title: Translational read-through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease.
abstract: Protein translation ends when a stop codon in a gene's messenger RNA transcript enters the ribosomal A site. Mutations that create premature stop codons (nonsense mutations) typically cause premature translation termination. An alternative outcome, read-through translation (or nonsense suppression), is well known in prokaryotic, viral, and yeast genes but has not been clearly documented in humans except in the context of pharmacological manipulations. Here, we identify and characterize native read-through of a nonsense mutation (R201X) in the human copper transport gene, ATP7A. Western blotting, in vitro expression analyses, immunohistochemistry, and yeast complementation assays using cultured fibroblasts from a classic Menkes disease patient all indicated small amounts of native ATP7A(R201X) read-through and were associated with a dramatic clinical response to early copper treatment.
authors.affiliation: Unit on Pediatric Genetics, Program in Molecular Medicine, National Institute of Child Health and Human Development, Bethesda, MD, USA. kalers@mail.nih.gov
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Kaler
authors.forename: Jingrong
authors.initials: J
authors.lastname: Tang
authors.forename: Anthony
authors.initials: A
authors.lastname: Donsante
authors.forename: Christine R
authors.initials: CR
authors.lastname: Kaneski
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D018389:Codon, Nonsense / Q000235:genetics*; D000073840:Copper-Transporting ATPases; D004252:DNA Mutational Analysis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005816:Genetic Complementation Test / Q000379:methods; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D007706:Menkes Kinky Hair Syndrome / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008958:Models, Molecular; D010443:Peptide Chain Termination, Translational / Q000235:genetics
chemical_list: D027682:Cation Transport Proteins; D018389:Codon, Nonsense; D000251:Adenosine Triphosphatases; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases