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Case Reports
. 2012 Sep;135(Pt 9):2875-82.
doi: 10.1093/brain/aws161. Epub 2012 Jun 26.

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease

Janel O Johnson  1 , J Raphael Gibbs, Andre Megarbane, J Andoni Urtizberea, Dena G Hernandez, A Reghan Foley, Sampath Arepalli, Amelie Pandraud, Javier Simón-Sánchez, Peter Clayton, Mary M Reilly, Francesco Muntoni, Yevgeniya Abramzon, Henry Houlden, Andrew B Singleton
Affiliations
Case Reports

Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease

Janel O Johnson et al. Brain. 2012 Sep.

Abstract

Brown-Vialetto-Van Laere syndrome was first described in 1894 as a rare neurodegenerative disorder characterized by progressive sensorineural deafness in combination with childhood amyotrophic lateral sclerosis. Mutations in the gene, SLC52A3 (formerly C20orf54), one of three known riboflavin transporter genes, have recently been shown to underlie a number of severe cases of Brown-Vialetto-Van Laere syndrome; however, cases and families with this disease exist that do not appear to be caused by SLC52A3 mutations. We used a combination of linkage and exome sequencing to identify the disease causing mutation in an extended Lebanese Brown-Vialetto-Van Laere kindred, whose affected members were negative for SLC52A3 mutations. We identified a novel mutation in a second member of the riboflavin transporter gene family (gene symbol: SLC52A2) as the cause of disease in this family. The same mutation was identified in one additional subject, from 44 screened. Within this group of 44 patients, we also identified two additional cases with SLC52A3 mutations, but none with mutations in the remaining member of this gene family, SLC52A1. We believe this strongly supports the notion that defective riboflavin transport plays an important role in Brown-Vialetto-Van Laere syndrome. Initial work has indicated that patients with SLC52A3 defects respond to riboflavin treatment clinically and biochemically. Clearly, this makes an excellent candidate therapy for the SLC52A2 mutation-positive patients identified here. Initial riboflavin treatment of one of these patients shows promising results.

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Figures

Figure 1
Figure 1
Pedigree of Lebanese family with Brown–Vialetto–Van Laere syndrome. Males are represented by squares and females are represented by circles. A blackened symbol indicates an affected individual, and a slash through a symbol indicates the individual is deceased. A double horizontal line indicates a consanguineous marriage.
Figure 2
Figure 2
Cross-species comparison of SLC52A2 protein sequence. Blue letters indicate the amino acid residue is not conserved. Red letters indicate position 306. Residue 306 is highly conserved.
Figure 3
Figure 3
Comparison of SLC52A2 and SLC52A1 protein sequence. Red letters indicate amino acid residue 306.
Figure 4
Figure 4
Structure of riboflavin and metabolites. RF and its cofactor forms containing additional ADP or phosphate groups at the 5′ hydroxyl side chain terminus of riboflavin to produce FMN or FAD. Riboflavin can freely diffuse in and out of the cell, FAD and FMN are metabolically trapped within the cell. FMN = flavin mononucleotide; FAD = flavin adenine dinucleotide; RF = riboflavin.
Figure 5
Figure 5
Riboflavin transport and metabolic trapping of FMN and FAD. The RFK product, riboflavin kinase, catalyzes the phosphorylation of riboflavin (vitamin B2) to form FMN. The FLAD1 product is thought to catalyze the adenylation of FMN to form FAD. ETF = electron transport flavoprotein; CoQ = coenzyme Q (ubiquinone); ETFDH = electron transport flavoprotein dehydrogenase; FMN = flavin mononucleotide; FAD = flavin adenine dinucleotide; RF = riboflavin. Note the three riboflavin transporters are variably expressed in disparate tissues (Yao et al., 2010).
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References

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