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U1 snRNA‐mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

U1 snRNA‐mediated gene therapeutic correction of splice defects caused by an exceptionally mild... 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.Hum Mutat 32:815–824, 2011. © 2011 Wiley‐Liss, Inc. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Human Mutation Wiley

U1 snRNA‐mediated gene therapeutic correction of splice defects caused by an exceptionally mild BBS mutation

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References (45)

Publisher
Wiley
Copyright
Copyright © 2011 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1059-7794
eISSN
1098-1004
DOI
10.1002/humu.21509
pmid
21520335
Publisher site
See Article on Publisher Site

Abstract

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.Hum Mutat 32:815–824, 2011. © 2011 Wiley‐Liss, Inc.

Journal

Human MutationWiley

Published: Jul 1, 2011

Keywords: retinitis pigmentosa; splice defect; gene therapy; BBS1; U1 snRNA; splicing

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