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Inactivation of Bardet-Biedl syndrome genes causes kidney defects.

ABSTRACT: Bardet-Biedl syndrome (BBS) is a rare hereditary autosomal recessive disease associated with several features including obesity, hypertension, and renal abnormalities. The underlying mechanisms of renal defects associated with BBS remain poorly defined. We examined the histological, molecular, and functional renal changes in BBS mouse models that have features of the human disorder. Interestingly, obese hypertensive Bbs4(-/-) mice exhibited inflammatory infiltration and renal cysts, whereas the obese normotensive Bbs2(-/-) mice had only minor inflammatory infiltration. Accordingly, the expression level of inducible nitric oxide synthase was elevated in the kidney of both BBS mice with a more marked increase in Bbs4(-/-) mice. In contrast, endothelial nitric oxide synthase expression was decreased in Bbs4(-/-), but not Bbs2(-/-), mice. Similarly, the expression levels of transient receptor potential vanilloid 1 and 4 channels as well as β- and γ-subunits of epithelial Na channel were significantly reduced only in the kidney of Bbs4(-/-) mice. Metabolic studies revealed changes in urine output and urinary concentrations of creatinine, blood urea nitrogen, sodium, and potassium with a more pronounced effect in Bbs4(-/-) mice. Finally, we found that calorie restriction which prevented obesity in BBS mice reversed the morphological and molecular changes found in Bbs2(-/-) and Bbs4(-/-) mice, indicating the kidney abnormalities associated with BBS are obesity related. These findings extend our understanding of the function of BBS proteins and emphasize the importance of these proteins in renal physiology.

SUBMITTER: Guo DF

PROVIDER: S-EPMC3043995 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Kidney failure in Bardet-Biedl syndrome.

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| S-EPMC9311438 | biostudies-literature

Loss of Bardet Biedl syndrome proteins causes defects in peripheral sensory innervation and function.

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Bardet-Biedl syndrome.

Project description:Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterised by retinal dystrophy, obesity, post-axial polydactyly, renal dysfunction, learning difficulties and hypogonadism. Many associated minor features can be helpful in making a diagnosis and are important in the clinical management of BBS. The diagnosis is based on clinical findings and can be confirmed by sequencing of known disease-causing genes in 80% of patients. BBS genes encode proteins that localise to the cilia and basal body and are involved in cilia biogenesis and function. Mutations lead to defective cilia accounting in part for the pleiotropic effects observed in BBS. We provide an overview of BBS including the clinical findings, current understanding of cilia biology, and a practical approach to diagnosis, genetic counselling and up-to-date management.

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Hyperactive neuroendocrine secretion causes size, feeding, and metabolic defects of C. elegans Bardet-Biedl syndrome mutants.

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Knockdown of Bardet-Biedl syndrome gene BBS9/PTHB1 leads to cilia defects.

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Loss of Bardet-Biedl syndrome proteins causes synaptic aberrations in principal neurons.

Project description:Bardet-Biedl syndrome (BBS), a ciliopathy, is a rare genetic condition characterised by retinal degeneration, obesity, kidney failure, and cognitive impairment. In spite of progress made in our general understanding of BBS aetiology, the molecular and cellular mechanisms underlying cognitive impairment in BBS remain elusive. Here, we report that the loss of BBS proteins causes synaptic dysfunction in principal neurons, providing a possible explanation for the cognitive impairment phenotype observed in BBS patients. Using synaptosomal proteomics and immunocytochemistry, we demonstrate the presence of Bbs proteins in the postsynaptic density (PSD) of hippocampal neurons. Loss of Bbs results in a significant reduction of dendritic spines in principal neurons of Bbs mouse models. Furthermore, we show that spine deficiency correlates with events that destabilise spine architecture, such as impaired spine membrane receptor signalling, known to be involved in the maintenance of dendritic spines. Our findings suggest a role for BBS proteins in dendritic spine homeostasis that may be linked to the cognitive phenotype observed in BBS.

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Project description:The Bardet-Biedl syndrome (BBS) is a significant genetic cause of chronic and end-stage renal failure in children. Despite being a relatively rare recessive condition, BBS has come to prominence during the past few years owing to revelations of primary cilia dysfunction underlying pathogenesis. The study of this multi-system disorder, which includes obesity, cognitive impairment, genito-urinary tract malformations and limb deformities, is beginning to reveal insights into several aspects of mammalian development and organogenesis. Involvement of BBS proteins in disparate pathways such as the non-canonical Wnt and Sonic Hedgehog pathways is highlighting their interplay in disease pathogenesis. Here we review the recent developments in this emerging field, with the emphasis on the renal component of the syndrome and potential future directions.

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Bardet-Biedl Syndrome Presenting in Adulthood.

Project description:Bardet-Biedl syndrome (BBS) is a rare disorder with a frequency of 1:1,60,000. The disease is inherited in an autosomal recessive manner. Less than 15 cases have been reported from India. We present a case of Bardet-Biedl syndrome presenting to the medical emergency with acute breathlessness because of de-compensated renal failure and salient features such as marked polydactyly, central obesity, retinitis pigmentosa, end-stage renal diseases, and mental retardation. Genetic study showed that the patient had BBS genetic variant 9 (MIM#615896), VUS variant. The patient was primarily treated for end-stage chronic renal failure with hemodialysis. We are reporting this case for its rarity and the presence of a novel genetic variant of an unidentified significance as per genome mapping. BBS is often not diagnosed at all or diagnosed late until end-stage renal failure sets in. Timely diagnosis might not help treat the condition but surely improve the quality of life for the patient.

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A novel mutation in BBS7 gene causes Bardet-Biedl syndrome in a Chinese family.

Project description:PurposeTo describe the clinical features of and identify a novel mutation in Bardet-Biedl syndrome 7 gene (BBS7) in a Chinese family.MethodsNineteen individuals at risk for inheriting Bardet-Biedl syndrome (BBS) in a Chinese family participated in the study. Physical examination was performed and blood was drawn for DNA extraction. Linkage analysis was conducted for all known BBS loci, and mutation screening of BBS7 gene and BBS12 gene was performed.ResultsA Chinese family with inherited BBS was identified. After performing linkage analysis on all 13 known loci, we found the disease phenotype of a Chinese family with BBS linked to a locus where BBS7 and BBS12 genes locate.ConclusionsThis study describes a novel mutation in BBS7 causing BBS in a Chinese family. This is the first report that a mutation in a BBS gene causes BBS in a Chinese population. These results expand the spectrum of human disease associated with mutations of BBS7 since the initial three mutations in BBS7 were first identified in 2003.

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Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families.

Project description:To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin.Linkage in two families (A and B) was established to BBS7 on chromosome 4q27, in family C to BBS8 on chromosome 14q32.1, and in family D to BBS10 on chromosome 12q21.2. Family E was investigated directly with exome sequence analysis.Sanger sequencing revealed two novel mutations and three previously reported mutations in the BBS genes. These mutations include two deletions (c.580_582delGCA, c.1592_1597delTTCCAG) in the BBS7 gene, a missense mutation (p.Gln449His) in the BBS8 gene, a frameshift mutation (c.271_272insT) in the BBS10 gene, and a nonsense mutation (p.Ser40*) in the MKKS (BBS6) gene.Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing BBS.

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