Usher syndrome type 2 caused by activation of an USH2A pseudoexon: Implications for diagnosis and therapy

✍ Scribed by Christel Vaché; Thomas Besnard; Pauline le Berre; Gema García-García; David Baux; Lise Larrieu; Caroline Abadie; Catherine Blanchet; Hanno Jörn Bolz; Jose Millan; Christian Hamel; Sue Malcolm; Mireille Claustres; Anne-Françoise Roux

• Book ID: 102261340
• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 239 KB
• Volume: 33
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.21634

✦ Synopsis

USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).