng. J. Med. 374: 795-797, 2016. [PubMed: 26933868] [Full Text: https://doi.org/10.1056/NEJMc1513610]
Taylor, R. T., Hanna, M. L. Folate-dependent enzymes in cultured Chinese hamster ovary cells: impaired mitochondrial serine hydroxymethyltransferase activity in two additional glycine-auxotroph complementation classes. Arch. Biochem. Biophys. 217: 609-623, 1982. [PubMed: 7138028] [Full Text: https://doi.org/10.1016/0003-9861(82)90543-4]
Titus, S. A., Moran, R. G. Retrovirally mediated complementation of the glyB phenotype: cloning of a human gene encoding the carrier for entry of folates into mitochondria. J. Biol. Chem. 275: 36811-36817, 2000. [PubMed: 10978331] [Full Text: https://doi.org/10.1074/jbc.M005163200]