Nonsense-mediated decay (NMD) is a eukaryotic cellular RNA surveillance and quality-control mechanism that degrades mRNA containing premature stop codons (nonsense mutations) that otherwise may exert a deleterious effect by the production of dysfunctional truncated proteins. Collagen X (COL10A1) nonsense mutations in Schmid-type metaphyseal chondrodysplasia are localized in a region toward the 3′ end of the last exon (exon 3) and result in mRNA decay, in contrast to most other genes in which terminal-exon nonsense mutations are resistant to NMD. We introduce nonsense mutations into the mouse Col10a1 gene and express these in a hypertrophic-chondrocyte cell line to explore the mechanism of last-exon mRNA decay of Col10a1 and demonstrate that mRNA decay is spatially restricted to mutations occurring in a 3′ region of the exon 3 coding sequence; this region corresponds to where human mutations have been described. This localization of mRNA-decay competency suggested that a downstream region, such as the 3′ UTR, may play a role in specifying decay of mutant Col10a1 mRNA containing nonsense mutations. We found that deleting any of the three conserved sequence regions within the 3′ UTR (region I, 23 bp; region II, 170 bp; and region III, 76 bp) prevented mutant mRNA decay, but a smaller 13 bp deletion within region III was permissive for decay. These data suggest that the 3′ UTR participates in collagen X last-exon mRNA decay and that overall 3′ UTR configuration, rather than specific linear-sequence motifs, may be important in specifying decay of Col10a1 mRNA containing nonsense mutations. © 2008 The American Society of Human Genetics.
Tan, J. T., Kremer, F., Freddi, S., Bell, K. M., Baker, N. L., Lamandé, S. R., & Bateman, J. F. (2008). Competency for Nonsense-Mediated Reduction in Collagen X mRNA Is Specified by the 3′ UTR and Corresponds to the Position of Mutations in Schmid Metaphyseal Chondrodysplasia. American Journal of Human Genetics, 82(3), 786–793. https://doi.org/10.1016/j.ajhg.2008.01.006