scholarly journals A 5′ splice site mutation affecting the pre-mRNA splicing of two upstream exons in the collagen COL1A1 gene. Exon 8 skipping and altered definition of exon 7 generates truncated proα1(I) chains with a non-collagenous insertion destabilizing the triple helix

1994 ◽  
Vol 302 (3) ◽  
pp. 729-735 ◽  
Author(s):  
J F Bateman ◽  
D Chan ◽  
I Moeller ◽  
M Hannagan ◽  
W G Cole
Keyword(s):  
Splice Site ◽  
De Novo ◽  
Donor Site ◽  
Mrna Splicing ◽  
Splice Donor Site ◽  
Sequence Motif ◽  
Type I ◽  
Splice Donor ◽  
Site Mutation ◽  
Definition Of

A heterozygous de novo G to A point mutation in intron 8 at the +5 position of the splice donor site of the gene for the pro alpha 1(I) chain of type I procollagen, COL1A1, was defined in a patient with type IV osteogenesis imperfecta. The splice donor site mutation resulted not only in the skipping of the upstream exon 8 but also unexpectedly had the secondary effect of activating a cryptic splice site in the next upstream intron, intron 7, leading to re-definition of the 3′ limit of exon 7. These pre-mRNA splicing aberrations cause the deletion of exon 8 sequences from the mature mRNA and the inclusion of 96 bp of intron 7 sequence. Since the mis-splicing of the mutant allele product resulted in the maintenance of the correct codon reading frame, the resultant pro alpha 1(I) chain contained a short non-collagenous 32-amino-acid sequence insertion within the repetitive Gly-Xaa-Yaa collagen sequence motif. At the protein level, the mutant alpha 1(I) chain was revealed by digestion with pepsin, which cleaved the mutant procollagen within the protease-sensitive non-collagenous insertion, producing a truncated alpha 1(I). This protease sensitivity demonstrated the structural distortion to the helical structure caused by the insertion. In long-term culture with ascorbic acid, which stimulates the formation of a mature crosslinked collagen matrix, and in tissues, there was no evidence of the mutant chain, suggesting that during matrix formation the mutant chain was unable to stably incorporated into the matrix and was degraded proteolytically.

scholarly journals Recurrent NUS1 canonical splice donor site mutation in two unrelated individuals with epilepsy, myoclonus, ataxia and scoliosis - a case report

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Kouhei Den ◽  
Yosuke Kudo ◽  
Mitsuhiro Kato ◽  
Kosuke Watanabe ◽  
Hiroshi Doi ◽  
...  
Keyword(s):  
Rna Splicing ◽  
De Novo ◽  
Involuntary Movement ◽  
Donor Site ◽  
Epileptic Seizures ◽  
Epileptic Encephalopathy ◽  
Protein Glycosylation ◽  
Splice Donor Site ◽  
Splice Donor ◽  
Site Mutation

Abstract Background We encountered two unrelated individuals suffering from neurological disorders, including epilepsy and scoliosis. Case presentation Whole-exome sequencing identified the same recurrent, de novo, pathogenic variant in NUS1 [NM_138459.4:c.691 + 1C > A] in both individuals. This variant is located in the conserved cis-prenyltransferase domain of the nuclear undecaprenyl pyrophosphate synthase 1 gene (NUS1), which encodes the Nogo-B receptor, an essential catalyst for protein glycosylation. This variant was confirmed to create a new splice donor site, resulting in aberrant RNA splicing resulting in a 91-bp deletion in exon 3 in both individuals. The mutant mRNA was partially degraded by nonsense mediated mRNA decay. To date, only four de novo variants and one homozygous variant have been reported in NUS1, which cause developmental and epileptic encephalopathy, early onset Parkinson’s disease, and a congenital disorder of glycosylation. Seven patients, including our two patients, have presented with epileptic seizures and intellectual disabilities. Conclusions Our study strongly supports the finding that this recurrent, de novo, variant in NUS1 causes developmental and epileptic encephalopathy with involuntary movement, ataxia and scoliosis.

A splice donor site mutation in HOXD13 underlies synpolydactyly with cortical bone thinning

Gene ◽  
2013 ◽  
Vol 532 (2) ◽  
pp. 297-301 ◽  
Author(s):  
Xiuyan Shi ◽  
Chunyan Ji ◽  
Lihua Cao ◽  
Yuhong Wu ◽  
Yuyang Shang ◽  
...  
Keyword(s):  
Cortical Bone ◽  
Donor Site ◽  
Splice Donor Site ◽  
Splice Donor ◽  
Site Mutation ◽  
Splice Donor Site Mutation

scholarly journals A Deep Exon Cryptic Splice Site Promotes Aberrant Intron Retention in a Von Willebrand Disease Patient

2021 ◽  
Vol 22 (24) ◽  
pp. 13248
Author(s):  
John G. Conboy
Keyword(s):  
Secondary Structure ◽  
Splice Site ◽  
Intron Retention ◽  
Donor Site ◽  
Von Willebrand Disease ◽  
Splice Donor Site ◽  
Cryptic Splice Site ◽  
Splice Donor ◽  
Nucleotide Mutation ◽  
Von Willebrand

A translationally silent single nucleotide mutation in exon 44 (E44) of the von Willebrand factor (VWF) gene is associated with inefficient removal of intron 44 in a von Willebrand disease (VWD) patient. This intron retention (IR) event was previously attributed to reordered E44 secondary structure that sequesters the normal splice donor site. We propose an alternative mechanism: the mutation introduces a cryptic splice donor site that interferes with the function of the annotated site to favor IR. We evaluated both models using minigene splicing reporters engineered to vary in secondary structure and/or cryptic splice site content. Analysis of splicing efficiency in transfected K562 cells suggested that the mutation-generated cryptic splice site in E44 was sufficient to induce substantial IR. Mutations predicted to vary secondary structure at the annotated site also had modest effects on IR and shifted the balance of residual splicing between the cryptic site and annotated site, supporting competition among the sites. Further studies demonstrated that introduction of cryptic splice donor motifs at other positions in E44 did not promote IR, indicating that interference with the annotated site is context dependent. We conclude that mutant deep exon splice sites can interfere with proper splicing by inducing IR.

Aberrant splicing caused by a MLH1 splice donor site mutation found in a young Japanese patient with Lynch syndrome

2012 ◽  
Vol 11 (4) ◽  
pp. 559-564 ◽  
Author(s):  
Masanobu Takahashi ◽  
Yoichi Furukawa ◽  
Hideki Shimodaira ◽  
Masato Sakayori ◽  
Takuya Moriya ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Japanese Patient ◽  
Donor Site ◽  
Splice Donor Site ◽  
Splice Donor ◽  
Site Mutation ◽  
Aberrant Splicing ◽  
Splice Donor Site Mutation

scholarly journals α-Thalassaemia as a result of a novel splice donor site mutation of the α1 -globin gene

2000 ◽  
Vol 110 (3) ◽  
pp. 694-698 ◽  
Author(s):  
C. L. Harteveld ◽  
C. Beijer ◽  
P. Van Delft ◽  
R. Zanardini ◽  
L. F. Bernini ◽  
...  
Keyword(s):  
Globin Gene ◽  
Donor Site ◽  
Splice Donor Site ◽  
Splice Donor ◽  
Site Mutation ◽  
Splice Donor Site Mutation

scholarly journals Comparison of in vitro and in vivo splice site selection in kappa-immunoglobulin precursor mRNA.

1988 ◽  
Vol 8 (6) ◽  
pp. 2610-2619 ◽  
Author(s):  
D E Lowery ◽  
B G Van Ness
Keyword(s):  
Splice Site ◽  
Site Selection ◽  
Donor Site ◽  
Splice Donor Site ◽  
Splice Sites ◽  
Splice Donor ◽  
Splice Site Selection ◽  
Nuclear Extracts

The processing of a number of kappa-immunoglobulin primary mRNA (pre-mRNA) constructs has been examined both in vitro and in vivo. When a kappa-immunoglobulin pre-mRNA containing multiple J segment splice sites is processed in vitro, the splice sites are used with equal frequency. The presence of signal exon, S-V intron, or variable (V) region has no effect on splice site selection in vitro. Nuclear extracts prepared from a lymphoid cell line do not restore correct splice site selection. Splice site selection in vitro can be altered by changing the position or sequence of J splice donor sites. These results differ from the processing of similar pre-mRNAs expressed in vivo by transient transfection. The 5'-most J splice donor site was exclusively selected in vivo, even in nonlymphoid cells, and even in transcripts where in vitro splicing favored a 3' J splice site. The in vitro results are consistent with a model proposing that splice site selection is influenced by splice site strength and proximity; however, our in vivo results demonstrate a number of discrepancies with such a model and suggest that splice site selection may be coupled to transcription or a higher-order nuclear structure.

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