Are splicing mutations the most frequent cause of hereditary disease?

@article{LpezBigas2005AreSM,
  title={Are splicing mutations the most frequent cause of hereditary disease?},
  author={N{\'u}ria L{\'o}pez-Bigas and Benjamin Audit and Christos A. Ouzounis and Gen{\'i}s Parra and Roderic Guig{\'o}},
  journal={FEBS Letters},
  year={2005},
  volume={579}
}
Disease‐causing point mutations are assumed to act predominantly through subsequent individual changes in the amino acid sequence that impair the normal function of proteins. However, point mutations can have a more dramatic effect by altering the splicing pattern of the gene. Here, we describe an approach to estimate the overall importance of splicing mutations. This approach takes into account the complete set of genes known to be involved in disease and suggest that, contrary to current… 
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References

SHOWING 1-10 OF 19 REFERENCES
Molecular basis of inherited diseases: a structural perspective.
TLDR
Although interpreting the effects of mutations in a protein structure can be difficult, it can provide more detailed information about the environment and role of a mutated residue than the protein sequence alone.
Listening to silence and understanding nonsense: exonic mutations that affect splicing
TLDR
As the splicing mechanisms that depend on exonic signals are elucidated, new therapeutic approaches to treating certain genetic diseases can begin to be explored.
Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.
TLDR
Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation ofExon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.
Missense, Nonsense, and Neutral Mutations Define Juxtaposed Regulatory Elements of Splicing in Cystic Fibrosis Transmembrane Regulator Exon 9*
TLDR
A systematic study of the effect on cystic fibrosis transmembrane regulator exon 9 splicing of natural and site-directed sequence mutations indicates a strict dependence between the two juxtaposed enhancer and silencer sequences and shows that many point mutations in these elements cause changes in splicing efficiency by different mechanisms.
Genomic variants in exons and introns: identifying the splicing spoilers
TLDR
An increasing amount of evidence indicates that genomic variants in both coding and non-coding sequences can have unexpected deleterious effects on the splicing of the gene transcript.
The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: Causes and consequences
TLDR
Evidence is presented that indicates that, at least for 5′ splice site mutations, crypticSplice site usage is favoured under conditions where (1) a number of such sites are present in the immediate vicinity and (2) these sites exhibit sufficient homology to thesplice site consensus sequence for them to be able to compete successfully with the mutated splice sites.
Splice‐site mutation in the PDS gene may result in intrafamilial variability for deafness in Pendred syndrome
TLDR
RNA analysis from lymphocytes of the affected patients showed that mutation 639+7A→G generates a new donor splice site, leading to an mRNA with an insertion of six nucleotides from intron 4 of PDS.
Genome-wide identification of genes likely to be involved in human genetic disease.
TLDR
A computational method is developed that allows the detection of genes likely to be involved in hereditary disease in the human genome and moreover can be used to predict novel disease genes.
Pre-mRNA splicing and human disease.
TLDR
The purpose of this review is to highlight the different mechanisms by which disruption of pre-mRNA splicing play a role in human disease.
Human Gene Mutation Database (HGMD®): 2003 update
TLDR
Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease‐associated and functional polymorphisms, as well as links to data present in publicly available online locus‐specific mutation databases.
...
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