Gayathri, S; Aravind, MK; Gowda, VK; Varalakshmi, P; Chatterjee, C; Matheshwaran, S; Efthymiou, S; ... Ashokkumar, B; + view all Gayathri, S; Aravind, MK; Gowda, VK; Varalakshmi, P; Chatterjee, C; Matheshwaran, S; Efthymiou, S; Houlden, H; Ashokkumar, B; - view fewer (2025) Brown-Vialetto-Van Laere syndrome patients with unusual phenotypes from Indian ethnicity: Functional analysis of clinical variants in SLC52A2 and SLC52A3 genes. Brain and Development , 47 (3) , Article 104355. 10.1016/j.braindev.2025.104355.

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Abstract

Background: BVVLS (Brown-Vialetto-Van Laere syndrome), a rare genetic condition characterized by progressive neuropathy, is caused by defects in SLC52A2 and SLC52A3 genes coding for hRFVT-2 and hRFVT-3. Methods: Five BVVLS cases were screened for disease-causing variants using exome sequencing and their functional contributions were evaluated by in silico analysis, riboflavin transport assay and confocal imaging. Results: Probands enrolled in this study were presented with unusual phenotypes like syndactyly, polydactyly, pedal edema and chronic osteomyelitis. Genetic testing disclosed heterozygous variants in all five cases including c.229G>A p.E77K, c.384G>A p.S128S, c.1245C>T p.G415G and c.843del p.L282Cfs*8 in SLC52A2 gene and c.833C>T p.T278M, c.907A>G p.I303V and c.62A>G p.N21S in SLC52A3 gene. Among them, p.L282Cfs*8 was diagnosed here for first-time, whereas p.E77K and p.S128S were reported previously with a variation at nucleotide position. Functional analysis of the variant p.E77K, p.S128S, p.T278M and p.I303V evidenced impairment in riboflavin transport, whereas p.G415G and p.L282Cfs*8 showed no significant changes. Despite of having reduction in riboflavin uptake, the presence of same polymorphic variant (p.T278M and p.I303V) in asymptomatic father suggests it as not likely associated with disease phenotypes. Meantime, membranous expression of hRFVT-2 variants p.S128S and p.E77K were abrogated and mostly internalized in cytoplasmic regions of transfected cells, whereas no change was observed with other variants than wild-type. Conclusion: These results show for the first-time that BVVLS associated hRFVT-2 variants p.S128S and p.E77K affected riboflavin transport function due to abrogation in membranous localization and/or activity of the transporter. The polymorphic variants p.T278M and p.I303V of hRFVT-3 are unlikely to be implicated functionally in the pathogenesis of the disease.

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