The evolutionarily conserved planar cell polarity (PCP) pathway (or noncanonical Wnt pathway) drives several important cellular processes, including epithelial cell polarization, cell migration and mitotic spindle orientation. In vertebrates, PCP genes have a vital role in polarized convergent extension movements during gastrulation and neurulation. Here we show that mice with mutations in genes involved in Bardet-Biedl syndrome (BBS), a disorder associated with ciliary dysfunction, share phenotypes with PCP mutants including open eyelids, neural tube defects and disrupted cochlear stereociliary bundles. Furthermore, we identify genetic interactions between BBS genes and a PCP gene in both mouse (Ltap, also called Vangl2) and zebrafish (vangl2). In zebrafish, the augmented phenotype results from enhanced defective convergent extension movements. We also show that Vangl2 localizes to the basal body and axoneme of ciliated cells, a pattern reminiscent of that of the BBS proteins. These data suggest that cilia are intrinsically involved in PCP processes.

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.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder characterized by multiple clinical features that include pigmentary retinal dystrophy, polydactyly, obesity, developmental delay, and renal defects. BBS is considered an autosomal recessive disorder, and recent positional cloning efforts have identified two BBS genes (BBS2 and BBS6). We screened our cohort of 163 BBS families for mutations in both BBS2 and BBS6 and report the presence of three mutant alleles in affected individuals in four pedigrees. In addition, we detected unaffected individuals in two pedigrees who carry two BBS2 mutations but not a BBS6 mutation. We therefore propose that BBS may not be a single-gene recessive disease but a complex trait requiring three mutant alleles to manifest the phenotype. This triallelic model of disease transmission may be important in the study of both Mendelian and multifactorial disorders.

Defects in cilia are associated with several human disorders, including Kartagener syndrome 1 , polycystic kidney disease 2,3 , nephronophthisis 4 and hydrocephalus 5 . We proposed that the pleiotropic phenotype of Bardet-Biedl syndrome (BBS), which encompasses retinal degeneration, truncal obesity, renal and limb malformations and developmental delay, is due to dysfunction of basal bodies and cilia 6,7 . Here we show that individuals with BBS have partial or complete anosmia. To test whether this phenotype is caused by ciliary defects of olfactory sensory neurons, we examined mice with deletions of Bbs1 or Bbs4. Loss of function of either BBS protein affected the olfactory, but not the respiratory, epithelium, causing severe reduction of the ciliated border, disorganization of the dendritic microtubule network and trapping of olfactory ciliary proteins in dendrites and cell bodies. Our data indicate that BBS proteins have a role in the microtubule organization of mammalian ciliated cells and that anosmia might be a useful determinant of other pleiotropic disorders with a suspected ciliary involvement.BBS is caused by mutations in at least eight loci, seven of which have been identified 6,[8][9][10][11][12][13][14] . Although the sequences of the BBS proteins have not provided any clues to their function, BBS4, BBS5 and BBS8 are localized to the basal body of cultured cells and at ciliated borders in tissues 6,7,10 . In addition, all known orthologs of the mammalian BBS proteins are expressed specifically in ciliated sensory neurons in Caenorhabditis elegans 6,10 , raising the possibility that disruption of these proteins will lead to ciliary defects.Although the capacity to generate cilia is shared by most mammalian cells, some cells develop specialized cilia that mediate sensory function. The olfactory receptor neuron is a highly specialized example of a ciliated cell in which the apical process terminates in a complex structure, the dendritic knob, containing multiple basal bodies 15 . Eight or more immotile cilia emanate from this dendritic knob and extend more than 60 mm into the mucus. Given that at least three BBS proteins localize to the olfactory epithelium 6,7 , we considered that if ciliary defects underlie BBS, then olfactory structure and sensory function should be compromised in individuals with BBS. To test this hypothesis, we evaluated 19 individuals with BBS from 14 unrelated families using the fully validated, 12-item smell identification test. To compensate for varying degrees of visual impairment in subjects, each test was administered in a controlled setting by the same personnel. The test has a maximum possible score of 12. We compared the score of each individual with sex-derived normative data, ranked the relative degree of olfactory function by percentile and categorized olfactory function as normal (score of 9-12), abnormal (score of 8) or Ten individuals, including all three o15 y of age, scored in the normal range (9-12). Two subjects were abnormal (score of 8), and seven scored in th...

Facial recognition is central to the diagnosis of many syndromes, and craniofacial patterns may reflect common etiologies. In the pleiotropic Bardet-Biedl syndrome (BBS), a primary ciliopathy with intraflagellar transport dysfunction, patients have a characteristic facial ''gestalt'' that dysmorphologists have found difficult to characterize. Here, we use dense surface modeling (DSM) to reveal that BBS patients and mouse mutants have mid-facial defects involving homologous neural crest-derived structures shared by zebrafish morphants. These defects of the craniofacial (CF) skeleton arise from aberrant cranial neural crest cell (NCC) migration. These effects are not confined to the craniofacial region, but vagal-derived NCCs fail to populate the enteric nervous system, culminating in disordered gut motility. Furthermore, morphants display hallmarks of disrupted Sonic Hedgehog (Shh) signaling from which NCCs take positional cues. We propose a model whereby Bbs proteins modulate NCC migration, contributing to craniofacial morphogenesis and development of the enteric nervous system. These migration defects also explain the association of Hirschsprung's disease (HD) with BBS. Moreover, this is a previously undescribed method of using characterization of facial dysmorphology as a basis for investigating the pathomechanism of CF development in dysmorphic syndromes.sonic hedgehog ͉ Wnt ͉ cilia ͉ cell migration R ecognition of the facial ''gestalt'' is central to diagnosis of many genetic disorders, but the great variability of features often hinders successful classification (1). Recently, noninvasive 3D surface imaging has characterized dysmorphology in syndromes (2, 3). None, however, has been used to either define subtle facial dysmorphism or aid investigation of mechanisms for craniofacial dysmorphology.Bardet-Biedl syndrome (BBS) causes retinal degeneration, postaxial polydactyly, obesity, renal dysfunction, and cognitive impairment. Twelve BBS genes (BBS1-BBS12) have been discovered, and pathogenesis lies in primary cilia dysfunction (4). BBS4, BBS6, and BBS8 (investigated in this study) are expressed in ciliated epithelia and localize to the centrosome and basal bodies of ciliated cells (5-7). Subtle craniofacial abnormalities in patients have been reported (8-10). Among the many additional features of BBS is Hirschsprung's disease (HD), a disorder of the enteric nervous system (ENS) (11).Streams of neural crest cells (NCCs) from the caudal brain form most of the craniofacial (CF) skeleton (see ref. 12 for review). Cranial NCCs (CNCC) follow defined paths to populate the frontonasal prominence and branchial arch mesenchyme. Here, they proliferate and differentiate into structures of the face and cranium. Sonic Hedgehog (Shh) expressed in the ventral brain and oral ectoderm is essential for the formation of most facial structures (12). Shh-deficient mice have severe loss of craniofacial bones, and, in humans, SHH mutations cause midline CF defects with holoprosencephaly (HPE) (12).The ENS regulates gastrointestina...

Bardet-Biedl syndrome (BBS) is a rare oligogenic disorder exhibiting both clinical and genetic heterogeneity. Although the BBS phenotype is variable both between and within families, the syndrome is characterized by the hallmarks of developmental and learning difficulties, post-axial polydactylia, obesity, hypogenitalism, renal abnormalities, retinal dystrophy, and several less frequently observed features. Eleven genes mutated in BBS patients have been identified, and more are expected to exist, since about 20-30% of all families cannot be explained by the known loci. To investigate the etiopathogenesis of BBS, we created a mouse null for one of the murine homologues, Bbs4, to assess the contribution of one gene to the pleiotropic murine Bbs phenotype. Bbs4 null mice, although initially runted compared to their littermates, ultimately become obese in a gender-dependent manner, females earlier and with more severity than males. Blood chemistry tests indicated abnormal lipid profiles, signs of liver dysfunction, and elevated insulin and leptin levels reminiscent of metabolic syndrome. As in patients with BBS, we found age-dependent retinal dystrophy. Behavioral assessment revealed that mutant mice displayed more anxiety-related responses and reduced social dominance. We noted the rare occurrence of birth defects, including neural tube defects and hydrometrocolpos, in the null mice. Evaluations of these null mice have uncovered phenotypic features with age-dependent penetrance and variable expressivity, partially recapitulating the human BBS phenotype.

Bardet-Biedl syndrome (BBS) is an uncommon multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction. BBS has been modeled historically as an autosomal recessive trait, under which premise six independent BBS loci (BBS1-BBS6) have been mapped in the human genome. However, extended mutational analyses of BBS2 and BBS6, the first two BBS genes cloned, suggest that BBS exhibits a more complex pattern of inheritance, in which three mutations at two loci simultaneously are necessary and sufficient in some families to manifest the phenotype. We evaluated the spectrum of mutations in the recently identified BBS4 gene with a combination of haplotype analysis and mutation screening on a multiethnic cohort of 177 families. Consistent with predictions from previous genetic analyses, our data suggest that mutations in BBS4 contribute to BBS in <3% of affected families. Furthermore, integrated mutational data from all three currently cloned BBS genes raise the possibility that BBS4 may participate in triallelic inheritance with BBS2 and BBS1, but not the other known loci. Establishment of the loci pairing in triallelism is likely to be important for the elucidation of the functional relationships among the different BBS proteins.

Bardet-Biedl syndrome (BBS) is an oligogenic syndrome whose manifestations include retinal degeneration, renal abnormalities, obesity and polydactylia. Evidence suggests that the main etiopathophysiology of this syndrome is impaired intraflagellar transport (IFT). In this study, we study the Bbs4-null mouse and investigate photoreceptor structure and function after loss of this gene. We find that Bbs4-null mice have defects in the transport of phototransduction proteins from the inner segments to the outer segments, before signs of cell death. Additionally, we show defects in synaptic transmission from the photoreceptors to secondary neurons of the visual system, demonstrating multiple functions for BBS4 in photoreceptors.