Key result
Native read-through of the R201X nonsense mutation in ATP7A produced small amounts of functional protein, which was associated with a dramatic clinical response to early copper treatment.
Case Report (n=1)
Native read-through of a nonsense mutation in ATP7A can occur in humans and may explain dramatic clinical responses to early copper treatment in Menkes disease.
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Hypothesis-generating for Menkes disease; leaves open human applicability and clinical translation.
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.
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Kaler et al. (2009) conducted a case report in Menkes disease (n=1). Native read-through of R201X mutation and early copper treatment was evaluated on Native ATP7A(R201X) read-through and clinical response. Native read-through of the R201X nonsense mutation in ATP7A produced small amounts of functional protein, which was associated with a dramatic clinical response to early copper treatment.
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