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Nonequivalence of Zfp423 premature termination codons in mice
Open accessPublished version of a preprint
Abstract
Genetic variants that introduce a premature termination codon (PTC) are often assumed equivalent and functionally null. Exceptions depend on the specific architectures of the affected mRNA and protein. Here we address phenotypic differences among early truncating variants of mouse Zfp423, whose phenotypes resemble Joubert Syndrome and Related Disorders. We replicate quantitative differences previously seen between presumptive null PTC variants based on their position in the coding sequence. We show with reciprocal congenic strains that large phenotype differences between two PTC variants with the same predicted stop and reinitiation codons are due to the specific allele rather than different strain backgrounds, with no evidence for induced exon skipping. Differences in RNA structure, however, could influence translation rate across the affected exon. Using a reporter assay, we find differences in translational reinitiation between 2 deletion variants that correlate with predicted RNA structure rather than distance from the canonical initiation codon. These results confirm and extend earlier evidence for differences among Zfp423 PTC variants, identify parameters for translational reinitiation after an early termination codon, and reinforce caution in the null interpretation of early PTC variants.
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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Highly accurate protein structure prediction for the human proteome
Tunyasuvunakool, K., Adler, J., Wu, Z., Green, T., Zielinski, M., Žídek, A., Bridgland, A., Cowie, A., Meyer, C., Laydon, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03828-1 · Cited by 3,025 · cited 1×
“…showed strong constraint against amino acid substitutions at most residue positions across diverse vertebrate lineages and identified a possible 31st zinc finger of C4 class (Hamilton 2020), subsequently supported by an AlphaFold2 structural model (Jumper et al. 2021; Tunyasuvunakool et al. 2021).”
Sequence-based characterization of structural variation in the mouse genome
Yalcin, B., Wong, K., Agam, A., Goodson, M., Keane, T. M., Gan, X., Nellåker, C., Goodstadt, L., Nicod, J., Bhomra, A., et al. (2011) · Nature · doi:10.1038/nature10432 · Cited by 301
Ishimura, R., Nagy, G., Dotu, I., Chuang, J. H., & Ackerman, S. L. (2016) · eLife · doi:10.7554/elife.14295 · Cited by 221
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Metadata
- Authors
- Concepcion, D., Liang, C., Kim, D., & Hamilton, B. A.
- Affiliations
- University of California San Diego (US)
- Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, University of California San Diego , 3147 Biomedical Sciences Way, La Jolla, CA 92093, USA
- Corresponding author
- Hamilton, Bruce A
- Venue
- GENETICS
- Publisher
- Oxford University Press (OUP)
- Published
- 2025-08-18
- Volume
- 231
- Issue
- 2
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC12505304
- OpenAlex
- W4413278842
- Cited by
- 1
- References
- 4
- Citations by year
- 2026: 1
- FWCI
- 0.30
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Genetics (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion, cc-by-nc)
- Funders
- National Institute of Neurological Disorders and Stroke
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- Zfp423, premature stop codon, null alleles, Joubert syndrome, exon skipping, RNA secondary structure, translation rate, truncating mutations
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