Bardet-Biedl syndrome (BBS) is a multisystem disorder caused by ciliary defects. 
To date, mutations in 15 genes have been associated with the disease and BBS1 is 
most frequently affected in patients with BBS. The use of homozygosity mapping 
in a large consanguineous family allowed us to identify the splice donor site 
(SD) mutation c.479G>A in exon 5 of BBS1. Clinically affected family members 
show symptoms of retinitis pigmentosa (RP) but lack other primary features that 
would clearly support the diagnosis of BBS. In agreement with this exceptionally 
mild BBS1-associated phenotype, we did not detect obvious ciliary defects in 
patient-derived cells. SDs are bound by the U1 small nuclear RNA (U1), a process 
that initiates exon recognition during splicing. The mutation described herein 
interferes with U1 binding and induces aberrant splicing of BBS1. For a gene 
therapeutic approach, we have adapted the sequence of U1 to increase its 
complementarity to the mutated SD. Lentiviral treatment of patient-derived 
fibroblasts with the adapted U1 partially corrected aberrant splicing of 
endogenously expressed BBS1 transcripts. This therapeutic effect was 
dose-dependent. Our results show that the adaptation of U1 can correct 
pathogenic effects of splice donor site mutations and suggest a high potential 
for gene therapy.