title: Hereditary cataract of the Nakano mouse: Involvement of a hypomorphic mutation in the coproporphyrinogen oxidase gene.
abstract: The Nakano cataract (NCT) is a recessive disorder in the mouse linked to the nct locus on chromosome 16. In this study, we positionally cloned the critical gene in the nct locus. Herein, we report that cataracts in the BALB/c-nct/nct mouse are caused by a hypomorphic mutation in the coproporphyrin oxidase gene (Cpox), encoding the enzyme responsible for catalyzing oxidative decarboxylation of the heme precursor, coproporphyrinogen III, in the heme biosynthetic pathway. BALB/c-nct/nct mice are homozygous for a G to T nucleotide substitution in the Cpox gene, which results in a p.R380L amino acid substitution in the CPOX protein. The CPOX isoform with the p.R380L substitution retained only 15% of the activity of the wild type isoform. BALB/c-nct/nct mice had excessive accumulation of coproporphyrin III in the lens. The NCT phenotype was normalized by the introduction of a wild type Cpox transgene. The mechanisms by which impairment of CPOX leads to lens opacity in the NCT are elusive. However, our data illuminate a hitherto unanticipated involvement of the heme biosynthesis pathway in lens physiology.
authors: Department of Aging Biology, Institute of Pathogenesis and Disease Prevention, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan. masamori@shinshu-u.ac.jp
authors: Masayuki
authors: M
authors: Mori
authors: Saki
authors: S
authors: Gotoh
authors: Shigeru
authors: S
authors: Taketani
authors: Hiroshi
authors: H
authors: Hiai
authors: Keiichi
authors: K
authors: Higuchi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000378:metabolism; D003304:Coproporphyrinogen Oxidase / Q000235:genetics* / Q000378:metabolism; D003306:Coproporphyrins / Q000378:metabolism; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006418:Heme / Q000378:metabolism; D006720:Homozygote; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D003306:Coproporphyrins; D012333:RNA, Messenger; C026971:coproporphyrin III; D006418:Heme; D003304:Coproporphyrinogen Oxidase