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Molecular basis of the obesity associated with Bardet-Biedl syndrome.

ABSTRACT: Bardet-Biedl Syndrome (BBS) is a rare human hereditary disorder associated with several features including obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. This article discusses the abnormalities accounting for energy imbalance leading to obesity in BBS, with emphasis on the recent evidence pointing to aberrations in hypothalamic action of leptin. Indeed, BBS proteins have emerged as important mediators of leptin receptor trafficking, and loss of BBS genes results in leptin resistance that could be due to abnormal leptin receptor handling in a subset of leptin-responsive neurons. These recent discoveries hold promise for improved clinical management of BBS patients. The relevance of these findings to non-syndromic common obesity is also discussed.

SUBMITTER: Guo DF

PROVIDER: S-EPMC3130119 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Molecular basis of the obesity associated with Bardet-Biedl syndrome.

Guo Deng-Fu DF Rahmouni Kamal K

Trends in endocrinology and metabolism: TEM 20110421 7

Bardet-Biedl Syndrome (BBS) is a rare human hereditary disorder associated with several features including obesity, retinopathy, renal defects, polydactyly, learning disabilities and hypogenitalism. This article discusses the abnormalities accounting for energy imbalance leading to obesity in BBS, with emphasis on the recent evidence pointing to aberrations in hypothalamic action of leptin. Indeed, BBS proteins have emerged as important mediators of leptin receptor trafficking, and loss of BBS g ...[more]

PMID: 21514177

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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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Bardet-Biedl syndrome: Weight patterns and genetics in a rare obesity syndrome.

Project description:BackgroundBardet-Biedl syndrome (BBS) is a rare genetic disorder that severely inhibits primary cilia function. BBS is typified by obesity in adulthood, but pediatric weight patterns, and thus optimal periods of intervention, are poorly understood.ObjectivesTo examine body mass differences by age, gender, and genotype in children and adolescents with BBS.MethodsWe utilized the largest international registry of BBS phenotypes. Anthropometric and genetic data were obtained from medical records or participant/family interviews. Participants were stratified by age and sex categories. Genotype and obesity phenotype were investigated in a subset of participants with available data.ResultsHeight and weight measurements were available for 552 unique individuals with BBS. The majority of birth weights were in the normal range, but rates of overweight or obesity rapidly increased in early childhood, exceeding 90% after age 5. Weight z-scores in groups >2 years were above 2.0, while height z-scores approached 1.0, but were close to 0.0 in adolescents. Relative to those with the BBS10 genotype, the BBS1 cohort had a lower BMI z-score in the 2-5 and 6-11 age groups, with similar BMI z-scores thereafter. Children with biallelic loss of function (LOF) genetic variants had significantly higher BMI z-scores compared to missense variants.ConclusionDespite normal birth weight, most individuals with BBS experience rapid weight gain in early childhood, with high rates of overweight/obesity sustained through adolescence. Children with LOF variants are disproportionally affected. Our findings support the need for earlier recognition and initiation of weight management therapies in BBS.

| S-EPMC7816264 | biostudies-literature

Bardet-Biedl syndrome: Genetics, molecular pathophysiology, and disease management.

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Bardet-Biedl syndrome: a molecular and phenotypic study of 18 families.

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| S-EPMC1050859 | biostudies-other

Bardet-Biedl syndrome: beyond the cilium.

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.

| S-EPMC6904379 | biostudies-literature

Prevalence of Bardet-Biedl syndrome in Tunisia.

Project description:Bardet-Biedl syndrome (BBS, OMIM 209900) is a ciliopathy causing multivisceral abnormalities. This disease is mainly characterized by obesity, post-axial polydactyly, hypogenitalism, intellectual disabilities, pigmentary retinopathy, and renal deficiency. The prevalence of BBS has been estimated in different populations, ranging from 1 in 160,000 in European populations to 1 in 13,000 in Bedouins from Kuwait. In the present report, we present the first epidemiological study of Bardet-Biedl syndrome in Tunisia. From 1984 to 2009, 46 Tunisian families, including 67 affected members, were diagnosed as BBS. The patients' ages ranged between 6 months and 37 years, with median age of 10.4 years. High level of consanguinity was noted in our cohort (93.47%). The overall minimum prevalence in our population was estimated to be approximately 1 in 156,000 individuals. Our study reflects the actual frequency of BBS in North Africa and showed that this disease seems uncommon.

| S-EPMC3186025 | biostudies-literature

Hyperphagia among patients with Bardet-Biedl syndrome.

Project description:BACKGROUND:The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. METHODS:We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. RESULTS:Total hyperphagia questionnaire score was higher in BBS than controls (27.6?±?9.0 vs. 19.1?±?7.9, P?=?0.005). Behaviour and drive subscales were higher for BBS than controls (12.5?±?4.1 vs. 7.8?±?3.2, P?=?0.001, and 11.2?±?4.1 vs. 8.3?±?3.8, P?=?0.04, respectively); severity was not significantly different between groups (3.8?±?1.5 vs. 3.0?±?1.3, P?=?0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. CONCLUSION:Appetite dysregulation may contribute to obesity in BBS.

| S-EPMC3901011 | biostudies-literature

Molecular architecture of the Bardet-Biedl syndrome protein 2-7-9 subcomplex.

Project description:Bardet-Biedl syndrome (BBS) is a genetic disorder characterized by malfunctions in primary cilia resulting from mutations that disrupt the function of the BBSome, an 8-subunit complex that plays an important role in protein transport in primary cilia. To better understand the molecular basis of BBS, here we used an integrative structural modeling approach consisting of EM and chemical cross-linking coupled with MS analyses, to analyze the structure of a BBSome 2-7-9 subcomplex consisting of three homologous BBS proteins, BBS2, BBS7, and BBS9. The resulting molecular model revealed an overall structure that resembles a flattened triangle. We found that within this structure, BBS2 and BBS7 form a tight dimer through a coiled-coil interaction and that BBS9 associates with the dimer via an interaction with the ?-helical domain of BBS2. Interestingly, a BBS-associated mutation of BBS2 (R632P) is located in its ?-helical domain at the interface between BBS2 and BBS9, and binding experiments indicated that this mutation disrupts the BBS2-BBS9 interaction. This finding suggests that BBSome assembly is disrupted by the R632P substitution, providing molecular insights that may explain the etiology of BBS in individuals harboring this mutation.

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Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome.

Project description:Aim: To report an analysis of ~1 year of setmelanotide treatment for obesity and hunger, as well as metabolic and cardiac outcomes, in individuals with Bardet-Biedl syndrome (BBS).Materials and methods: Individuals aged 12?years and older with BBS received once-daily setmelanotide. The dose was titrated every 2?weeks to establish the individual therapeutic dose (?3?mg); treatment continued for an additional 10?weeks. Participants who lost 5 kg or more (or ?5% of body weight if <100?kg at baseline) continued into the 52-week extension phase. The primary outcome was mean percent change from baseline in body weight at 3 months. Hunger scores and safety were secondary outcomes.Results: From February 2017 and February 2018, 10 individuals were screened; eight completed the 3-month treatment phase and seven completed the extension phase. Mean percent change in body weight from baseline to 3 months was -5.5% (90% CI, -9.3% to -1.6%; n = 8); change from baseline was -11.3% (90% CI, -15.5% to -7.0%; n = 8) at 6 months and -16.3% (90% CI, -19.9% to -12.8%; n = 7) at 12?months. All participants reported at least one treatment-emergent adverse event (AE), most commonly injection-site reaction. No AEs led to study withdrawal or death. Most, morning, and average hunger scores were reduced across time points.Conclusions: Setmelanotide reduced body weight and hunger in individuals with BBS and had a safety profile consistent with previous reports. Setmelanotide may be a treatment option in individuals with BBS-associated obesity and hyperphagia.

| S-EPMC7689750 | biostudies-literature

Update on the genetics of bardet-biedl syndrome.

Project description:Bardet-Biedl syndrome (BBS) is an autosomal recessive disease characterized by retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, renal involvement, and male hypogenitalism. BBS is genetically heterogeneous, and to date 18 genes (BBS1-18) have been described. Mutations in known BBS genes account for approximately 70-80% of cases, and triallelic inheritance has been suggested in about 5%. Many minor features can be helpful in making the clinical diagnosis. Recently, the use of next-generation sequencing technologies has accelerated the identification of novel genes and causative disease mutations in known genes. This report presents a concise overview of the current knowledge on clinical data in BBS and the progress in molecular genetics research. A future objective will be the development of BBS diagnosis kits in order to offer genetic counseling for families at risk.

| S-EPMC3977223 | biostudies-literature

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