Journal
RNA
Volume 24, Issue 3, Pages 396-409Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.062844.117
Keywords
minor spliceosome; U11/U12 di-snRNP; U11/U12-65K; RNA-protein interactions; RNA recognition motif
Categories
Funding
- Academy of Finland [140087, 308657, 278798, 277335]
- Biocentrum Helsinki
- Biocenter Finland
- Sigrid Juselius Foundation
- Integrative Life Science doctoral program at the University of Helsinki
- HiLIFE
- Academy of Finland (AKA) [140087, 308657, 278798, 140087, 277335, 278798, 277335, 308657] Funding Source: Academy of Finland (AKA)
Ask authors/readers for more resources
Mutations in the components of the minor spliceosome underlie several human diseases. A subset of patients with isolated growth hormone deficiency (IGHD) harbors mutations in the RNPC3 gene, which encodes the minor spliceosome-specific U11/U12-65K protein. Although a previous study showed that IGHD patient cells have defects in U12-type intron recognition, the biochemical effects of these mutations on the 65K protein have not been characterized. Here, we show that a proline-to-threonine missense mutation (P474T) and a nonsense mutation (R502X) in the C-terminal RNA recognition motif (C-RRM) of the 65K protein impair the binding of 65K to U12 and U6atac snRNAs. We further show that the nonsense allele is targeted to the nonsense-mediated decay (NMD) pathway, but in an isoform-specific manner, with the nuclear-retained 65K long-3'UTR isoform escaping the NMD pathway. In contrast, the missense P474T mutation leads, in addition to the RNA-binding defect, to a partial defect in the folding of the C-RRM and reduced stability of the full-length protein, thus reducing the formation of U11/U12 di-snRNP complexes. We propose that both the C-RRM folding defect and NMD-mediated decrease in the levels of the U11/U12-65K protein reduce formation of the U12-type intron recognition complex and missplicing of a subset of minor introns leading to pituitary hypoplasia and a subsequent defect in growth hormone secretion.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available