A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.
(49/151)
Primary cilium dysfunction underlies the pathogenesis of Bardet-Biedl syndrome (BBS), a genetic disorder whose symptoms include obesity, retinal degeneration, and nephropathy. However, despite the identification of 12 BBS genes, the molecular basis of BBS remains elusive. Here we identify a complex composed of seven highly conserved BBS proteins. This complex, the BBSome, localizes to nonmembranous centriolar satellites in the cytoplasm but also to the membrane of the cilium. Interestingly, the BBSome is required for ciliogenesis but is dispensable for centriolar satellite function. This ciliogenic function is mediated in part by the Rab8 GDP/GTP exchange factor, which localizes to the basal body and contacts the BBSome. Strikingly, Rab8(GTP) enters the primary cilium and promotes extension of the ciliary membrane. Conversely, preventing Rab8(GTP) production blocks ciliation in cells and yields characteristic BBS phenotypes in zebrafish. Our data reveal that BBS may be caused by defects in vesicular transport to the cilium. (+info)
Gene expression analysis of photoreceptor cell loss in bbs4-knockout mice reveals an early stress gene response and photoreceptor cell damage.
(50/151)
PURPOSE: To identify and characterize gene expression changes associated with photoreceptor cell loss in a Bbs4-knockout mouse model of retinal degeneration. METHODS: Differential gene expression in the eyes of 5-month-old Bbs4(-/-) mice undergoing retinal degeneration were analyzed using gene microarrays (Affymetrix, Santa Clara, CA). Elevated ocular transcripts were confirmed by Northern blotting of RNA from Bbs4(-/-) and three additional mouse models of Bardet-Biedl Syndrome (BBS). TUNEL assays and transmission electron microscopy were used to study cell death and photoreceptor morphology in these mice. RESULTS: Three hundred fifty-four probes were differentially expressed in Bbs4(-/-) eyes compared with controls using a twofold cutoff. Numerous vision-related transcripts decreased because of photoreceptor cell loss. Increased expression of the stress response genes Edn2, Lcn2, Serpina3n, and Socs3 was noted at 5 months of age and as early as postnatal week 4 in the eyes of four BBS mouse model strains. A burst of apoptotic activity in the photoreceptor outer nuclear layer at postnatal week 2 and highly disorganized outer segments by postnatal weeks 4 to 6 was observed in all four strains. CONCLUSIONS: The specific loss of photoreceptors in Bbs4(-)(/)(-) mice allows us to identify a set of genes that are preferentially expressed in photoreceptors compared with other cell types found in the eye and is a valuable resource in the continuing search for genes involved in retinal disease. The molecular and morphologic changes observed in young BBS animal model eyes implies that BBS proteins play a critical, early role in establishing the correct structure and function of photoreceptors. (+info)
Renal transplantation in patients with Bardet-Biedl syndrome.
(51/151)
BACKGROUND: Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, polydactyly of hands and feet, retinitis pigmentosa, hypogenitalism, various degrees of intellectual impairment and renal anomalies. Other clinical features include speech disorder, brachydactyly, developmental delay, polyuria/polydipsia, ataxia, poor coordination/clumsiness, diabetes mellitus, left ventricular hypertrophy, hepatic fibrosis, and renal hypoplasia/dysplasia. If spasticity and mental retardation present, it fulfills the criteria for Laurence-Moon-Bardet-Biedl syndrome. METHODS: Between July 1985 and January 2005, 2,282 kidney transplantations were performed at Labbafinejad Medical Center, of whom 262 were children under 15 years of age (61% males). Among children, five (four females) had Bardet-Biedl syndrome who were transplanted preemptively. Kidneys were taken from living unrelated donors. RESULTS: All five patients had retinitis pigmentosa and obesity with body mass index up to 39.33 kg/m(2). The cause of end-stage renal failure was reflux nephropathy in one, neurogenic bladder in one, and renal hypoplasia/dysplasia in three patients. The mean age at transplantation was 11 years (range: 6-17 years). Immunosuppressives administered were prednisolone, cyclosporine, and mycophenolate mofetil. All of them suffered at least one episode of acute rejection shortly after transplantation but reversed with methylprednisolone pulses; in the last follow-up, the mean creatinine was 1.2 (range: 0.6 - 2.3 mg/dL). The mean glomerular filtration rate before transplantation was 10 mL/min/1.73 m(2); in the last follow-up it was 79 (range: 38-137). CONCLUSION: Renal transplantation is a safe and successful procedure and renal replacement therapy of choice in patients with Bardet-Biedl syndrome and end-stage renal failure, but special attention should be paid to body mass index and steroid-free immunosuppression if other suitable drugs, such as sirolimus and basiliximab are affordable. (+info)
Retinal degeneration in children: dark adapted visual threshold and arteriolar diameter.
(52/151)
To assess the condition of the retina in children with retinal degeneration due to Bardet-Biedl syndrome (BBS, n=41), Leber congenital amaurosis (LCA, n=31), or Usher syndrome (USH, n=13), the dark adapted visual threshold (DAT) and arteriolar diameters were measured. Compared to controls, the initial DATs of nearly all (83/85) were significantly elevated, and in 26/62 with serial DATs, significant progressive elevation occurred. Arteriolar diameters were significantly attenuated and narrowed with age in BBS and USH, but not LCA. Higher DATs were associated with narrower arterioles. Such non-invasive procedures can document the natural history of these retinal diseases and have the potential to assess response to future treatment. (+info)
Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function.
(53/151)
Reception and interpretation of environmental stimuli is critical for the survival of all organisms. Here, we show that the ablation of BBS1 and BBS4, two genes mutated in Bardet-Biedl syndrome and that encode proteins that localize near the centrioles of sensory neurons, leads to alterations of s.c. sensory innervation and trafficking of the thermosensory channel TRPV1 and the mechanosensory channel STOML3, with concomitant defects in peripheral thermosensation and mechanosensation. The thermosensory phenotype is recapitulated in Caenorhabditis elegans, because BBS mutants manifest deficient thermosensory responses at both physiological and nociceptive temperatures and defective trafficking of OSM-9, a polymodal sensory channel protein and a functional homolog of TRPV1 or TRPV4. Our findings suggest a hitherto unrecognized, but essential, role for mammalian basal body proteins in the acquisition of mechano- and thermosensory stimuli and highlight potentially clinical features of ciliopathies in humans. (+info)
Retinal morphology in patients with BBS1 and BBS10 related Bardet-Biedl Syndrome evaluated by Fourier-domain optical coherence tomography.
(54/151)
Retinal dystrophy in Bardet-Biedl Syndrome (BBS) is caused by defective genes that are expressed within ciliated cells such as photoreceptors. The purpose of this study was to characterize and compare the retinal structure and lamination of two groups of patients, carrying mutations in BBS1 or BBS10. Eight patients with BBS (ages 11.9-28.5 years) and mutations in BBS1 (4/8) or BBS10 (4/8) were tested. A high-resolution hand-held probe Fourier-domain optical coherence tomography system (Fd-OCT) was used for retinal image acquisition. Macular scans were evaluated with respect to structure, retinal layering and photoreceptor integrity. Micro-structural in-vivo analysis showed abnormalities within retinal layers but preserved retinal lamination. Photoreceptor integrity was disrupted in all patients. Macular scans from patients with BBS10 mutations most often showed 'deposits' adjacent and anterior to Bruch's membrane. Age, genotype and presence of macular changes did not correlate with the structural changes observed. Retinal dystrophy in BBS is reflected by major changes in the outer retinal layers. This is the first report of in-vivo micro-structural analysis of retinal layers in patients with BBS. Mutations in different BBS genes seem to be associated with similar micro-structural changes in retinal layers. (+info)
Impaired photoreceptor protein transport and synaptic transmission in a mouse model of Bardet-Biedl syndrome.
(55/151)
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. (+info)
Making sense of cilia and flagella.
(56/151)
Data reported at an international meeting on the sensory and motile functions of cilia, including the primary cilium found on most cells in the human body, have thrust this organelle to the forefront of studies on the cell biology of human disease. (+info)