Human Molecular Genetics Advance Access originally published online on April 1, 2008
Human Molecular Genetics 2008 17(13):1956-1967; doi:10.1093/hmg/ddn093
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Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning
1 Department of Pediatrics, Howard Hughes Medical Institute 2 Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA
* To whom correspondence should be addressed at: University of Iowa, 4181 MERF, Iowa City, IA 52242, USA. Tel.: +1 3193356898; Fax: +1 3193357588; Email: val-sheffield{at}uiowa.edu
Received December 20, 2007; Revised March 6, 2008; Accepted March 18, 2008
Bardet-Biedl syndrome (BBS) is a pleiotropic, genetically heterogeneous disorder characterized by obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, as well as hypertension and diabetes. Multiple genes are known to independently cause BBS. These genes do not appear to code for the same functional category of proteins; yet, mutation of each results in a similar phenotype. Gene knockdown of different BBS genes in zebrafish shows strikingly overlapping phenotypes including defective melanosome transport and disruption of the ciliated Kupffer's vesicle. Here, we demonstrate that individual knockdown of bbs1 and bbs3 results in the same prototypical phenotypes as reported previously for other BBS genes. We utilize the zebrafish system to comprehensively determine whether simultaneous pair-wise knockdown of BBS genes reveals genetic interactions between BBS genes. Using this approach, we demonstrate eight genetic interactions between a subset of BBS genes. The synergistic relationships between distinct combinations are not due to functional redundancy but indicate specific interactions within a multi-subunit BBS complex. In addition, we utilize the zebrafish model system to investigate limb development. Human polydactyly is a cardinal feature of BBS not reproduced in BBS-mouse models. We evaluated zebrafish fin bud patterning and observed altered Sonic hedgehog (shh) expression and subsequent changes to fin skeletal elements. The SHH fin bud phenotype was also used to confirm specific genetic interactions between BBS genes. This study reveals an in vivo requirement for BBS function in limb bud patterning. Our results provide important new insights into the mechanism and biological significance of BBS.
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