rs148234606 — SLC52A2 Leu339Pro

SLC52A2 Leu339Pro — When the Brain Cannot Import Vitamin B2

Inside the blood-brain barrier, a protein called RFVT2 (encoded by SLC52A2) works as the primary gate that moves riboflavin — vitamin B2 — from the bloodstream into neurons. Without it, brain and brainstem cells starve for the vitamin that powers FAD- and FMN-dependent enzymes at the core of cellular energy metabolism. The p.Leu339Pro variant is a missense mutation that abolishes riboflavin transport activity¹¹ missense mutation that abolishes riboflavin transport activity
c.1016T>C substitutes leucine with proline at position 339, disrupting the transmembrane helix architecture of RFVT2. When two loss-of-function copies are inherited — in homozygosity or compound heterozygosity with a second SLC52A2 pathogenic variant — the result is Brown-Vialetto-Van Laere syndrome type 2 (BVVLS2/RTD2), a rare but treatable childhood neuronopathy.

The Mechanism

SLC52A2 encodes riboflavin transporter 2 (RFVT2/RFT3), one of three human riboflavin transporters. RFVT2 is expressed most highly in brain, brainstem, and spinal cord²² RFVT2 is expressed most highly in brain, brainstem, and spinal cord
GTEx data confirm SLC52A2 is enriched in CNS tissues relative to peripheral tissues; SLC52A3 handles intestinal riboflavin absorption. Riboflavin is the precursor to FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide), coenzymes required by dozens of enzymes including those in the mitochondrial respiratory chain and acyl-CoA dehydrogenases. When RFVT2 is lost, cranial and spinal motor neurons are selectively deprived of these cofactors, producing a cascade of metabolic dysfunction that manifests as progressive neuronopathy. Crucially, plasma riboflavin concentrations can be normal — the transport defect is at the tissue level, not absorption — making standard blood vitamin panels uninformative for diagnosis.

The L339P substitution changes a leucine residue within a predicted transmembrane domain to proline, a helix-breaking amino acid. Functional studies in HEK293 cells confirmed complete abolition of radiolabeled riboflavin uptake and a marked decrease in RFVT2 protein expression, indicating both loss of function and protein destabilisation.

The Evidence

Haack et al. (2012)³³ Haack et al. (2012) identified p.Leu339Pro in compound heterozygosity with p.Leu123Pro in a girl who developed progressive hearing loss, optic atrophy, ataxia, and nystagmus from age 3. Within 4 weeks of starting riboflavin supplementation at 10 mg/kg/day, six of seven elevated acylcarnitine species normalised — a biochemical signature of restored FAD-dependent acyl-CoA dehydrogenase activity — accompanied by moderate motor improvement.

Foley et al. (2014)⁴⁴ Foley et al. (2014) expanded the picture to 18 patients from 13 families. Every patient had sensorineural deafness; 94% had optic atrophy; 72% needed respiratory support. Riboflavin at 10–50 mg/kg/day produced biochemical improvements in 10 of 18 patients and clinical improvements in the majority, with the best outcomes in those treated earliest. L339P appeared among the recurring pathogenic variants in this cohort.

GeneReviews (Cali et al. 2015)⁵⁵ GeneReviews (Cali et al. 2015) confirmed that untreated RTD2 has a median survival of 7.5 years, with most deaths from respiratory failure. Treatment with riboflavin is described as "possibly lifesaving" and should begin as soon as the diagnosis is suspected, even before genetic confirmation.

Practical Actions

For homozygous individuals (CC) — a genotype virtually undetectable in population databases — biallelic loss of RFVT2 is a medical emergency requiring immediate specialist evaluation, riboflavin loading, and investigation of the full phenotype. For heterozygous carriers (CT), current evidence does not demonstrate clinical symptoms; single-copy SLC52A2 function is sufficient for normal riboflavin transport. The primary clinical value of carrier status is reproductive counselling: two CT carriers face a 25% chance per pregnancy of an affected child.

Because riboflavin supplementation is safe, some practitioners recommend heterozygous carriers maintain dietary adequacy for riboflavin from animal products (liver, dairy, eggs) and consider supplementation during high-demand states (pregnancy, illness, caloric restriction). This is a conservative precaution rather than an evidence-based mandate.

Interactions

SLC52A2 and SLC52A3 (encoding intestinal riboflavin transporter RFVT3) operate in series: SLC52A3 governs gut absorption, SLC52A2 governs CNS uptake. Compound heterozygosity across both genes — one pathogenic SLC52A2 variant and one SLC52A3 variant in the same individual — has been documented and can cause BVVLS⁶⁶ Compound heterozygosity across both genes — one pathogenic SLC52A2 variant and one SLC52A3 variant in the same individual — has been documented and can cause BVVLS, though such cases are exceedingly rare. Within SLC52A2, multiple pathogenic variants have been described; compound heterozygosity (two different pathogenic alleles, one per chromosome) is the most common disease configuration. Homozygosity for a single variant is rarer and typically reflects a founder effect, most notably the p.Gly306Arg allele (rs398124641) enriched in Lebanese populations.