An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency

• Published in: Molecular genetics and metabolism Vol. 122; no. 4; pp. 182 - 188
• Main Authors: Mosegaard, Signe, Bruun, Gitte Hoffmann, Flyvbjerg, Karen Freund, Bliksrud, Yngve Thomas, Gregersen, Niels, Dembic, Maja, Annexstad, Ellen, Tangeraas, Trine, Olsen, Rikke Katrine Jentoft, Andresen, Brage S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2017
• Subjects: hnRNP A1; MADD; Riboflavin; Splicing silencer; Riboflavin; MADD; hnRNP A1; Splicing silencer
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2017.10.014

Vitamin B2, riboflavin is essential for cellular function, as it participates in a diversity of redox reactions central to human metabolism, through its role as precursor for the cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), which are electron carriers. The electron transfer flavoprotein (ETF) and its dehydrogenase (ETFDH), uses FAD as cofactor. The ETF and ETFDH are forming the electron transport pathway for many mitochondrial flavoprotein dehydrogenases involved in fatty acid, amino acid and choline metabolism. A variation in either ETF or ETFDH causes multiple acyl-CoA dehydrogenation deficiency (MADD), but genetic variations in the riboflavin metabolism or transportation of riboflavin can also cause MADD. The most common variations are located in the riboflavin transporter 2 (RFVT2) and 3 (RFVT3), that are highly expressed in brain and intestinal tissues, respectively. Deficiency of riboflavin transporter 1 (RFVT1), encoded by the SLC52A1 gene, highly expressed in the placenta, has only been reported once. We here report a case of transient MADD, caused by a heterozygous intronic variation, c.1134+11G>A, in the SLC52A1 gene encoding RFVT1. This variation creates a binding site for the splice inhibitory hnRNP A1 protein and causes exon 4 skipping. Riboflavin deficiency and maternal malnutrition during pregnancy might have been the determining factor in the outcome of this case. •Heterozygosity for an intronic variant, c.1134+11G>A, in the SLC52A1 gene may cause transient MADD in newborns. We investigate the underlying mechanism.•The variant creates an intronic splicing silencer (ISS), which binds the splicing inhibitory hnRNP A1/A2 proteins.•Creation of the ISS causes skipping of exon 4 in the SLC52A1 gene encoding the riboflavin transporter RFVT1.•Riboflavin deficiency and maternal malnutrition during pregnancy might have been the determining factors.