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

Qihong Zhang; Seongjin Seo; Kevin Bugge; Edwin M Stone; Val C Sheffield

doi:10.1093/hmg/dds004

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

Journal article

Open access

Peer reviewed

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

Qihong Zhang, Seongjin Seo, Kevin Bugge, Edwin M Stone and Val C Sheffield

Human molecular genetics, Vol.21(9), pp.1945-1953

05/01/2012

DOI: 10.1093/hmg/dds004

PMCID: PMC3315203

PMID: 22228099

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Abstract

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.

Bardet-Biedl Syndrome - metabolism

Microtubule-Associated Proteins - genetics

Receptors, G-Protein-Coupled - metabolism

Microtubule-Associated Proteins - metabolism

Humans

Hedgehog Proteins - metabolism

Male

Transfection

Hedgehog Proteins - genetics

Smoothened Receptor

Tumor Suppressor Proteins - genetics

Bardet-Biedl Syndrome - genetics

Female

Patched Receptors

Recombinant Proteins - metabolism

Tumor Suppressor Proteins - metabolism

Signal Transduction

Cells, Cultured

Mutant Proteins - genetics

Receptors, Cell Surface - metabolism

Mutant Proteins - metabolism

Recombinant Proteins - genetics

Cilia - metabolism

Mice, Knockout

Pregnancy

Phenotype

Animals

Mice

Receptors, G-Protein-Coupled - genetics

Patched-1 Receptor

Receptors, Cell Surface - genetics

Details

Title: Subtitle: BBS proteins interact genetically with the IFT pathway to influence SHH-related phenotypes
Creators: Qihong Zhang - Department of Pediatrics, Howard Hughes Medical Institute, University of Iowa, 4181 MERF, Iowa City, IA 52242, USA
Seongjin Seo
Kevin Bugge
Edwin M Stone
Val C Sheffield
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.21(9), pp.1945-1953
DOI: 10.1093/hmg/dds004
PMID: 22228099
PMCID: PMC3315203
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: Howard Hughes Medical Institute R01EY017168 / NEI NIH HHS R01EY110298 / NEI NIH HHS
Language: English
Date published: 05/01/2012
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983979957602771

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