title: SLC52A3, A Brown-Vialetto-van Laere syndrome candidate gene is essential for mouse development, but dispensable for motor neuron differentiation.
abstract: Riboflavin, also known as vitamin B2, is essential for cellular reduction-oxidation reactions, but is not readily synthesized by mammalian cells. It has been proposed that riboflavin absorption occurs through solute carrier family 52 members (SLC52) A1, A2 and A3. These transporters are also candidate genes for the childhood onset-neural degenerative syndrome Brown-Vialetto-Van Laere (BVVL). Although riboflavin is an essential nutrient, why mutations in its transporters result in a neural cell-specific disorder remains unclear. Here, we provide evidence that Slc52a3 is the mouse ortholog of SLC52A3 and show that Slc52a3 deficiency results in early embryonic lethality. Loss of mutant embryos was associated with both defects in placental formation and increased rates of apoptosis in embryonic cells. In contrast, Slc52a3 -/- embryonic stem cell lines could be readily established and differentiated into motor neurons, suggesting that this transporter is dispensable for neural differentiation and short-term maintenance. Consistent with this finding, examination of Slc52a3 gene products in adult tissues revealed expression in the testis and intestine but little or none in the brain and spinal cord. Our results suggest that BVVL patients with SCL52A3 mutations may be good candidates for riboflavin replacement therapy and suggests that either the mutations these individuals carry are hypomorphic, or that in these cases alternative transporters act during human embryogenesis to allow full-term development.
authors.affiliation: Department of Stem Cell and Regenerative Biology, The Harvard Stem Cell Institute, Harvard University, Sherman Fairchild Building, 7 Divinity Avenue, Cambridge, MA 02138, USA and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Intoh
authors.affiliation: Department of Stem Cell and Regenerative Biology, The Harvard Stem Cell Institute, Harvard University, Sherman Fairchild Building, 7 Divinity Avenue, Cambridge, MA 02138, USA and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Department of Stem Cell and Regenerative Biology, The Harvard Stem Cell Institute, Harvard University, Sherman Fairchild Building, 7 Divinity Avenue, Cambridge, MA 02138, USA and.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Koszka
authors.affiliation: Department of Stem Cell and Regenerative Biology, The Harvard Stem Cell Institute, Harvard University, Sherman Fairchild Building, 7 Divinity Avenue, Cambridge, MA 02138, USA and The Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA eggan@mcb.harvard.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D000818:Animals; D010244:Bulbar Palsy, Progressive / Q000235:genetics* / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D055495:Neurogenesis
chemical_list: D026901:Membrane Transport Proteins; C548553:SLC52A3 protein, human