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Genes 2018, 9(2), 73;

Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders

Regional Coordinator Centre for Rare Diseases, Academic Hospital “Santa Maria della Misericordia”, P.le Santa Maria della Misericordia 15, 33100 Udine, Italy
International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy, I.C.G.E.B., Padriciano 99, 34149 Trieste, Italy
Author to whom correspondence should be addressed.
Received: 15 December 2017 / Revised: 19 January 2018 / Accepted: 31 January 2018 / Published: 6 February 2018
(This article belongs to the Special Issue Aberrant Pre-mRNA Splicing in Disease)
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Lysosomal storage disorders (LSDs) represent a group of more than 50 severe metabolic diseases caused by the deficiency of specific lysosomal hydrolases, activators, carriers, or lysosomal integral membrane proteins, leading to the abnormal accumulation of substrates within the lysosomes. Numerous mutations have been described in each disease-causing gene; among them, about 5–19% affect the pre-mRNA splicing process. In the last decade, several strategies to rescue/increase normal splicing of mutated transcripts have been developed and LSDs represent excellent candidates for this type of approach: (i) most of them are inherited in an autosomic recessive manner and patients affected by late-onset (LO) phenotypes often retain a fair amount of residual enzymatic activity; thus, even a small recovery of normal splicing may be beneficial in clinical settings; (ii) most LSDs still lack effective treatments or are currently treated with extremely expensive approaches; (iii) in few LSDs, a single splicing mutation accounts for up to 40–70% of pathogenic alleles. At present, numerous preclinical studies support the feasibility of reverting the pathological phenotype by partially rescuing splicing defects in LSDs. This review provides an overview of the impact of splicing mutations in LSDs and the related therapeutic approaches currently under investigation in these disorders. View Full-Text
Keywords: antisense oligonucleotides; splicing mutations; lysosomal storage diseases antisense oligonucleotides; splicing mutations; lysosomal storage diseases

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Dardis, A.; Buratti, E. Impact, Characterization, and Rescue of Pre-mRNA Splicing Mutations in Lysosomal Storage Disorders. Genes 2018, 9, 73.

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