SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere Syndrome in an Indian patient: First genetically proven case with mutations in two riboflavin transporters

Abstract

Background Brown-Vialetto-Van Laere Syndrome (BVVLS), a rare neurological disorder characterized by bulbar palsies and sensorineural deafness, is mainly associated with defective riboflavin transporters encoded by the SLC52A2 and SLC52A3 genes. Methods Here we present a 16-year-old BVVLS patient belonging to a five generation consanguineous family from Indian ethnicity with two homozygous missense mutations viz., c.421C>A [p.P141T] in SLC52A2 and c.62A>G [p.N21S] in SLC52A3. Results Functional characterization based on 3H-riboflavin uptake assay and live-cell confocal imaging revealed that the effect of mutation c.421C>A [p.P141T] identified in SLC52A2 had a slight reduction in riboflavin uptake; on the other hand, the c.62A>G [p.N21S] identified in SLC52A3 showed a drastic reduction in riboflavin uptake, which appeared to be due to impaired trafficking and membrane targeting of the hRFVT-3 protein. Conclusions This is the first report presenting mutations in both riboflavin transporters hRFVT-2 and hRFVT-3 in the same BVVLS patient. Also, c.62A>G [p.N21S] in SLC52A3 appears to contribute more to the disease phenotype in this patient than c.421C>A [p.P141T] in SLC52A2.

An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency

“…The possibility that both heterozygous mutations within the two different riboflavin genes are synergistically disrupting the same metabolic pathway to a pathogenic level cannot be excluded, however. Finally, a patient with homozygous mutations in both SLC52A2 and SLC52A3 has also been described (RTD2/3). In total, various degrees of information are available on 109 patients (52 RTD2, 56 RTD3, and 1 RTD2/3) with 71 different SLC52A mutations (24 SLC52A2 , 47 SLC52A3 ) (Table ).…”

“…48 Using heterologous expression systems the impact of different pathogenic SLC52A2/3 mutations on RFVT2/3 function has been assessed in vitro. 11,18,31,44,57,58 In most cases the disease causing mutation reduces RFVT cell surface expression which when assessed appears to be due to retainment in the endoplasmic reticulum (ER), indicative of protein misfolding and/or trafficking defect. In some instances, riboflavin transport is impaired but with an apparently normal cell surface expression.…”

Clinical, pathological and functional characterization of riboflavin-responsive neuropathy

“…The role of another riboflavin transporter-encoding gene, SLC52A1 , in BVVL syndrome pathogenicity is still uncertain, as it was found to be defective in only one case ( Ho et al , 2011 ). SLC52A2 and SLC52A3 mutations include missense, nonsense, frame-shift, and splice-site alterations, but uniformly result in loss-of-function through reduced riboflavin transporter expression and/or riboflavin uptake ( Foley et al , 2014 ; Udhayabanu et al , 2016 ).…”

Control of metabolite efflux in microbial cell factories: current advances and future prospects

“…The other major industrial producer is B. subtilis [120], where an efflux transporter from Streptomyces davawensis has been used to improve productivity [124]. Of course, since a vitamin is by definition not synthesised therein, all human cells require [125] and express [126] the relevant uptake transporters, in this case of the SLC52 family [127].…”