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.
authors.affiliation: Cell and Virus Genetics Group, Institute for Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Langemeier
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Schrom
authors.forename: Alona
authors.initials: A
authors.lastname: Rabner
authors.forename: Maximilian
authors.initials: M
authors.lastname: Radtke
authors.forename: Daniela
authors.initials: D
authors.lastname: Zychlinski
authors.forename: Anna
authors.initials: A
authors.lastname: Saborowski
authors.forename: Georg
authors.initials: G
authors.lastname: Bohn
authors.forename: Yael
authors.initials: Y
authors.lastname: Mandel-Gutfreund
authors.forename: Jochen
authors.initials: J
authors.lastname: Bodem
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Jens
authors.initials: J
authors.lastname: Bohne
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D011992:Endosomes / Q000648:ultrastructure; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D006657:Histones / Q000502:physiology; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008322:Mammals / Q000235:genetics; D008969:Molecular Sequence Data; D060172:Morpholinos / Q000494:pharmacology; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics; D017354:Point Mutation; D026723:Polyadenylation / Q000187:drug effects / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000187:drug effects; D020871:RNA Stability; D012333:RNA, Messenger / Q000096:biosynthesis; D012342:RNA, Small Nuclear / Q000235:genetics*; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D006657:Histones; D060172:Morpholinos; D022821:RNA Splice Sites; D012333:RNA, Messenger; D012342:RNA, Small Nuclear; C405483:U1 small nuclear RNA; C577278:LAMTOR2 protein, human