BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes

There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet–Biedl syndrome (BBS) is a hetero...

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Main Authors:	Zhang, Qihong, Seo, Seongjin, Bugge, Kevin, Stone, Edwin M., Sheffield, Val C.
Format:	Online
Language:	English
Published:	Oxford University Press 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315203/

id	pubmed-3315203
recordtype	oai_dc
spelling	pubmed-33152032012-03-30 BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes Zhang, Qihong Seo, Seongjin Bugge, Kevin Stone, Edwin M. Sheffield, Val C. Articles There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet–Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7−/− mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect. Oxford University Press 2012-05-01 2012-01-06 /pmc/articles/PMC3315203/ /pubmed/22228099 http://dx.doi.org/10.1093/hmg/dds004 Text en © The Author 2012. Published by Oxford University Press http://creativecommons.org/licenses/by-nc/2.5/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zhang, Qihong Seo, Seongjin Bugge, Kevin Stone, Edwin M. Sheffield, Val C.
spellingShingle	Zhang, Qihong Seo, Seongjin Bugge, Kevin Stone, Edwin M. Sheffield, Val C. BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
author_facet	Zhang, Qihong Seo, Seongjin Bugge, Kevin Stone, Edwin M. Sheffield, Val C.
author_sort	Zhang, Qihong
title	BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
title_short	BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
title_full	BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
title_fullStr	BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
title_full_unstemmed	BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
title_sort	bbs proteins interact genetically with the ift pathway to influence shh-related phenotypes
description	There are numerous genes for which loss-of-function mutations do not produce apparent phenotypes even though statistically significant quantitative changes to biological pathways are observed. To evaluate the biological meaning of small effects is challenging. Bardet–Biedl syndrome (BBS) is a heterogeneous autosomal recessive disorder characterized by obesity, retinopathy, polydactyly, renal malformations, learning disabilities and hypogenitalism, as well as secondary phenotypes including diabetes and hypertension. BBS knockout mice recapitulate most human phenotypes including obesity, retinal degeneration and male infertility. However, BBS knockout mice do not develop polydacyly. Here we showed that the loss of BBS genes in mice result in accumulation of Smoothened and Patched 1 in cilia and have a decreased Shh response. Knockout of Bbs7 combined with a hypomorphic Ift88 allele (orpk as a model for Shh dysfuction) results in embryonic lethality with e12.5 embryos having exencephaly, pericardial edema, cleft palate and abnormal limb development, phenotypes not observed in Bbs7−/− mice. Our results indicate that BBS genes modulate Shh pathway activity and interact genetically with the intraflagellar transport (IFT) pathway to play a role in mammalian development. This study illustrates an effective approach to appreciate the biological significance of a small effect.
publisher	Oxford University Press
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315203/
_version_	1611517583160246272

BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes

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