Alternative titles; symbols
HGNC Approved Gene Symbol: SLC52A2
Cytogenetic location: 8q24.3 Genomic coordinates (GRCh38) : 8:144,358,552-144,361,272 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q24.3 | Brown-Vialetto-Van Laere syndrome 2 | 614707 | Autosomal recessive | 3 |
SLC52A2 (RFT3, RFVT2) is a transmembrane protein that mediates cellular uptake of riboflavin. 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 (summary by Yao et al., 2010).
GPCR41 and GPCR42 (607883) act as receptors for porcine endogenous retrovirus subgroup A (PERV-A). Ericsson et al. (2003) identified a HeLa cell cDNA encoding GPCR41, which they designated PAR1, based on its ability to confer PERV-A infectivity in a resistant rabbit cell line. They obtained the full-length clone by rescreening the HeLa cell cDNA library. The deduced 445-amino acid protein is a putative G protein-coupled receptor and contains 10 or 11 putative transmembrane regions similar to other gammaretrovirus receptors. PAR1 shares significant homology with PAR2 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.
By searching a human database for sequences similar to RFT1 (SLC52A1; 607883), followed by RT-PCR of human small intestine total RNA, Yao et al. (2010) cloned SLC52A2, which they called RFT3. The deduced 445-amino acid protein has 10 putative transmembrane domains and shares 86.7% and 44.1% identity with RFT1 and RFT2 (SLC52A3; 613350), respectively. Real-time PCR detected variable RFT3 expression in all tissues examined, with highest expression in adult and fetal whole brain, followed by salivary gland. Fluorescence-tagged RFT3 was expressed in the plasma membrane of transfected HEK293 cells.
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, and RFT3 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.
Ericsson et al. (2003) determined that the PAR1 gene contains at least 3 exons.
By genomic sequence analysis, Ericsson et al. (2003) mapped the PAR1 gene to chromosome 8.
Hartz (2012) mapped the SLC52A2 gene to chromosome 8q24.3 based on an alignment of the SLC52A2 sequence (GenBank AK021918) with the genomic sequence (GRCh37).
In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707), Johnson et al. (2012) identified a homozygous mutation in the SLC52A2 gene (G306R; 607882.0001). A Scottish girl with the disorder was also found to be homozygous for the G306R mutation; she was the only child from a cohort of 44 patients with childhood motor neuron disease who carried an SLC52A2 mutation, suggesting that such defects are rare. The phenotype was characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting resulting in respiratory insufficiency and loss of independent ambulation.
In a girl with BVVLS2, Haack et al. (2012) identified compound heterozygous mutations in the SLC52A2 gene (607882.0002 and 607882.0003).
In a boy with severe early-onset BVVLS2 resulting in death at age 3, Ciccolella et al. (2013) identified compound heterozygous mutations in the SLC52A2 gene (607882.0004-607882.0005). Each of the unaffected parents was heterozygous for 1 of the mutations. Patient cells showed significantly decreased riboflavin transport (about 29%) compared to controls.
By Sanger sequencing of the SLC52A2 gene in 78 patients of various origins with a phenotype of cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency from 21 medical centers Foley et al. (2014) identified 8 different biallelic mutations (see, e.g., 607882.0001; 607882.0003; 607882.0006-607882.0007) in 13 probands (including the Scottish patient previously reported by Johnson et al., 2012) and 5 affected family members. The most common mutation was G306R, which was found in homozygous state in 3 Lebanese families and in compound heterozygous state in 2 families and 3 singleton patients. In vitro functional expression studies showed that the mutations caused reduced or absent riboflavin uptake and reduced riboflavin transporter protein expression.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human SLC52A2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Meehan et al. (2017) reported that knockout of Slc52a2 in mice caused increased or absent threshold for auditory brainstem response.
In affected members of a large consanguineous Lebanese family with severe Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707) originally reported by Megarbane et al. (2000), Johnson et al. (2012) identified a homozygous 916G-A transition in exon 3 of the SLC52A2 gene, resulting in a gly306-to-arg (G306R) substitution at a highly conserved residue. The mutation was identified by autozygosity mapping followed by exome sequencing, and was not found in 1,400 control chromosomes. A Scottish girl with the disorder was also found to be homozygous for the G306R mutation; she was the only child from a cohort of 44 patients with childhood motor neuron disease who carried an SLC52A2 mutation, suggesting that such defects are rare.
Foley et al. (2014) found that the G306R mutation was the most common mutation in their series of 13 probands with BVVLS2. Three families of Lebanese origin carried G306R in the homozygous state, suggesting a founder effect, whereas affected members of 2 additional families and 3 singleton patients carried it in compound heterozygosity with another pathogenic SLC52A2 mutation (see, e.g., L339P, 607882.0003; A284D, 607882.0006; and Y305C, 607882.0007). In vitro cellular expression studies showed that the G306R mutation caused a moderate but significant reduction in riboflavin uptake and a decrease in SLC52A2 protein expression.
In a girl with Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707), Haack et al. (2012) identified compound heterozygous mutations in the SLC52A2 gene: a 368T-C transition resulting in a leu123-to-pro (L123P) substitution, and a 1016T-C transition resulting in a leu339-to-pro (L339P; 607882.0003) substitution. Both mutations occurred at highly conserved residues. The mutations were found by exome sequencing and confirmed by Sanger sequencing. The 368T-C transition was absent from public SNP databases, but 1016T-C was found 3 times in the heterozygous state in 5,375 control exomes. Each unaffected parent was heterozygous for 1 of the mutations. Transfection of the mutations in HEK293 cells showed that both caused a significant decrease in SLC52A2 transporter activity compared to wildtype. At age 3 years, the patient presented with hearing impairment, progressive optic atrophy, and severe ataxia. Laboratory studies showed increased levels of several acylcarnitine and hydroxy-acylcarnitine species. Oral riboflavin supplementation resulted in improved fine motor skills and assisted gait and normalization of laboratory values.
For discussion of the leu339-to-pro (L339P) mutation in the SLC52A2 gene that was found in compound heterozygous state in a patient with Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707) by Haack et al. (2012), see 607882.0002.
Foley et al. (2014) found the L339P mutation in compound heterozygosity with a G306R mutation (607882.0001). In vitro cellular expression studies by Foley et al. (2014) indicated that the L339P mutation completely abolished riboflavin uptake and caused a decrease in SLC52A2 protein expression.
This variant is also referred to as c.968T-C, resulting in a leu323-to-pro substitution, based on a different SLC52A2 sequence (c.968T-C, NM_024531.4) (Gorcenco et al., 2019).
In a 3-year-old boy with severe, early-onset fatal Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707), Ciccolella et al. (2013) identified compound heterozygosity for 2 mutations in the SLC52A2 gene: a 155C-T transition, resulting in a ser52-to-phe (S52F) substitution, and a 1255G-A transition resulting in a gly419-to-ser (G419S) (607882.0005) substitution. Both mutations occurred at highly conserved residues. Each unaffected parent was heterozygous for 1 of the mutations, and neither mutation was found in 200 control chromosomes or in 10,000 control exomes. Patient cells showed significantly decreased RFT3 mRNA (45%), lack of RFT3 protein, and decreased riboflavin transport (29%) compared to controls. Patient cells also showed no detectable RFT1 protein (SLC52A1; 607883). Fibroblasts from the father, who carried the S52F mutation, showed decreased RFT3 mRNA levels, at about 48% of controls, whereas mRNA levels in the mother were normal.
For discussion of the gly419-to-ser (G419S) mutation in the SLC52A2 gene that was found in compound heterozygous state in a patient with Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707) by Ciccolella et al. (2013), see 607882.0004.
In 2 sibs with Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707), Foley et al. (2014) identified compound heterozygous mutations in the SLC52A2 gene: a c.851C-A transversion resulting in an ala284-to-asp (A284D) substitution, and G306R (607882.0001). In vitro cellular expression studies indicated that the A284D mutation completely abolished riboflavin uptake and caused a decrease in SLC52A2 protein expression.
In an Irish infant with Brown-Vialetto-Van Laere syndrome-2 (BVVLS2; 614707), Foley et al. (2014) identified compound heterozygous mutations in the SLC52A2 gene: a c.914A-G transition, resulting in a tyr305-to-cys (Y305C) substitution, and G306R (607882.0001). In vitro cellular expression studies indicated that the Y305C mutation completely abolished riboflavin uptake and caused a decrease in SLC52A2 protein expression.
Ciccolella, M., Corti, S., Catteruccia, M., Petrini, S., Tozzi, F., Rizza, T., Carrozzo, R., Nizzardo, M., Bordoni, A., Ronchi, D., D'Amico, A., Rizzo, C., Comi, G. P., Bertini, E. Riboflavin transporter 3 involvement in infantile Brown-Vialetto-Van Laere disease: two novel mutations. J. Med. Genet. 50: 104-107, 2013. [PubMed: 23243084] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101204]
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
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]
Foley, A. R., Menezes, M. P., Pandraud, A., Gonzalez, M. A., Al-Odaib, A., Abrams, A. J., Sugano, K., Yonezawa, A., Manzur, A. Y., Burns, J., Hughes, I., McCullagh, B. G., and 42 others. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 137: 44-56, 2014. [PubMed: 24253200] [Full Text: https://doi.org/10.1093/brain/awt315]
Gorcenco, S., Vaz, F. M., Tracewska-Siemiatkowska, A., Tranebjaerg, L., Cremers, F. P. M., Ygland, E., Kicsi, J., Rendtorff, N. D. Moller, C., Kjellstrom, U., Andreasson, S., Puschmann, A. Oral therapy for riboflavin transporter deficiency--what is the regimen of choice? Parkinsonism Relat. Disord. 61: 245-247, 2019. [PubMed: 30343981] [Full Text: https://doi.org/10.1016/j.parkreldis.2018.10.017]
Haack, T. B., Makowski, C., Yao, Y., Graf, E., Hempel, M., Wieland, T., Tauer, U., Ahting, U., Mayr, J. A., Freisinger, P., Yoshimatsu, H., Inui, K., Strom, T. M., Meitinger, T., Yonezawa, A., Prokisch, H. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J. Inherit. Metab. Dis. 35: 943-948, 2012. [PubMed: 22864630] [Full Text: https://doi.org/10.1007/s10545-012-9513-y]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/11/2012.
Johnson, J. O., Gibbs, J. R., Megarbane, A., Urtizberea, J. A., Hernandez, D. G., Foley, A. R., Arepalli, S., Pandraud, A., Simon-Sanchez, J., Clayton, P., Reilly, M. M., Muntoni, F., Abramzon, Y., Houlden, H., Singleton, A. B. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 135: 2875-2882, 2012. [PubMed: 22740598] [Full Text: https://doi.org/10.1093/brain/aws161]
Meehan, T. F., Conte, N., West, D. B., Jacobsen, J. O., Mason, J., Warren, J., Chen, C.-K., Tudose, I., Relac, M., Matthews, P., Karp, N., Santos, L., and 52 others. Disease model discovery from 3,328 gene knockouts by the International Mouse Phenotyping Consortium. Nature Genet. 49: 1231-1238, 2017. [PubMed: 28650483] [Full Text: https://doi.org/10.1038/ng.3901]
Megarbane, A., Desguerres, I., Rizkallah, E., Delague, V., Nabbout, R., Barois, A., Urtizberea, A. Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance? Am. J. Med. Genet. 92: 117-121, 2000. [PubMed: 10797435] [Full Text: https://doi.org/10.1002/(sici)1096-8628(20000515)92:2<117::aid-ajmg7>3.0.co;2-c]
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]