Alternative titles; symbols
HGNC Approved Gene Symbol: SLC52A1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:5,032,602-5,042,414 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Riboflavin deficiency | 615026 | Autosomal dominant | 3 |
GPCR41 (607882) and GPCR42 act as receptors for porcine endogenous retrovirus subgroup A (PERV-A).
The water-soluble vitamin riboflavin is converted to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), and is essential for normal cellular functions. SLC52A1, or RFT1, is a transmembrane protein that mediates cellular uptake of riboflavin (summary by Yao et al., 2010).
By database screening for homologs of GPCR41, Ericsson et al. (2003) identified GPCR42, which they designated PAR2. They cloned full-length PAR2 from a 293-cell cDNA library. The deduced 448-amino acid protein is a putative G protein-coupled receptor and contains 10 or 11 putative transmembrane regions similar to other gammaretrovirus receptors. PAR2 shares significant homology with PAR1 and with PAR proteins from baboon, pig, and mouse. Northern blot analysis using a probe that did not differentiate between PAR1 and PAR2 detected expression in all tissues examined, with the possible exception of bladder. Highest expression was in testis. RT-PCR detected PAR1 and PAR2 expression in peripheral blood mononuclear cells of 11 healthy volunteers. Confocal microscopy detected expression of fluorescence-tagged PAR2 at the plasma membrane and in the perinuclear region of transfected rabbit corneal fibroblasts.
Using real-time PCR, Yao et al. (2010) detected highly specific RFT1 expression in placenta. Much lower expression was detected in small intestine, thymus, and trachea, with little to none in other tissues examined. Fluorescence-tagged RFT1 was expressed in the plasma membrane of transfected HEK293 cells.
By genomic sequence analysis, Ericsson et al. (2003) mapped the GPR172B gene to chromosome 17.
Hartz (2012) mapped the SLC52A1 gene to chromosome 17p13.2 based on an alignment of the SLC52A1 sequence (GenBank AK000922) with the genomic sequence (GRCh37).
Ericsson et al. (2003) determined that expression of PAR1 or PAR2 in transfected rabbit corneal fibroblasts and mouse NIH 3T3 fibroblasts mediated both the entry and the productive replication of PERV-A. Expression of PAR1 and PAR2 did not alter the sensitivity of the rabbit cells to PERV-B or -C. The results suggested that PAR2 may mediate a higher level of PERV infection than PAR1. Ericsson et al. (2003) noted that the presence of these PERV-A receptors highlights a risk faced by xenotransplant recipients.
Using transfected HEK293 cells, Yao et al. (2010) showed that RFT1, RFT2 (SLC52A3; 613350), and RFT3 (SLC52A2; 607882) mediated uptake of radiolabeled riboflavin in a time- and concentration-dependent manner. All 3 transporters also mediated riboflavin uptake independent of extracellular Na+ and Cl-. RFT2, but not RFT1 or RFT3, showed reduced riboflavin uptake when extracellular pH was increased from 5.4 to 8.4. For all 3, radiolabeled riboflavin transport was completely inhibited by excess unlabeled riboflavin and lumiflavine, and modestly inhibited by FMN. FAD slightly but significantly inhibited RFT3-mediated riboflavin uptake. Little to no effect was observed with other riboflavin analogs, D-ribose, organic ions, or other vitamins.
In a woman with riboflavin deficiency (RBFVD; 615026) who had an infant with transient neonatal riboflavin deficiency (Chiong et al., 2007), Ho et al. (2011) identified a de novo heterozygous 1.9-kb deletion within the SLC52A1 gene (607883.0001), predicted to result in haploinsufficiency. The infant did not carry the deletion. These findings confirmed that the transient clinical and metabolic abnormalities in the infant were the result of maternal riboflavin deficiency.
In a child with transient neonatal riboflavin deficiency, Mosegaard et al. (2017) identified heterozygosity for an intronic mutation in the SLC52A1 gene (607883.0002). Her mother, who was also heterozygous for the mutation, had experienced hyperemesis gravidarum and lost 20 kg during the pregnancy and had a low-normal riboflavin level (307 nmol/l; normal, 300-509 nmol/l). The father was not available for study.
In a woman with riboflavin deficiency (RBFVD; 615026), Ho et al. (2011) identified a de novo heterozygous 1.9-kb deletion in the SLC52A1 gene, resulting in the deletion of exons 2 and 3 and predicted to cause haploinsufficiency. The woman was clinically asymptomatic, but showed biochemical evidence of riboflavin deficiency, manifest as increased serum acylcarnitines. She was originally ascertained (Chiong et al., 2007) after her newborn daughter presented soon after birth with poor suck, hypoglycemia, and metabolic acidosis. The child had dicarboxylic aciduria and elevated plasma acylcarnitine levels, initially thought to be consistent with multiple acyl-CoA dehydrogenase deficiency (MADD; 231680). Treatment with oral riboflavin resulted in complete resolution of the clinical and biochemical findings. The findings were consistent with transient neonatal riboflavin deficiency secondary to maternal riboflavin deficiency that was exacerbated during pregnancy. The infant did not carry the deletion.
Mosegaard et al. (2017) reported a child with transient neonatal riboflavin deficiency (RBFVD; 615026) who had an acylcarnitine profile consistent with multiple acyl-CoA carboxylase deficiency (MADD; 231680). After excluding mutations in known genes associated with MADD, the authors identified heterozygosity for an intronic mutation (c.234+11G-A, NM_071986.3) in the SLC52A1 gene. The patient's mother, who was also heterozygous for the mutation, had experienced hyperemesis gravidarum and lost 20 kg during the pregnancy and had a low-normal riboflavin level (307 nmol/l; normal, 300-509 nmol/l). The father was not available for study. Mosegaard et al. (2017) demonstrated that the splicing factor HNRNPA1 (164017) binds the mutated sequence to a much higher degree than the wildtype sequence. Functional studies in HeLa and HEK293 cells showed that the variant and HNRNPA1 binding increased skipping of exon 4. The variant had a minor allele frequency of 0.2% in the ExAC database.
Chiong, M. A., Sim, K. G., Carpenter, K., Rhead, W., Ho, G., Olsen, R. K., Christodoulou, J. Transient multiple acyl-CoA dehydrogenation deficiency in a newborn female caused by maternal riboflavin deficiency. Molec. Genet. Metab. 92: 109-114, 2007. [PubMed: 17689999] [Full Text: https://doi.org/10.1016/j.ymgme.2007.06.017]
Ericsson, T. A., Takeuchi, Y., Templin, C., Quinn, G., Farhadian, S. F., Wood, J. C., Oldmixon, B. A., Suling, K. M., Ishii, J. K., Kitagawa, Y., Miyazawa, T., Salomon, D. R., Weiss, R. A., Patience, C. Identification of receptors for pig endogenous retrovirus. Proc. Nat. Acad. Sci. 100: 6759-6764, 2003. [PubMed: 12740431] [Full Text: https://doi.org/10.1073/pnas.1138025100]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/11/2012.
Ho, G., Yonezawa, A., Masuda, S., Inui, K., Sim, K. G., Carpenter, K., Olsen, R. K. J., Mitchell, J. J., Rhead, W. J., Peters, G., Christodoulou, J. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B. Hum. Mutat. 32: E1976-E1984, 2011. Note: Electronic Article. [PubMed: 21089064] [Full Text: https://doi.org/10.1002/humu.21399]
Mosegaard, S., Bruun, G. H,, Flyvbjerg, K. F., Bliksrud, Y. T., Gregersen, N., Dembic, M., Annexstad, E., Tangeraas, T., Olsen, R. K. J., Andresen, B. S. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Molec. Genet. Metab. 122: 182-188, 2017. [PubMed: 29122468] [Full Text: https://doi.org/10.1016/j.ymgme.2017.10.014]
Yao, Y., Yonezawa, A., Yoshimatsu, H., Masuda, S., Katsura, T., Inui, K. Identification and comparative functional characterization of a new human riboflavin transporter hRFT3 expressed in the brain. J. Nutr. 140: 1220-1226, 2010. [PubMed: 20463145] [Full Text: https://doi.org/10.3945/jn.110.122911]