title: The silkworm mutant lemon (lemon lethal) is a potential insect model for human sepiapterin reductase deficiency.
abstract: Tetrahydrobiopterin (BH4) is an essential cofactor for aromatic acid hydroxylases, which control the levels of monoamine neurotransmitters. BH4 deficiency has been associated with many neuropsychological disorders. An inherited defect in BH4 biosynthesis is caused by the deficiency of sepiapterin reductase (SPR), which catalyzes the biosynthesis of BH4 from guanosine triphosphate at the terminal step. The human SPR gene has been mapped at the PARK3 locus, which is related to the onset of Parkinson disease. In this study, we report that mutant strains, lemon (lem) and its lethal allele lemon lethal (lem(1)) with yellow body coloration, of the silkworm Bombyx mori could be used as the first insect model for human SPR deficiency diseases. We demonstrated that mutations in the SPR gene (BmSpr) were responsible for the irregular body coloration of lem and lem(l). Moreover, biochemical analysis revealed that SPR activity in lem(l) larvae was almost completely diminished, resulting in a lethal phenotype that the larvae cannot feed and that die immediately after the first ecdysis. Oral administration of BH4 and dopamine to lem(l) larvae effectively increased their survival rates and feeding abilities. Our data demonstrate that BmSPR plays a crucial role in the generation of BH4, and monoamine neurotransmitters in silkworms and the lem (lem(l)) mutant strains will be an invaluable resource to address many questions regarding SPR and BH4 deficiencies.
authors.affiliation: Department of Agricultural and Environmental Biology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Meng
authors.forename: Susumu
authors.initials: S
authors.lastname: Katsuma
authors.forename: Takaaki
authors.initials: T
authors.lastname: Daimon
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Banno
authors.forename: Keiro
authors.initials: K
authors.lastname: Uchino
authors.forename: Hideki
authors.initials: H
authors.lastname: Sezutsu
authors.forename: Toshiki
authors.initials: T
authors.lastname: Tamura
authors.forename: Kazuei
authors.initials: K
authors.lastname: Mita
authors.forename: Toru
authors.initials: T
authors.lastname: Shimada
mesh_terms: D000429:Alcohol Oxidoreductases / Q000172:deficiency*; D000595:Amino Acid Sequence; D000818:Animals; D012831:Bombyx / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007313:Insecta; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid
chemical_list: D017931:DNA Primers; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase