Ataluren, a New Therapeutic for Alpha-1 Antitrypsin-Deficient Individuals with Nonsense Mutations

After sequencing of all coding exons (II-V) of the SERPINA1 gene, the patient was identified as homozygous for the Q0bolton mutation, with two PTCs at amino acid 373 and 374 on exon V. Molecular dynamics simulations of Q0bolton-AAT suggested sufficient interactions to stabilize native-like protein s...

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Published in:American journal of respiratory and critical care medicine 2018-10, Vol.198 (8), p.1099-1102
Main Authors: Reeves, Emer P, O'Dwyer, Ciara A, Dunlea, Danielle M, Wormald, Mark R, Hawkins, Padraig, Alfares, Mohammad, Kotton, Darrell N, Rowe, Steven M, Wilson, Andrew A, McElvaney, Noel G
Format: Article
Language:English
Subjects:
Chromatography
Chronic obstructive pulmonary disease
Correspondence
Cystic fibrosis
Investigations
Muscular dystrophy
Mutation
Plasma
Proteins
Software
Stem cells
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Summary:After sequencing of all coding exons (II-V) of the SERPINA1 gene, the patient was identified as homozygous for the Q0bolton mutation, with two PTCs at amino acid 373 and 374 on exon V. Molecular dynamics simulations of Q0bolton-AAT suggested sufficient interactions to stabilize native-like protein structure, should it form during the early steps of protein folding. For Q0bolton-iPSC-hepatic cells, a significant 10-fold increase in AAT mRNA expression levels was observed compared with untreated cells (P < 0.05). [...]a significant 2-fold increase in the concentration of secreted Q0bolton-AAT protein was recorded with ataluren treatment (P < 0.001; Figure 2A). [...]for PTCs located more than 50 bp upstream of the most 3' exon-exon junction of the mRNA, nonsense-mediated decay is thought to eradicate the transcript (9). [...]this study demonstrates the potential use of ataluren to induce production and secretion of functional Q0bolton-AAT protein in vivo.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201802-0338LE