Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA

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Norppa , A J , Kauppala , T M , Heikkinen , H A , Verma , B , Iwai , H & Frilander , M J 2018 , ' Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA ' , RNA , vol. 24 , no. 3 , pp. 396-409 . https://doi.org/10.1261/rna.062844.117

Title: Mutations in the U11/U12-65K protein associated with isolated growth hormone deficiency lead to structural destabilization and impaired binding of U12 snRNA
Author: Norppa, Antto J.; Kauppala, Tuuli M.; Heikkinen, Harri A.; Verma, Bhupendra; Iwai, Hideo; Frilander, Mikko J.
Contributor organization: Institute of Biotechnology
Minor spliceosome
Date: 2018-03
Language: eng
Number of pages: 14
Belongs to series: RNA
ISSN: 1355-8382
DOI: https://doi.org/10.1261/rna.062844.117
URI: http://hdl.handle.net/10138/298261
Abstract: 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.
Subject: minor spliceosome
U11/U12 di-snRNP
U11/U12-65K
RNA-protein interactions
RNA recognition motif
PRE-MESSENGER-RNA
MINOR SPLICEOSOME FUNCTION
DISORDER MOPD I
AT-AC INTRON
NMR-SPECTROSCOPY
DEVELOPMENTAL DISORDER
NUCLEAR RIBONUCLEOPROTEINS
U12-DEPENDENT INTRONS
BACKBONE DYNAMICS
U12-TYPE INTRONS
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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