Alternative titles; symbols
HGNC Approved Gene Symbol: SLC52A3
SNOMEDCT: 230246005; ICD10CM: G12.1;
Cytogenetic location: 20p13 Genomic coordinates (GRCh38) : 20:760,080-780,033 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20p13 | ?Fazio-Londe disease | 211500 | Autosomal recessive | 3 |
| Brown-Vialetto-Van Laere syndrome 1 | 211530 | Autosomal recessive | 3 |
SLC52A3 (RFT2, RFVT3) 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).
By searching a database for orthologs of rat Rft2, followed by RT-PCR of small intestine total RNA, Yamamoto et al. (2009) cloned human RFT2. The deduced 469-amino acid protein shares 83% similarity with rat Rft2, which contains 11 potential membrane-spanning domains and a putative N-glycosylation site. Northern blot analysis of rat tissues showed highest Rft2 expression in jejunum, ileum, and testis, with lower expression in lung, kidney, stomach, and colon. RT-PCR analysis revealed Rft2 expression in all rat tissues examined.
Using real-time PCR, Yao et al. (2010) detected very high RFT2 expression in testis. High expression was also detected in small intestine and prostate, and much lower expression was detected in most other tissues examined. Fluorescence-tagged RFT2 was expressed in the plasma membrane of transfected HEK293 cells.
Hartz (2010) mapped the C20ORF54 gene to chromosome 20p13 based on an alignment of the C20ORF54 sequence (GenBank BC009750) with the genomic sequence (GRCh37).
Yamamoto et al. (2009) showed that rat and human RFT2 mediated riboflavin uptake following transfection in human embryonic kidney cells. Biochemical characterization revealed that riboflavin uptake by rat Rft2 was saturable and Na(+) independent, with a pH optimum between 5 and 6. Riboflavin appeared to be the primary molecule transported by Rft2. Riboflavin transport could be competitively inhibited by the riboflavin derivatives lumiflavin, flavin mononucleotide, and flavin adenine dinucleotide, and to a lesser extent by alloxazine and the organic cation amiloride, but not by D-ribose or organic anions. Yamamoto et al. (2009) concluded that RFT2-mediated riboflavin transport is likely electroneutral facilitated diffusion.
Using transfected HEK293 cells, Yao et al. (2010) showed that RFT1 (607883), RFT2, 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.
Brown-Vialetto-Van Laere Syndrome 1
By autozygosity mapping followed by candidate gene analysis of a consanguineous Pakistani family with Brown-Vialetto-Van Laere syndrome-1 (BVVLS1; 211530), Green et al. (2010) identified a homozygous mutation in the C20ORF54 gene (613350.0001). Analysis of other families with the disorder identified 7 additional homozygous or compound heterozygous C20ORF54 mutations (see, e.g., 613350.0002-613350.0006). Five of 9 patients had onset in the first decade of bulbar palsy, muscle weakness, and respiratory insufficiency, and leading to early death. Others had later onset, more usually associated with sensorineural hearing loss. Green et al. (2010) noted that the C20ORF54 gene is thought to play a role in riboflavin transport. Riboflavin is essential for synthesis of the cofactors flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are involved in energy metabolism. It is plausible that the C20ORF54 protein has a maintenance function in the nervous system, and that the disease is precipitated by defect in a pathway tightly regulated by this protein.
In 3 affected members of a consanguineous Turkish family with Brown-Vialetto-Van Laere syndrome, Johnson et al. (2010) identified a homozygous mutation in the C20ORF54 gene (P28T; 613350.0007). The authors used an exome sequencing technique to identify the candidate gene.
Bosch et al. (2011) identified compound heterozygous mutations in the C20ORF54 gene (see 613350.0009) responsible for Brown-Vialetto-Van Laere syndrome.
Fazio-Londe Disease
Bosch et al. (2011) identified a homozygous mutation in the C20ORF54 gene (613350.0008) in 2 sibs from a consanguineous family with Fazio-Londe disease (211500).
Associations Pending Confirmation
For discussion of a possible association between variation in the C20ORF54 gene and susceptibility to esophageal squamous cell carcinoma and gastric cardia adenocarcinoma, see 133239.
Intoh et al. (2016) showed that a homozygous Slc52A3 knockout in mouse resulted in embryonic lethality during mid-gestation at about day 10.5, which was apparently due to failure of placental development. Intoh et al. (2016) concluded that Slc52a3 functions during early development. Quantitative RT-PCR detected highest expression of Slc52a3 in adult intestine, testis, and placenta. It was expressed in the intestinal villus, suggesting that SLC52A3 may play a role in the absorption of riboflavin from the diet. The authors suggested the possibility of riboflavin replacement therapy.
In 2 Arab patients, born in a consanguineous family, with Brown-Vialetto-Van Laere syndrome-1 (BVVLS1; 211530), Green et al. (2010) identified a homozygous 2-bp deletion (1325delTG) in exon 5 of the C20ORF54 gene, resulting in a frameshift and a mutant protein 35 amino acids longer than the wildtype protein. The mutation was not found in 210 control chromosomes. The patients had onset at age 13 and 6 months, respectively, of hypotonia and bulbar palsy with respiratory compromise. One showed anterior horn involvement and deafness.
In a female patient of European ancestry with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Green et al. (2010) identified a homozygous 211G-T transversion in exon 2 of the C20ORF54 gene, resulting in a glu71-to-ter (E71X) substitution. The mutation was not found in 210 control chromosomes. She had onset at age 16 months of a progressive bulbar palsy and developed an anterior horn neuropathy, leading to death before age 3 years.
In 2 Pakistani sisters, born of consanguineous parents, with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Green et al. (2010) identified a homozygous 394C-T transition in exon 2 of the C20ORF54 gene, resulting in an arg132-to-trp (R132W) substitution. The mutation was not found in 210 control chromosomes. Both sisters presented at age 12 years with deafness, 1 also with tongue wasting and fasciculations, and both later developed respiratory insufficiency with stridor and muscle weakness. They both had a slowly progressive course and were alive in their late twenties and thirties, respectively.
In a Pakistani girl with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530) previously reported by Dipti et al. (2005), Green et al. (2010) identified a homozygous 670T-C transition in exon 3 of the C20ORF54 gene, resulting in a phe224-to-leu (F224L) substitution. The mutation was not found in 210 control chromosomes. She presented at age 5 years with tongue fasciculations and facial palsy, and later developed progressive muscle weakness and respiratory compromise followed by death at age 14 years.
In a European man with a relatively mild form of Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Green et al. (2010) identified compound heterozygosity for 2 missense mutations in the C20ORF54 gene: a 106G-A transition in exon 2, resulting in a glu36-to-lys (E36K) substitution, and a 1237T-C transition in exon 5, resulting in a val413-to-ala (V413A; 613350.0006) substitution. Neither mutation was found in 210 control chromosomes. He developed the condition in his early twenties, presenting with a peripheral neuropathy. He later developed hearing loss, but did not have respiratory compromise. He was still alive at age 57 with progressive weakness, muscle wasting, and truncal ataxia. Green et al. (2010) noted the mild phenotype in this patient.
For discussion of the val413-to-ala (V413A) mutation in the SLC52A3 gene that was found in compound heterozygous state in a patient with a mild form of Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530) by Green et al. (2010), see 613350.0005.
In 3 affected members of a consanguineous Turkish family with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Johnson et al. (2010) identified a homozygous 82C-A transversion in the C20ORF54 gene, resulting in a pro28-to-thr (P28T) substitution.
In 2 sibs with Fazio-Londe disease (211500) from a consanguineous union, Bosch et al. (2011) identified homozygosity for a splice site mutation, 1198-2A-C, in the C20ORF54 gene. Both parents were heterozygous.
In a patient with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Bosch et al. (2011) identified compound heterozygosity for mutations in the C20ORF54 gene, a T-to-C transition at nucleotide 49 resulting in a tryptophan-to-arginine substitution at codon 17 (W17R) and a nonsense mutation (Y213X; 613350.0010). The tryptophan at codon 17 is highly conserved in orthologs of different species. Feeding problems and slow motor development had been present since birth. At age 5 months the patient had generalized muscle weakness and respiratory insufficiency necessitating artificial ventilation due to diaphragmatic paralysis. Severe sensorineural hearing loss was detected.
In a patient with Brown-Vialetto-Van Laere syndrome (BVVLS1; 211530), Bosch et al. (2011) identified compound heterozygosity for a C-to-G transversion at nucleotide 639 of the C20ORF54 gene, resulting in a tyrosine-to-termination substitution at codon 213 (Y213X), and a missense mutation (W17R; 613350.0009). The nonsense mutation had been identified by Green et al. (2010).
Bosch, A. M., Abeling, N. G. G. M., IJlst, L., Knoester, H., van der Pol., W. L., Stroomer, A. E. M., Wanders, R. J., Visser, G., Wijburg, F. A., Duran, M., Waterham, H. R. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment. J. Inherit. Metab. Dis. 34: 159-164, 2011. [PubMed: 21110228] [Full Text: https://doi.org/10.1007/s10545-010-9242-z]
Dipti, S., Childs, A. M., Livingston, J. H., Aggarwal, A. K., Miller, M, Williams, C., Crow, Y. J. Brown-Vialetto-Van Laere syndrome; variability in age at onset and disease progression highlighting the phenotypic overlap with Fazio-Londe disease. Brain Dev. 27: 443-446, 2005. [PubMed: 16122634] [Full Text: https://doi.org/10.1016/j.braindev.2004.10.003]
Green, P., Wiseman, M., Crow, Y. J., Houlden, H., Riphagen, S., Lin, J.-P., Raymond, F. L., Childs, A.-M., Sheridan, E., Edwards, S., Josifova, D. J. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in C20ORF54. Am. J. Hum. Genet. 86: 485-489, 2010. [PubMed: 20206331] [Full Text: https://doi.org/10.1016/j.ajhg.2010.02.006]
Hartz, P. A. Personal Communication. Baltimore, Md. 4/9/2010.
Intoh, A., Suzuki, N., Koszka, K., Eggan, K. SLC52A3, a Brown-Vialetto-van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation. Hum. Molec. Genet. 25: 1814-1823, 2016. [PubMed: 26976849] [Full Text: https://doi.org/10.1093/hmg/ddw053]
Johnson, J. O., Gibbs, J. R., Van Maldergem, L., Houlden, H., Singleton, A. B. Exome sequencing in Brown-Vialetto-van Laere syndrome. (Letter) Am. J. Hum. Genet. 87: 567-569, 2010. [PubMed: 20920669] [Full Text: https://doi.org/10.1016/j.ajhg.2010.05.021]
Yamamoto, S., Inoue, K., Ohta, K., Fukatsu, R., Maeda, J., Yoshida, Y., Yuasa, H. Identification and functional characterization of rat riboflavin transporter 2. J. Biochem. 145: 437-443, 2009. [PubMed: 19122205] [Full Text: https://doi.org/10.1093/jb/mvn181]
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]