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Establishing a connection between cilia and Bardet–Biedl Syndrome

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Abstract

Bardet–Biedl Syndrome (BBS) is a genetic disorder with the primary features of retinal dystrophy, obesity, polydactyly, structural and functional renal abnormalities, and learning disabilities. In addition to displaying remarkable pleiotropy, BBS is a heterogeneous disorder with linkage to at least eight loci. The identification of the first five BBS genes provided little insight into BBS protein function. Ansley et al. have now identified a sixth BBS gene (BBS8) and provide evidence that the BBS8 protein and other BBS proteins localize to the basal body of ciliated cells, suggesting that BBS is a ciliary dysfunction disorder.

Section snippets

Complex inheritance of BBS

Substantial inter- and intrafamilial clinical variation in families with BBS is recognized [4]. Patients with the same mutation can manifest the disorder very differently, suggesting the existence of modifier genes. These modifier genes might be the BBS genes themselves, or other genes that do not individually result in the BBS phenotype when mutated. In support of a modifier role for the BBS genes, three families with BBS have been reported in which some, but not all, affected individuals

BBS gene identification and expression

The first three BBS genes to be identified (BBS6, BBS2 and BBS4) were identified using positional cloning and do not display homology with each other 2, 3, 7, 8. Subsequently, bioinformatic comparison of protein sequences has aided in the identification of additional BBS genes that demonstrate similarity to known BBS genes. In each case where similarity between BBS proteins has been found, the similarity is limited to small regions of the two proteins under comparison. For example, the

Cilia structure and function

Cilia are appendages that extend from the basal bodies of cells, and are classified as either motile or primary. Motile cilia, such as those that line the respiratory tract, are involved in generating flow or movement. Primary cilia, which are present in most vertebrate cells, are generally non-motile and are thought, in at least some cases, to act as sensors [14]. All cilia contain a central core structure called an axoneme, which comprises microtubules and their associated proteins arranged

Disorders of cilia function

Primary ciliary dyskinesia (PCD) comprises a group of human disorders characterized by bronchiectasis, sinusitis, dextrocardia and infertility. These disorders result from abnormalities in the genes encoding axonemal structures that are necessary for the generation of motility, most notably the dynein arms. When PCD is associated with situs inversus due to randomization of left–right asymmetry, it is called Kartagener syndrome (KS).

Defects in primary cilia are also known to cause human disease.

Unanswered questions and future research

The findings of Ansley et al. that the BBS proteins localize to the basal body of ciliated cells lead to the hypothesis that BBS results from a defect in cilia function and lay the foundation for future experiments. However, this hypothesis raises several questions that must be addressed in order to understand how basal body or ciliary dysfunction results in the pleiotropic features of BBS. For example, do BBS proteins play a role in ciliogenesis, cilia maintenance or intraflagellar transport?

Acknowledgements

This work was supported by grants from the National Institutes of Health. V.C. Sheffield is an investigator of the Howard Hughes Medical Institute.

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