Abnormal RNA processing due to the exon mutation of βE-globin gene
Abstract
As is typical of all beta-thalassaemias, the erythroid cells of individuals with the variant haemoglobin E (alpha 2 beta 2(26Glu leads to Lys)) exhibit a quantitative deficiency in their content of beta-globin (in this case beta E-globin) and its messenger RNA2,3. To determine the molecular basis of this phenotype, we have investigated the structure and expression of cloned beta E-globin genes. We report here that the complete nucleotide sequence of a beta E-gene revealed the expected GAG leads to AAG change in codon 26 but no other mutations. Expression of beta E-globin genes introduced into HeLa cells revealed two abnormalities of RNA processing: slow excision of intervening sequence-1 (IVS-1) and alternative splicing into exon-1 at a cryptic donor sequence within which the codon 26 nucleotide substitution resides. These results demonstrate a disturbance in the expression of the beta E-gene attributable solely to the exon mutation-a novel mechanism for gene dysfunction.
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Among about 300 characterized point mutations in hemoglobin, none increase expression, although missplicing of a pseudo-intron in hemoglobin E decreases expression.
“Of some 300 characterized point mutations in hemoglobin (56), none result in increased expression, though missplicing of a pseudo-intron in hemoglobin E ((#26 Glu -.Lys) results in decreased expression (57).”
From Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. (1987) · cites this paper as [57]
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Negre, O., Eggimann, A.-V., Beuzard, Y., Ribeil, J.-A., Bourget, P., Borwornpinyo, S., Hongeng, S., Hacein-Bey, S., Cavazzana, M., Leboulch, P., et al. (2016) · Human Gene Therapy · doi:10.1089/hum.2016.007 · Cited by 159 · see citing works
Wardell, M. R., Brennan, S. O., Janus, E. D., Fraser, R., & Carrell, R. W. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113096 · Cited by 159 · see citing works
- Authors
- Orkin, S. H., Kazazian, H. H., Antonarakis, S. E., Ostrer, H., Goff, S. C., & Sexton, J. P.
- Affiliations
- Harvard University (US)
- Johns Hopkins University (US)
- Venue
- Nature
- Published
- 1982-12
- Volume
- 300
- Issue
- 5894
- Pages
- 768-769
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2012256960
- Cited by
- 298
- References
- 0
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 9 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 4 · 2013: 9 · 2012: 10
- FWCI
- 17.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- beta-thalassemia, hemoglobin E, beta-globin gene, exon mutations, alternative splicing, mRNA processing, gene expression, erythroid cells
- MeSH terms
- Base Sequence, Gene Expression Regulation, Globins, HeLa Cells, Humans, Mutation, RNA Processing, Post-Transcriptional, RNA Splicing, Thalassemia
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