Disruption of Slc52a3 gene causes abnormalities of energy metabolism and brain development in mice with riboflavin deficiency

[Speaker] Congyun Jin:1,2
[Co-author] Hiroki Yoshimatsu:1,2, Atsushi Yonezawa:1,2, Kaori Yamanishi:1,2, Yoshiaki Yao:1,2, Shunsaku Nakagawa:1, Satoshi Imai:1, Tomohiro Omura:1, Takayuki Nakagawa:1, Kazuo Matsubara:1
1:Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan, 2:Graduate School of Pharmaceutical Sciences, Kyoto University, Japan

Background: Riboflavin is a water-soluble vitamin, known as Vitamin B2. It is converted to the coenzyme forms, FMN and FAD, which act as intermediaries in essential biochemical oxidation-reduction reactions. Riboflavin transporters have been considered to play important roles in the maintenance of riboflavin homeostasis. Riboflavin transporter 3 (RFVT3), encoded by the SLC52A3 gene, is expressed in the small intestine, kidney, testis and placenta. The mutations in SLC52A3 gene cause a neurological disorder, known as Brown-Vialetto-Van Laere syndrome. However, the physiological significance of RFVT3 remains unclear. Here, we investigated the physiological roles of RFVT3 using Slc52a3 knockout (Slc52a3-/-) mice.

Methods: Slc52a3-/- mice were obtained from Knockout Mouse Project repository. The riboflavin, acylcarnitine and glutaric acid concentrations in plasma and tissues were measured at postnatal day 0. Histological analysis of brain was performed at embryo day 13.5, 18.5 and postnatal day 0.

Results: Most of the newborn Slc52a3-/- mice were alive for more than 8 hr, but died within 48 hr after birth. The body weights were significantly lower than those in WT mice. In Slc52a3-/- newborn pups, tissue and plasma riboflavin concentration was significantly lower than in WT littermates. Meanwhile, abnormal levels of plasma acylcarnitines and urinary glutaric acid were observed in Slc52a3-/- pups. Interestingly, histological analysis of Slc52a3-/- brains during embryonal period showed the hypoplasia of brain. The cortical layers of brain at embryo day 13.5, 18.5 and postnatal day 0 were thinner and somewhat disorganized.

Conclusion: These findings demonstrated that disruption of Slc52a3 gene causes riboflavin deficiency, and leads to metabolic disorder and brain hypoplasia in mice.

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