Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning

Marwan K Tayeh; Hsan-Jan Yen; John S Beck; Charles C Searby; Trudi A Westfall; Hilary Griesbach; Val C Sheffield; Diane C Slusarski

doi:10.1093/hmg/ddn093

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Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning

Journal article

Open access

Peer reviewed

Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning

Marwan K Tayeh, Hsan-Jan Yen, John S Beck, Charles C Searby, Trudi A Westfall, Hilary Griesbach, Val C Sheffield and Diane C Slusarski

Human molecular genetics, Vol.17(13), pp.1956-1967

07/01/2008

DOI: 10.1093/hmg/ddn093

PMCID: PMC2900902

PMID: 18381349

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Abstract

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.

Polydactyly - genetics

Species Specificity

Cartilage - pathology

Polydactyly - physiopathology

Zebrafish Proteins - metabolism

Humans

Embryo, Nonmammalian - metabolism

Gene Expression Regulation

Gene Silencing

Hedgehog Proteins - metabolism

Zebrafish

Bardet-Biedl Syndrome - physiopathology

Extremities - embryology

Phenotype

Animals

Body Patterning

Bardet-Biedl Syndrome - genetics

Zebrafish Proteins - genetics

Embryo, Nonmammalian - physiology

Disease Models, Animal

Extremities - physiopathology

Details

Title: Subtitle: Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning
Creators: Marwan K Tayeh - Department of Pediatrics, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA
Hsan-Jan Yen
John S Beck
Charles C Searby
Trudi A Westfall
Hilary Griesbach
Val C Sheffield
Diane C Slusarski
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.17(13), pp.1956-1967
Publisher: England
DOI: 10.1093/hmg/ddn093
PMID: 18381349
PMCID: PMC2900902
ISSN: 0964-6906
eISSN: 1460-2083
Grant note: EY017168 / NEI NIH HHS Howard Hughes Medical Institute CA112369 / NCI NIH HHS EY011298 / NEI NIH HHS
Language: English
Date published: 07/01/2008
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Biology; Ophthalmology and Visual Sciences
Record Identifier: 9983992098002771

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