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[摘要]：Familial dysoutonomia (FD), also known as Riley-Day syndrome or recessive hereditary sensory and autonomic neuropathy type III (HSAN Ill), is caused by a single-base noncoding mutation in intron 20 (IVS20+6T > C) of the IKBKAP/ELP1 gene. This mutation results in variable skipping of exon 20 in IKBKAP/ELP1 transcripts, which leads to tissue-specific reduction of ELP1(IKBKAP) protein, particularly in the nervous system. FD is a devastating disorder with a high mortality rate due primarily to autonomic dysfunction. The identification of the gene and the disease-causing mutation has promised the development of potential treatments that directly target mRNA splicing to increase normal mRNA and protein. FD is a developmental disease with diagnostic symptoms present at birth, whereas patients show progressive neurodegeneration throughout life. Drugs that con increase ELP1 protein may slow this degeneration and improve the quality of life in aging patients. Since these compounds target the mRNA splicing mechanism and not a specific gene, it is likely that they will prove useful in other disorders with similar splice-site mutations. Given that 20-30% of human mutations are predicted to alter mRNA splicing, direct modification of splicing efficiency poses an important target for the design of therapeutics in the future. |
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