Minor spliceosome and disease

Verma, Bhupendra; Akinyi, Maureen Veronica; Norppa, Antto Juhani; Frilander, Mikko J.

doi:10.1016/j.semcdb.2017.09.036

Cited by 89 publications

(101 citation statements)

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“…The protein-protein interactions we found between RBM48 with U2AF, RGH3, and ARMC7 may help explain the impact on U2-type introns in a subset of U12 splicing mutants (Verma et al, 2017). A low frequency of U2 splicing defects have been observed for mutations in ZRSR2 homologs and RNPC3 (Madan et al, 2015;Gault et al, 2017;Horiuchi et al, 2018;Argente et al, 2014).…”

Section: Rbm48 Interacts With U2af Rgh3 and Armc7mentioning

confidence: 73%

“…These examples suggest a common requirement for U12 splicing to promote the differentiation of a subset of eukaryotic cell types. However, minor splicing mutations cause a range of human diseases and diverse phenotypes in animal models (Horiuchi et al, 2018;Verma et al, 2017;Pessa et al, 2010;Markmiller et al, 2014). The similarity of endosperm defects in rbm48 and rgh3 suggest a mutant ideotype for the developmental pathways sensitive to U12 splicing efficiency.…”

Section: Divergence Of U12 Splicing Phenotypes Likely Results From Framentioning

confidence: 99%

“…Both U2AF and ZRSR2 are responsible for 3' splice site recognition of U2-type and U12-type introns, respectively (Shen et al, 2010). By contrast, U2 splicing defects have not been reported in human mutant alleles of U4atac, which are expected to recognize U12-type introns but not complete splicing reactions (Verma et al, 2017). The interaction data and the presence of a low frequency of U2-type splicing defects suggest that RBM48 and ARMC7 may also participate in U12-type intron recognition.…”

Section: Rbm48 Interacts With U2af Rgh3 and Armc7mentioning

confidence: 95%

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RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

Bai

Corll

Shodja

et al. 2018

Preprint

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The last eukaryotic common ancestor had two classes of introns that are still found in most eukaryotic lineages. Common U2-type and rare U12-type introns are spliced by the major and minor spliceosomes, respectively. Relatively few splicing factors have been shown to be specific to the minor spliceosome. We found that the maize RNA Binding Motif Protein48 (RBM48) is a U12 splicing factor that functions to promote cell differentiation and repress cell proliferation. RBM48 is coselected with the U12 splicing factor, ZRSR2/RGH3. Protein-protein interactions between RBM48, RGH3, and U2 Auxiliary Factor (U2AF) subunits suggest major and minor spliceosome factors may form complexes during intron recognition. Human RBM48 interacts with ARMC7.Maize RBM48 and ARMC7 have a conserved protein-protein interaction. These data predict that RBM48 is likely to function in U12 splicing throughout eukaryotes and that U12 splicing promotes endosperm cell differentiation in maize.

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Section: Rbm48 Interacts With U2af Rgh3 and Armc7mentioning

confidence: 73%

Section: Divergence Of U12 Splicing Phenotypes Likely Results From Framentioning

confidence: 99%

Section: Rbm48 Interacts With U2af Rgh3 and Armc7mentioning

confidence: 95%

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RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

Bai

Corll

Shodja

et al. 2018

Preprint

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“…The vast majority of eukaryotic introns are spliced by the U2 spliceosome (the only alternative U12 spliceosome is responsible for <0.5% of all introns (Parada, Munita, Cerda, & Gysling, ; Turunen, Niemela, Verma, & Frilander, ; Verma, Akinyi, Norppa, & Frilander, ), which interacts with RNA sequences specifying the 5′ and 3′ splice sites (Papasaikas & Valcarcel, ; Sharp & Burge, ). In vertebrates, the 9‐bp consensus sequence for the U2‐type 5′ splice site (5′SS) has traditionally been described as 5′‐MAG/GURAGU‐3′ (where M denotes C or A, R denotes A or G and / denotes the exon‐intron boundary; the corresponding nucleotide positions are denoted −3_−1/ + 1_ + 6) although in reality this consensus sequence does not reflect the true extent of sequence variability (Abril, Castelo, & Guigo, ; Burset, Seledtsov, & Solovyev, ; Mount, ; Roca et al, ; Roca, Krainer, & Eperon, ; Wong, Kinney, & Krainer, ).…”

Section: Introductionmentioning

confidence: 99%

First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

et al. 2019

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It has long been known that canonical 5′ splice site (5′SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5′SSs capable of generating wild‐type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta‐analysis of 45 human disease‐causing 5′SS GT>GC variants and a cell culture‐based full‐length gene splicing assay of 103 5′SS GT>GC substitutions, we estimate that ~15–18% of canonical GT 5′SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5′SSs in which substitution of GT by GC‐generated normal transcripts exhibit stronger complementarity to the 5′ end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild‐type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5′SS GT>GC variants that generated wild‐type transcripts from those that did not. Our findings imply that 5′SS GT>GC variants in human disease genes may not invariably be pathogenic.

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“…The vast majority of eukaryotic introns are spliced by the U2 spliceosome (the only alternative U12 spliceosome is responsible for <0.5% of all introns [1-3]), which interacts with RNA sequences specifying the 5’ and 3’ splice sites [4, 5]. In vertebrates, the 9-bp consensus sequence for the U2-type 5’ splice site (5’SS) has traditionally been described as 5’-MAG/GURAGU-3’ (where M denotes C or A, R denotes A or G and / denotes the exon-intron boundary; the corresponding nucleotide positions are denoted −3_-1/+1_+6) although in reality this consensus sequence does not reflect the true extent of sequence variability [6-11].…”

Section: Introductionmentioning

confidence: 99%

First estimation of the scale of canonical 5’ splice site GT>GC mutations generating wild-type transcripts and their medical genetic implications

Lin

Tang

Boulling

et al. 2018

Preprint

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24It has long been known that canonical 5' splice site (5'SS) GT>GC mutations may be compatible with 25 normal splicing. However, to date, the true scale of canonical 5'SS GT>GC mutations generating wild-26 type transcripts, both in the context of the frequency of such mutations and the level of wild-type 27 transcripts generated from the mutation alleles, remain unknown. Herein, combining data derived from a 28 meta-analysis of 45 informative disease-causing 5'SS GT>GC mutations (from 42 genes) and a cell 29 culture-based full-length gene splicing assay of 103 5'SS GT>GC mutations (from 30 genes), we 30 estimate that ~15-18% of the canonical GT 5'SSs are capable of generating between 1 and 84% normal 31 transcripts as a consequence of the substitution of GT by GC. We further demonstrate that the 32 canonical 5'SSs whose substitutions of GT by GC generated normal transcripts show stronger 33 complementarity to the 5' end of U1 snRNA than those sites whose substitutions of GT by GC did not 34 lead to the generation of normal transcripts. We also observed a correlation between the generation of 35 wild-type transcripts and a milder than expected clinical phenotype but found that none of the available 36 splicing prediction tools were able to accurately predict the functional impact of 5'SS GT>GC mutations. 37Our findings imply that 5'SS GT>GC mutations may not invariably cause human disease but should also 38 help to improve our understanding of the evolutionary processes that accompanied GT>GC subtype 39 switching of U2-type introns in mammals. 40 41 Keywords: Canonical 5' splice site, Full-length gene splicing assay, Genotype and phenotype 42 relationship, Human Gene Mutation Database, Human inherited disease, Meta-analysis, Non-canonical 43 splice donor site, U2-type intron 44 45 49 5' splice site (5'SS) has traditionally been described as 5'-MAG/GURAGU-3' (where M denotes C or A, 50R denotes A or G and / denotes the exon-intron boundary; the corresponding nucleotide positions are 51 denoted -3_-1/+1_+6) although in reality this consensus sequence does not reflect the true extent of 52 sequence variability [6][7][8][9][10][11]. Base-pairing of this 9-bp sequence with 3'-GUCCAUUCA-5' at the 5' end of 53 U1 snRNA ( Figure 1A) is critical for splicing to occur [10,[12][13][14][15]. Although the GT dinucleotide in the 54 first two intronic positions (in the context of DNA sequence) is the most highly conserved portion of the 55 U2-type 5'SS, it was reported, as early as 1983, that GC occasionally occurs in place of GT [16][17][18]. 56Subsequent genome-wide analyses have established that this non-canonical 5'SS GC is present as 57 wild-type in ~1% of human U2-type introns [2, 7, 8, 19, 20]. Importantly, the remaining nucleotides in 58 these evolutionarily fixed non-canonical GC 5'SSs exhibit a stronger complementarity to the 3'-59 GUCCAUUCA-5' sequence at the 5' end of U1 snRNA than those in the canonical GT 5'SSs ( Figure 60 1A), thereby in all likelihood compensating for the decreased complementarity between the ...

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Minor spliceosome and disease

Cited by 89 publications

References 74 publications

RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

RNA Binding Motif Protein 48 is required for U12 splicing and maize endosperm differentiation

First estimate of the scale of canonical 5′ splice site GT>GC variants capable of generating wild‐type transcripts

First estimation of the scale of canonical 5’ splice site GT>GC mutations generating wild-type transcripts and their medical genetic implications

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