Back to Search
Start Over
Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis
- Source :
- Blood Cells, Molecules and Diseases, Blood Cells, Molecules and Diseases, Elsevier, 2010, 45 (4), pp.284-8. ⟨10.1016/j.bcmd.2010.08.011⟩
- Publication Year :
- 2010
-
Abstract
- International audience; We describe a new approach to stabilize nonsense mRNA, based on the inhibition of the NMD mechanism, by combining cycloheximide-mediated inhibition of translation, and caffeine-mediated inhibition of UPF1 phosphorylation. This approach aimed to identify the impact of a 4.1R splicing mutation. This mutation is involved in a partial deficiency of 4.1R in the homozygous state in a patient with hereditary elliptocytosis and a moderated hemolytic anemia. We show that, in addition to two known minor shortened and stable spliceoforms, the mutation activates an intronic cryptic splice site, which results in a nonsense mRNA major isoform, targeted to degradation in intact cells by NMD. This accounts for the main cause of 4.1R partial deficiency. In a general perspective, blocking the NMD mechanism would help to identify a missing isoform, and pave the path for a molecular targeting strategy to circumvent a deleterious splicing pathway in favor of a therapeutic splicing pathway.
- Subjects :
- MESH: Cytoskeletal Proteins
MESH: Introns
Hereditary elliptocytosis
media_common.quotation_subject
RNA Stability
Nonsense-mediated decay
Nonsense
Nonsense mutation
MESH: Elliptocytosis, Hereditary
MESH: Protein Isoforms
Biology
medicine.disease_cause
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Protein Isoforms
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
MESH: Codon, Nonsense
RNA, Messenger
Molecular Biology
MESH: RNA, Messenger
030304 developmental biology
media_common
0303 health sciences
Mutation
Messenger RNA
MESH: Humans
MESH: Alternative Splicing
Elliptocytosis, Hereditary
Membrane Proteins
MESH: RNA Stability
Cell Biology
Hematology
MRNA stabilization
medicine.disease
Molecular biology
Introns
Alternative Splicing
Cytoskeletal Proteins
Codon, Nonsense
RNA splicing
Molecular Medicine
MESH: Membrane Proteins
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 10960961 and 10799796
- Volume :
- 45
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Blood cells, moleculesdiseases
- Accession number :
- edsair.doi.dedup.....c8ba004f08fc92c250118a6c76df69e8