Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy.
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).
CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.
Christel
C
Vaché
Thomas
T
Besnard
Pauline
P
le Berre
Gema
G
García-García
David
D
Baux
Lise
L
Larrieu
Caroline
C
Abadie
Catherine
C
Blanchet
Hanno Jörn
HJ
Bolz
Jose
J
Millan
Christian
C
Hamel
Sue
S
Malcolm
Mireille
M
Claustres
Anne-Françoise
AF
Roux
D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005060:Europe; D059472:Exome; D005091:Exons / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D005838:Genotype; D006239:Haplotypes; D006319:Hearing Loss, Sensorineural / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use; D010375:Pedigree; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D017423:Sequence Analysis, RNA; D012720:Severity of Illness Index; D052245:Usher Syndromes / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*
D016326:Extracellular Matrix Proteins; D016376:Oligonucleotides, Antisense; C112735:USH2A protein, human