Journal
HUMAN MUTATION
Volume 30, Issue 12, Pages 1676-1682Publisher
WILEY
DOI: 10.1002/humu.21118
Keywords
methylmalonyl-CoA mutase; MUT; methylmalonic acidemia; antisense therapy; intronic mutations; dendrimers
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Funding
- Fondo de Investigaciones Sanitarias [PI060512]
- Comision Interministerial de Ciencia y Tecnologia [SAF2007-61350]
- CIBER [INTRA/07/720.1]
- Fundacion Ramon Areces
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Development of pseudoexon exclusion therapies by antisense modification of pre-mRNA splicing represents a type of personalized genetic medicine. Here we present the cellular antisense therapy and the cell-based splicing assays to investigate the effect of two novel deep intronic changes c.1957-898A>G and c.1957-920C>A identified in the methylmalonyl-coenzyme A (CoA) mutase (MUT) gene. The results show that the nucleotide change c.1957-898A>G is a pathological mutation activating pseudoexon insertion and that antisense morpholino oligonucleotide (AMO) treatment in patient fibroblasts leads to recovery of MUT activity to levels 25 to 100% of control range. On the contrary, the change c.1957-920C>A, identified in two fibroblasts cell lines in cis with c.1885A>G (p.R629G) or c.458T>A (p.D153V), appears to be a rare variant of uncertain clinical significance. The functional analysis of c.1885A>G and c.458T>A indicate that they are the disease-causing mutations in these two patients. The results presented here highlight the necessity of scanning the described intronic region for mutations in MUT-affected patients, followed by functional analyses to demonstrate the pathogenicity of the identified changes, and extend previous work of the applicability of the antisense approach in methylmalonic aciduria (MMAuria) for a novel intronic mutation. Hum Mutat 30:1676-1682, 2009. (C) 2009 Wiley-Liss, Inc.
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