A complex immunodeficiency is based on U1 snRNP-mediated poly(A) site suppression Journal Article


Authors: Langemeier, J.; Schrom, E. M.; Rabner, A.; Radtke, M.; Zychlinski, D.; Saborowski, A.; Bohn, G.; Mandel-Gutfreund, Y.; Bodem, J.; Klein, C.; Bohne, J.
Article Title: A complex immunodeficiency is based on U1 snRNP-mediated poly(A) site suppression
Abstract: Biallelic mutations in the untranslated regions (UTRs) of mRNAs are rare causes for monogenetic diseases whose mechanisms remain poorly understood. We investigated a 3′UTR mutation resulting in a complex immunodeficiency syndrome caused by decreased mRNA levels of p14/robld3 by a previously unknown mechanism. Here, we show that the mutation creates a functional 5′ splice site (SS) and that its recognition by the spliceosomal component U1 snRNP causes p14 mRNA suppression in the absence of splicing. Histone processing signals are able to rescue p14 expression. Therefore, the mutation interferes only with canonical poly(A)-site 3′ end processing. Our data suggest that U1 snRNP inhibits cleavage or poly(A) site recognition. This is the first description of a 3′UTR mutation that creates a functional 5′SS causative of a monogenetic disease. Moreover, our data endorse the recently described role of U1 snRNP in suppression of intronic poly(A) sites, which is here deleterious for p14 mRNA biogenesis. © 2012 European Molecular Biology Organization.
Keywords: protein expression; human cell; mutation; neutropenia; animals; intron; introns; gene expression regulation; conserved sequence; molecular sequence data; species specificity; messenger rna; rna, messenger; sequence alignment; histone; adaptor proteins, signal transducing; base sequence; genes, reporter; 3' untranslated region; rna stability; spliceosome; sequence homology, nucleic acid; immune deficiency; point mutation; mammals; small nuclear ribonucleoprotein; histones; immunologic deficiency syndromes; rna splicing; biogenesis; 3' untranslated regions; rna splice sites; polyadenylation; endosomes; polyadenylic acid; rna, small nuclear; 30 utr mutation; u1 site; morpholinos
Journal Title: EMBO Journal
Volume: 31
Issue: 20
ISSN: 0261-4189
Publisher: Wiley Blackwell  
Date Published: 2012-10-17
Start Page: 4035
End Page: 4044
Language: English
DOI: 10.1038/emboj.2012.252
PROVIDER: scopus
PMCID: PMC3474926
PUBMED: 22968171
DOI/URL:
Notes: --- - "Export Date: 2 November 2012" - "CODEN: EMJOD" - "Source: Scopus"
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