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Citation
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HERO ID
2283305
Reference Type
Journal Article
Title
Functional analysis and in vitro correction of splicing FAH mutations causing tyrosinemia type I
Author(s)
Pérez-Carro, R; Sánchez-Alcudia, R; Pérez, B; Navarrete, R; Pérez-Cerdá, C; Ugarte, M; Desviat, L
Year
2014
Is Peer Reviewed?
Yes
Journal
Clinical Genetics
ISSN:
0009-9163
EISSN:
1399-0004
Volume
86
Issue
2
Page Numbers
167-171
Language
English
PMID
23895425
DOI
10.1111/cge.12243
Abstract
Hereditary tyrosinemia type I (HT1) is a rare disease caused by a deficiency of fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway, resulting mainly in hepatic alterations due to accumulation of the toxic metabolites fumarylacetoacetate, maleylacetoacetate and succinylacetone. We have characterized using minigenes four splicing mutations affecting exonic or intronic nucleotides of the FAH gene identified in two HT1 patients. Two of the mutations are novel, c.82-1G>A and c.913G>C and the other two have been previously associated with a splicing defect (c.836A>G and c.1062+5G>A). All mutations were confirmed to affect splicing in minigenes, resulting in exon skipping or activation of a cryptic splice site. We have analyzed the effect of different compounds known to modulate splicing (valproic acid, phenyl butyrate, M344, EIPA, and resveratrol) and the overexpression of splice factors of the SR protein family on the transcriptional profile of the mutant minigenes. For the c.836A>G mutation, a partial recovery of the correctly spliced transcript was observed. These results confirm the relevance of performing functional studies for mutations potentially affecting the splicing process and open the possibility of supplementary therapeutic approaches to diseases caused by splicing defects.
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n-Butanol
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Pubmed
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Pubmed - 3/2014
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Not chemical specific
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