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PMID: 18381349 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Human molecular genetics ·Vol. 17 ·No. 13 ·2008-07-01 ·Pages 1956-67

Tayeh MK, Yen HJ, Beck JS, Searby CC, Westfall TA, Griesbach H, Sheffield VC, Slusarski DC

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.

MeSH Terms
Animals Bardet-Biedl Syndrome/genetics,physiopathology Body Patterning Cartilage/pathology Disease Models, Animal Embryo, Nonmammalian/metabolism,physiology Extremities/embryology,physiopathology Gene Expression Regulation Gene Silencing Hedgehog Proteins/metabolism Humans Phenotype Polydactyly/genetics,physiopathology Species Specificity Zebrafish Zebrafish Proteins/genetics,metabolism
Chemicals
Bbs1 protein, zebrafish Hedgehog Proteins Zebrafish Proteins
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Tayeh Marwan K
Department of Pediatrics, Howard Hughes Medical Institute, University of Iowa, Iowa City, IA 52242, USA.
Yen Hsan-Jan
Beck John S
Searby Charles C
Westfall Trudi A
Griesbach Hilary
Sheffield Val C
Slusarski Diane C
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Article Info
Journal
Human molecular genetics
Abbr.
Hum Mol Genet
ISSN
1460-2083
DOI
10.1093/hmg/ddn093
Published
2008-07-01
Epub
2008-00-01
Pages
1956-67
Language
English
Region
England
NLM ID
9208958
PMCID
PMC2900902
Subset
IM
Grants
NCI NIH HHS · CA112369 · United States
NEI NIH HHS · EY011298 · United States
NEI NIH HHS · EY017168 · United States
Howard Hughes Medical Institute · United States
External Links
PubMed source DOI: 10.1093/hmg/ddn093 PMC Full Text View journal details
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