What mutations affect splicing?
Table 1
| Disease | Gene | Type of splicing mutation |
|---|---|---|
| Neurofibromatosis type 1 (NF1) | NF1 | Deep intronic variants |
| Cystic fibrosis (CF) | CFTR | |
| Androgen insensitivity syndrome | AR | |
| Fabry disease | GLA |
How do deep intronic mutations affect splicing?
Taken together, deep intronic mutations can induce partial intron retention or pseudoexon activation by creating the canonical sequences that can serve as splicing donors. Whereas the donor mutations were concentrated near the SS, the mutations associated with acceptor gain were scattered across the SS (Fig.
What are Exonic mutations?
In general, exonic point mutations are categorized into missense, silent, or nonsense mutations, and it is well known that point mutations that damage the authentic splice sites cause abnormal splicing.
Can mutations occur during RNA splicing?
RNA splicing mutations occur at splice junctions (the invariant donor 5′ GT and acceptor 3′ AG dinucleotides of the introns), in consensus sequences around splice junctions, in introns to produce new donor and acceptor cryptic splice sites, and in cryptic splice sites in exons.
What is splice acceptor variant?
A genetic alteration in the DNA sequence that occurs at the boundary of an exon and an intron (splice site). This change can disrupt RNA splicing resulting in the loss of exons or the inclusion of introns and an altered protein-coding sequence.
What are exonic regions?
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term exon refers to both the DNA sequence within a gene and to the corresponding sequence in RNA transcripts.
What are deep intronic mutations?
Additionally, deep intronic mutations can disrupt transcription regulatory motifs and non-coding RNA genes. This review aims to highlight the importance of studying variation in deep intronic sequence as a cause of monogenic disorders as well as hereditary cancer syndromes.
Where does mRNA splicing take place?
the nucleus
Splicing occurs in the nucleus before the RNA migrates to the cytoplasm. Once splicing is complete, the mature mRNA (containing uninterrupted coding information), is transported to the cytoplasm where ribosomes translate the mRNA into protein.
Is RNA splicing part of transcription?
For nuclear-encoded genes, splicing occurs in the nucleus either during or immediately after transcription. For those eukaryotic genes that contain introns, splicing is usually needed to create an mRNA molecule that can be translated into protein.
When does RNA splicing occur?
Splicing occurs in the nucleus before the RNA migrates to the cytoplasm. Once splicing is complete, the mature mRNA (containing uninterrupted coding information), is transported to the cytoplasm where ribosomes translate the mRNA into protein.
How do splice site mutations affect the production of proteins?
The deletion of the splicing site results in one or more introns remaining in mature mRNA and may lead to the production of abnormal proteins. When a splice site mutation occurs, the mRNA transcript possesses information from these introns that normally should not be included.
What is canonical splicing?
This type of splicing is termed canonical splicing or termed the lariat pathway, which accounts for more than 99% of splicing. By contrast, when the intronic flanking sequences do not follow the GU-AG rule, noncanonical splicing is said to occur (see “minor spliceosome” below).
How do Exonic mutations affect splicing in humans?
However, there is increasing evidence that many human disease genes harbour exonic mutations that affect pre-mRNA splicing. Nonsense, missense and even translationally silent mutations can inactivate genes by inducing the splicing machinery to skip the mutant exons.
What is the exonic splicing enhancer disruption model?
In the exonic splicing enhancer (ESE)-disruption model ( d ), the PTC fortuitously disrupts the recognition motif for an RNA-binding protein that enhances splicing, such as an SR protein, and exon inclusion is no longer favoured 67, 79. A similar disruption might be caused by certain missense or translationally silent mutations.
How do exon skipping mutations affect protein structure?
Those mutations that inactivate an ESE can result in partial or complete exon skipping, and can therefore markedly affect the structure or amounts of the expressed protein product. An increasing proportion of point mutations are being reported to affect pre-mRNA splicing.
What are exonic point mutations and how are they classified?
In general, exonic point mutations are categorized into missense, silent, or nonsense mutations, and it is well known that point mutations that damage the authentic splice sites cause abnormal splicing.