title: Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome.
abstract: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized primarily by retinal dystrophy, obesity, polydactyly, renal malformations and learning disabilities. Although five BBS genes have been cloned, the molecular basis of this syndrome remains elusive. Here we show that BBS is probably caused by a defect at the basal body of ciliated cells. We have cloned a new BBS gene, BBS8, which encodes a protein with a prokaryotic domain, pilF, involved in pilus formation and twitching mobility. In one family, a homozygous null BBS8 mutation leads to BBS with randomization of left-right body axis symmetry, a known defect of the nodal cilium. We have also found that BBS8 localizes specifically to ciliated structures, such as the connecting cilium of the retina and columnar epithelial cells in the lung. In cells, BBS8 localizes to centrosomes and basal bodies and interacts with PCM1, a protein probably involved in ciliogenesis. Finally, we demonstrate that all available Caenorhabditis elegans BBS homologues are expressed exclusively in ciliated neurons, and contain regulatory elements for RFX, a transcription factor that modulates the expression of genes associated with ciliogenesis and intraflagellar transport.
authors.affiliation: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Ansley
authors.forename: Jose L
authors.initials: JL
authors.lastname: Badano
authors.forename: Oliver E
authors.initials: OE
authors.lastname: Blacque
authors.forename: Josephine
authors.initials: J
authors.lastname: Hill
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.forename: Jun Chul
authors.initials: JC
authors.lastname: Kim
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ross
authors.forename: Erica R
authors.initials: ER
authors.lastname: Eichers
authors.forename: Tanya M
authors.initials: TM
authors.lastname: Teslovich
authors.forename: Allan K
authors.initials: AK
authors.lastname: Mah
authors.forename: Robert C
authors.initials: RC
authors.lastname: Johnsen
authors.forename: John C
authors.initials: JC
authors.lastname: Cavender
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Lewis
authors.forename: Michel R
authors.initials: MR
authors.lastname: Leroux
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018385:Centrosome / Q000378:metabolism / Q000473:pathology; D002923:Cilia / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D011506:Proteins; D012333:RNA, Messenger; C478138:TTC8 protein, human