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Brown−Vialetto−Van Laere and Fazio−Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance

Gayathri, S; Gowda, VK; Udhayabanu, T; O'Callaghan, B; Efthymiou, S; Varalakshmi, P; Benakappa, N; ... Ashokkumar, B; + view all (2020) Brown−Vialetto−Van Laere and Fazio−Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance. European Journal of Neurology 10.1111/ene.14682. (In press).

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Abstract

BACKGROUND: Brown-Vialetto-Van Laere Syndrome (BVVLS) and Fazio-Londe Disease (FLD) are rare neurological disorders presenting with pontobulbar palsy, muscle weakness, and respiratory insufficiency. Mutations in SLC52A2 (hRFVT-2) or SLC52A3 (hRFVT-3) genes can be responsible for these disorders with an autosomal recessive pattern of inheritance. The aim of this study is to screen for mutations in SLC52A2 and SLC52A3 among Indian families diagnosed with BVVLS and FLD. METHODS: SLC52A2 and SLC52A3 were screened in one FLD and three BVVLS patients by exon-specific amplification using PCR and sequencing. In silico predictions using bioinformatics tools and confocal imaging using HEK-293 cells were performed to determine the functional impact of identified mutations. RESULTS: Genetic analysis of a mother and son with BVVLS was identified with a novel homozygous mutation c.710C>T (p.Ala237Val) in SLC52A3. This variant was found to have autosomal pseudo-dominant pattern of inheritance, which was neither listed in the Exome variant server or in 1000 genomes database. In silico analysis and confocal imaging of the p.Ala237Val variant showed higher degree of disorderness in hRFVT3 that could affect riboflavin transport. Furthermore, a common homozygous mutation c.62A>G (p.Asn21Ser) was identified in other BVVLS and FLD patients. Despite having different clinical phenotypes, both BVVLS and FLD disorder can be attributed to this mutation. CONCLUSION: A rare and peculiar pattern of autosomal pseudo-dominant inheritance is observed for the first time in two genetically related BVVLS cases with Indian origin and a common mutation c.62A>G (p.Asn21Ser) in SLC52A3 can be responsible for both BVVLS and FLD with variable phenotypes.

Type: Article
Title: Brown−Vialetto−Van Laere and Fazio−Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance
Location: England
DOI: 10.1111/ene.14682
Publisher version: https://doi.org/10.1111/ene.14682
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: SLC52A2, SLC52A3, Autosomal pseudo-dominance, Brown-Vialetto-Van Laere syndrome, Fazio-Londe disease, riboflavin transporter deficiency
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10118246
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