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The prevalent deep intronic c. 639+919 GNA GLA mutation causes pseudoexon activation and Fabry disease by abolishing the binding of hnRNPA1 and hnRNP A2/B1 to a splicing silencer

Mol Genet Metab. 2016-11; 
Palhais B, Dembic M, Sabaratnam R, Nielsen KS, Doktor TK, Bruun GH, Andresen BS.
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Mutagenesis Services The minigenes containing the c.936+919GNA and the A1-2ANC mutations in the GLA pseudoexon were provided by GeneScript Inc. (GenScript, Piscataway, NJ, USA). Get A Quote

摘要

Fabry disease is an X-linked recessive inborn disorder of the glycosphingolipid metabolism, caused by total or partial deficiency of the lysosomal α-galactosidase A enzyme due to mutations in the GLA gene. The prevalent c.639+919 G>A mutation in GLA leads to pathogenic insertion of a 57bp pseudoexon sequence from intron 4, which is responsible for the cardiac variant phenotype. In this study we investigate the splicing regulatory mechanism leading to GLA pseudoexon activation. Splicing analysis of GLA minigenes revealed that pseudoexon activation is influenced by cell-type. We demonstrate that the wild-type sequence harbors an hnRNP A1 and hnRNP A2/B1-binding exonic splicing silencer (ESS) overlapping the 5'sp... More

关键词

ESE; ESS; Fabry disease; GLA; Pseudoexon; Splice switching oligonucleotide (SSO); hnRNP A1 hnRNP A2/B1; hnRNP F/H