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Translational read‐through of a nonsense mutation in ATP7A impacts treatment outcome in Menkes disease
Author(s) -
Kaler Stephen G.,
Tang Jingrong,
Donsante Anthony,
Kaneski Christine R.
Publication year - 2009
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21576
Subject(s) - menkes disease , nonsense mutation , biology , atp7a , nonsense , genetics , mutation , complementation , translation (biology) , context (archaeology) , gene , messenger rna , stop codon , microbiology and biotechnology , phenotype , missense mutation , chemistry , copper metabolism , paleontology , organic chemistry , transporter , copper
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. Ann Neurol 2009;65:108–113