Monday 29 September 2003
Definition: Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive genetic disorder with the primary features of obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism.
Bardet-Biedl syndrome (BBS) is characterised by progressive pigmentary retinopathy, obesity, hypogenitalism, renal involvement (including cysts, renal cortical loss or reduced ability to concentrate urine), mild mental retardation and postaxial polydactyly of the hands and feet.
BBS is genetically heterogeneous with at least 12 loci and 10 genes identified, all involved in ciliary function. Hirschsprung disease has been reported in several BBS cases.
BBS and MKS, although distinct clinically, are allelic forms of the same molecular spectrum (MKS1, MKS3 and CEP290-NPHP6 germline mutations).
- situs inversus (#17163542#, #10602122#)
- progressive retinal dystrophy
- rod-cone dystrophy, onset be end of 2nd decade (major)
- retinitis pigmentosa
- high arched palate
- dental crowding
- small tooth roots
- left ventricular hypertrophy
- cardiac malformations
- with bile-duct proliferation
- without bile-duct proliferation
Hirschsprung disease (<10%) (#10602122#)
renal anomalies (major)
- medullary-predominant cystic kidneys
nephrogenic diabetes insipidus
postaxial polydactyly (major)
Etiology (Seven loci)
Eight BBS-associated genes have been identified so far by positional cloning. For most of the encoded proteins it was shown that they localize to basal bodies and/or centrosomes.
BBS1 (11q13) (#12524598#) (30-40%)
BBS3 (3p13-p12) (ARL6)
- Using bioinformatic screens for ciliary genes in combination with data from positional cloning, mutations in ADP-ribosylation factor-like 6 (ARL6) were identified as responsible for BBS3.
- ARL6, a small GTPase, is specifically expressed in ciliated cells and undergoes intraflagellar transport.
- BBS4 protein, as BBS8, (also known as tetratricopeptide repeat domain 8, TTC8) directly interacts with pericentriolar material 1 (PCM1), a component of the pericentriolar material.
- BBS4 is essential for recruiting proteins to the pericentrosomal matrix, confirming the role of centrosomal function in the pathogenesis of BBS.
- A bioinformatics approach that is based on the ciliary and basal body hypothesis of BBS pathogenesis also helped to identify the BBS5 gene, which encodes a novel protein.
-* BBS8 protein (also known as tetratricopeptide repeat domain 8, TTC8), as BBS4, directly interacts with pericentriolar material 1 (PCM1), a component of the pericentriolar material.
Genetic and mutational analyses have indicated that, in some families, a combination of three mutant alleles at two loci (triallelic inheritance) is necessary for pathogenesis (oligogenic disease transmission).
Most Bardet-Biedl syndrome (BBS) protein orthologues are expressed in basal bodies of motile cilia throughout evolution, including in the flagella of the unicellular organism Chlamydomonas reinhardtii; mutations in these genes lead to defective intraflagellar transport (IFT) or propulsion.
BBS is a pleiotropic disorder that is characterized by retinal degeneration, obesity, learning difficulties and polydactyly, as well as gonadal malformations and renal malformations including cystic kidney diseases (CKDs). These defects are thought to be caused by centrosomal and ciliary dysfunction.
Thus, the importance of the centrosome and the basal body in orchestrating and possibly regulating cargo trafficking to maintain structural and functional ciliary integrity is highlighted by recent studies in BBS.
In mammalian cell lines, at least two of the eight known BBS proteins, BBS4 and BBS8, localize to centrosomes and basal bodies.
Yeast two-hybrid assays and co-immunoprecipitation in mammalian cells shows that these proteins interact with PCM1, a known component of the pericentriolar satellites.
In vitro and in vivo studies have demonstrated that BBS4 is required for the correct localization of PCM1 to the pericentriolar satellites and that depletion of BBS4 through RNAi leads to microtubule network disorganization.
Consistent with a role of the BBS proteins (BBSs) in centrosome/basal body organization and ciliary function, translational Bbs-Gfp transgenes for bbs-1, bbs-2, bbs-7 and bbs-8 show specific signals at the ciliary transition zones (basal bodies) and axonemes, BBS-GFP fusion proteins undergo IFT, and loss of function of bbs-7 and bbs-8 leads to shortened cilia and defective IFT of some IFT proteins.
For example, loss of BBS-7 and BBS-8 in Caenorhabditis elegans causes defective IFT of OSM-5 and CHE-11 - proteins that are involved in osmotic avoidance and chemotaxis respectively.
Similarly to inversin (INVS), some of the BBS proteins could also provide a functional link between cilia and the interior of the cell.
BBS8 shows limited similarity to the budding yeast cdc23 protein, a member of the APC, although the biological relevance of these findings needs further evaluation.
BBS3 is a member of the ARF family of small GTP-binding proteins that regulate vesicle trafficking. In C. elegans, BBS-3 localizes to the cytoplasm, transition zone (basal body) and cilia of ciliated sensory neurons and undergoes IFT, thereby offering a possible direct link between axonemal and cytoplasmic transport of specific cargo.
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