leptin and Bardet-Biedl-Syndrome

Obesity is a global health problem that is associated with adverse consequences such as the development of metabolic disorders, including cardiovascular disease, neurodegenerative disorders, and type 2 diabetes. A major cause of obesity is metabolic imbalance, which results from insufficient physical activity and excess energy intake. Understanding the pathogenesis of obesity, as well as other metabolic disorders, is important in the development of methods for prevention and therapy. The coordination of energy balance takes place in the hypothalamus, a major brain region that maintains body homeostasis. The primary cilium is an organelle that has recently received attention because of its role in controlling energy balance in the hypothalamus. Defects in proteins required for ciliary function and formation, both in humans and in mice, have been shown to cause various metabolic disorders. In this review, we provide an overview of the critical functions of primary cilia, particularly in hypothalamic areas, and briefly summarize the studies on the primary roles of cilia in specific neurons relating to metabolic homeostasis.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Energy Metabolism; Homeostasis; Humans; Hypothalamus; Leptin; Metabolic Diseases; Mice; Neurons; Obesity; Proteins

The prevalence of pediatric obesity in the United States is nearly 17%. Most cases are "exogenous", resulting from excess energy intake relative to energy expenditure over a prolonged period of time. However, some cases of obesity are "endogenous", associated with hormonal, genetic, or syndromic disorders such as hypothyroidism, Cushing's syndrome, growth hormone deficiency, defective leptin signaling, mutations in the melanocortin 4 receptor, and Prader-Willi and Bardet-Biedl syndromes. This article reviews the hormonal, monogenic, and syndromic causes of childhood obesity and identifies critical features that distinguish "endogenous" obesity disorders from the more common exogenous obesity. Findings that raise suspicion for endogenous obesity include onset in infancy, lack of satiety, poor linear growth, dysmorphic features, and cognitive dysfunction. Selection and interpretation of appropriate laboratory tests and indications for subspecialist referral are also discussed.

Topics: Bardet-Biedl Syndrome; Biomarkers; Child; Diagnosis, Differential; Endocrine System Diseases; Genetic Markers; Humans; Infant; Leptin; Mutation; Pediatric Obesity; Prader-Willi Syndrome; Receptor, Melanocortin, Type 4

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.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Disease Models, Animal; Ependyma; Humans; Leptin; Obesity

Human obesity has a strong genetic component. Most genes that influence an individual's predisposition to gain weight are not yet known. However, the study of extreme human obesity caused by single gene defects has provided a glimpse into the long-term regulation of body weight. These monogenic obesity disorders have confirmed that the hypothalamic leptin-melanocortin system is critical for energy balance in humans, because disruption of these pathways causes the most severe obesity phenotypes. Approximately 20 different genes and at least three different mechanisms have been implicated in monogenic causes of obesity; however, they account for fewer than 5% of all severe obesity cases. This finding suggests that the genetic basis for human obesity is likely to be extremely heterogeneous, with contributions from numerous genes acting by various, yet undiscovered, molecular mechanisms.

Topics: Bardet-Biedl Syndrome; Basic Helix-Loop-Helix Transcription Factors; Brain-Derived Neurotrophic Factor; Humans; Leptin; Mutation; Obesity; Pro-Opiomelanocortin; Proprotein Convertase 1; Receptor, Melanocortin, Type 4; Receptors, Leptin; Repressor Proteins

Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.

Topics: alpha-MSH; Bardet-Biedl Syndrome; Cell Cycle Proteins; Child; Child, Preschool; Endocrine System Diseases; Female; Fibrous Dysplasia, Polyostotic; Fragile X Syndrome; Humans; Leptin; Male; Membrane Proteins; Obesity; Prader-Willi Syndrome; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Syndrome; Vesicular Transport Proteins; WAGR Syndrome

Consanguine families display a high degree of homozygosity which increases the risk of family members suffering from autosomal recessive disorders. Thus, homozygous mutations in monogenic obesity genes may be a more frequent cause of childhood obesity in a consanguineous population.. We identified 23 probands from 23 Pakistani families displaying autosomal recessive obesity. We have previously excluded mutations in MC4R, LEP and LEPR in all probands. Using a chip-based, target-region capture array, 31 genes involved in monogenic forms of obesity, were screened in all probands.. We identified 31 rare non-synonymous possibly pathogenic variants (28 missense and three nonsense) within the 31 selected genes. All variants were heterozygous, thus no homozygous pathogenic variants were found. Two of the rare heterozygous nonsense variants identified (p.R75X and p.R481X) were found in BBS9 within one proband, suggesting that obesity is caused by compound heterozygosity. Sequencing of the parents supported the compound heterozygous nature of obesity as each parent was carrying one of the variants. Subsequent clinical investigation strongly indicated that the proband had Bardet-Biedl syndrome.. Mutation screening in 31 genes among probands with severe early-onset obesity from Pakistani families did not reveal the presence of homozygous obesity causing variants. However, a compound heterozygote carrier of BBS9 mutations was identified, indicating that compound heterozygosity must not be overlooked when investigating the genetic etiology of severe childhood obesity in populations with a high degree of consanguinity.

Topics: Bardet-Biedl Syndrome; Body Mass Index; Child, Preschool; Codon, Nonsense; Consanguinity; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Heterozygote; Homozygote; Humans; Leptin; Male; Mutation; Pakistan; Pediatric Obesity; Pedigree; Receptor, Melanocortin, Type 4; Receptors, Leptin

Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet-Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1-/- mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Cytoskeleton; Disease Models, Animal; Energy Metabolism; Female; Fibroblasts; Hypothalamus; Leptin; Male; Mice, Inbred C57BL; Mice, Mutant Strains; Obesity; Prosencephalon; Receptors, Leptin; Signal Transduction; Transcription Factors

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by obesity, retinal degeneration, polydactyly, hypogenitalism and renal defects. Recent findings have associated the etiology of the disease with cilia, and BBS proteins have been implicated in trafficking various ciliary cargo proteins. To date, 17 different genes have been reported for BBS among which BBS1 is the most common cause of the disease followed by BBS10, and BBS4. A murine model of Bbs4 is known to phenocopy most of the human BBS phenotypes, and it is being used as a BBS disease model. To better understand the in vivo localization, cellular function, and interaction of BBS4 with other proteins, we generated a transgenic BBS4 mouse expressing the human BBS4 gene under control of the beta actin promoter. The transgene is expressed in various tissues including brain, eye, testis, heart, kidney, and adipose tissue. These mice were further bred to express the transgene in Bbs4 null mice, and their phenotype was characterized. Here we report that despite tissue specific variable expression of the transgene, human BBS4 was able to complement the deficiency of Bbs4 and rescue all the BBS phenotypes in the Bbs4 null mice. These results provide an encouraging prospective for gene therapy for BBS related phenotypes and potentially for other ciliopathies.

Topics: Animals; Bardet-Biedl Syndrome; Cilia; Disease Models, Animal; Female; Gene Expression; Genotype; Humans; Hydrocephalus; Infertility, Male; Kidney; Leptin; Male; Mice; Mice, Knockout; Mice, Transgenic; Microtubule-Associated Proteins; Obesity; Phenotype; Proteins; Retinal Diseases; Sympathetic Nervous System; Testis; Transgenes

Although primary cilia are well established as important sensory and signaling structures, their function in most tissues remains unknown. Obesity is a feature associated with some syndromes of cilia dysfunction, such as Bardet-Biedl syndrome (BBS) and Alström syndrome, as well as in several cilia mutant mouse models. Recent data indicate that obesity in BBS mutant mice is due to defects in leptin receptor trafficking and leptin resistance. Furthermore, induction of cilia loss in leptin-responsive proopiomelanocortin neurons results in obesity, implicating cilia on hypothalamic neurons in regulating feeding behavior. Here, we directly test the importance of the cilium as a mediator of the leptin response. In contrast to the current dogma, a longitudinal study of conditional Ift88 cilia mutant mice under different states of adiposity indicates that leptin resistance is present only when mutants are obese. Our studies show that caloric restriction leads to an altered anticipatory feeding behavior that temporarily abrogates the anorectic actions of leptin despite normalized circulating leptin levels. Interestingly, preobese Bbs4 mutant mice responded to the anorectic effects of leptin and did not display other phenotypes associated with defective leptin signaling. Furthermore, thermoregulation and activity measurements in cilia mutant mice are inconsistent with phenotypes previously observed in leptin deficient ob/ob mice. Collectively, these data indicate that cilia are not directly involved in leptin responses and that a defect in the leptin signaling axis is not the initiating event leading to hyperphagia and obesity associated with cilia dysfunction.

Topics: Animals; Bardet-Biedl Syndrome; Body Composition; Cilia; Disease Models, Animal; Feeding Behavior; Leptin; Mice; Mice, Obese; Mice, Transgenic; Motor Activity; Mutation; Neurons; Obesity; Phenotype; Signal Transduction; Temperature

Bardet-Biedl syndrome (BBS) is a genetic disorder with obesity as one of the major phenotypic criterion, which is proposed to be of neuroendocrine origin. Therefore, disturbances in appetite-regulating hormones have been considered as causative factors. Acyl ghrelin is an orexigenic hormone, whereas its desacylated form, obestatin, and leptin have the opposite functions. Ghrelin is negatively regulated in relation to nutritional status. The aim of this study was to evaluate the impact of hormone alterations on obesity development in BBS patients.. Total and acylated ghrelin, obestatin, leptin and adiponectin were measured in eight children with BBS. The results were analyzed in relation to auxological parameters [body mass index (BMI), height].. The mean BMI was significantly increased in BBS patients compared to the controls. Plasma levels of acylated ghrelin, total ghrelin and obestatin were slightly elevated in BBS patients compared to controls, as was the acyl/total ghrelin ratio. Leptin levels were significantly elevated in BBS patients.. BBS patients lack the negative regulatory mechanisms of appetite-regulating hormones with respect to nutritional status and exhibit resistance to anorexigenic leptin. This results in a shift towards the orexigenic effects of this self-regulating system. These alterations may in part be responsible for the disturbed appetite regulation in BBS patients.

Topics: Acylation; Adiponectin; Adolescent; Analysis of Variance; Appetite Regulation; Bardet-Biedl Syndrome; Body Height; Body Mass Index; Case-Control Studies; Child; Child, Preschool; Feedback, Physiological; Feeding Behavior; Female; Ghrelin; Humans; Leptin; Male; Nutritional Status; Obesity; Peptide Hormones; Signal Transduction

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls.. Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype.. Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations.. Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

Topics: Absorptiometry, Photon; Adiposity; Adolescent; Adult; Bardet-Biedl Syndrome; Blood Glucose; Blood Pressure; Body Composition; Body Height; Body Mass Index; Child; Child, Preschool; DNA; Female; Humans; Insulin; Insulin Resistance; Leptin; Male; Middle Aged; Mutation; Obesity; Reverse Transcriptase Polymerase Chain Reaction; Triglycerides; Young Adult

Hypogonadotropic hypogonadism (HH) secondary to hypothalamic gonadotropin-releasing hormone deficiency is a notable feature of a number of rare syndromes, where unlike idiopathic (isolated) HH, other endocrinopathies may also be apparent. The presence of a particular spectrum of clinical features in addition to HH may suggest a particular underlying diagnosis. Placing the diagnosis of HH into that context will then have important implications in terms of management and predicting long-term functional outcome. In some instances, establishing the genetic basis of a particular syndrome or disorder has advanced the understanding of normal hypothalamo-pituitary-gonadal function (e.g. LEP deficiency, DAX-1 and CHARGE syndrome) whilst in other disorders much has still to be learnt (e.g. Bardet-Biedl and Prader-Willi syndrome). In this chapter the above syndromes, where HH is a feature in most or all affected individuals, will be discussed. Recent advances in our understanding of the pathophysiology of the HH will be highlighted and management options presented. Longer term therapy with sex steroid replacement is becoming even more important if improvements in life expectancy are to be matched by improvements in quality of life.

Topics: Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Animals; Bardet-Biedl Syndrome; CHARGE Syndrome; DAX-1 Orphan Nuclear Receptor; Female; Genetic Diseases, X-Linked; Hormone Replacement Therapy; Humans; Hypoadrenocorticism, Familial; Hypogonadism; Leptin; Male; Mice; Prader-Willi Syndrome; Proprotein Convertase 1

Obesity is a major public health problem in most developed countries and a major risk factor for diabetes and cardiovascular disease. Emerging evidence indicates that ciliary dysfunction can contribute to human obesity but the underlying molecular and cellular mechanisms are unknown. Bardet-Biedl syndrome (BBS) is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction. BBS proteins are thought to play a role in cilia function and intracellular protein/vesicle trafficking. Here, we show that BBS proteins are required for leptin receptor (LepR) signaling in the hypothalamus. We found that Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice are resistant to the action of leptin to reduce body weight and food intake regardless of serum leptin levels and obesity. In addition, activation of hypothalamic STAT3 by leptin is significantly decreased in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. In contrast, downstream melanocortin receptor signaling is unaffected, indicating that LepR signaling is specifically impaired in Bbs2(-/-), Bbs4(-/-) and Bbs6(-/-) mice. Impaired LepR signaling in BBS mice was associated with decreased Pomc gene expression. Furthermore, we found that BBS1 protein physically interacts with the LepR and that loss of BBS proteins perturbs LepR trafficking. Our data indicate that BBS proteins mediate LepR trafficking and that impaired LepR signaling underlies energy imbalance in BBS. These findings represent a novel mechanism for leptin resistance and obesity.

Topics: Animals; Bardet-Biedl Syndrome; Caloric Restriction; Cell Line; Group II Chaperonins; Humans; Hypothalamus; Leptin; Melanocortins; Mice; Mice, Knockout; Microtubule-Associated Proteins; Molecular Chaperones; Neurons; Pro-Opiomelanocortin; Protein Binding; Protein Transport; Proteins; Receptors, Leptin; Signal Transduction

Two recent, large whole-genome association studies (GWAS) in European populations have associated a approximately 47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4 degrees C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the Ay, Lep ob, Lepr db, Cpe fat, or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 preferentially bound CUTL1[corrected] in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed "ciliopathy." FTM has recently been shown to be a ciliary basal body protein.

Topics: Adaptor Proteins, Signal Transducing; Adipocytes; Adipose Tissue; Adiposity; Alpha-Ketoglutarate-Dependent Dioxygenase FTO; Animals; Bardet-Biedl Syndrome; Cells, Cultured; Cytoskeletal Proteins; Disease Models, Animal; Eating; Embryo, Mammalian; Energy Metabolism; Fasting; Gene Expression Regulation; Gene Expression Regulation, Developmental; Homeodomain Proteins; Humans; Hypothalamus; Hypothermia, Induced; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Mixed Function Oxygenases; Nuclear Proteins; Obesity; Oxo-Acid-Lyases; Polymorphism, Single Nucleotide; Proteins; Repressor Proteins; RNA, Messenger; Stromal Cells; Transcription Factors; Transfection

Bardet-Biedl syndrome (BBS) is a heterogeneous genetic disorder characterized by many features, including obesity and cardiovascular disease. We previously developed knockout mouse models of 3 BBS genes: BBS2, BBS4, and BBS6. To dissect the mechanisms involved in the metabolic disorders associated with BBS, we assessed the development of obesity in these mouse models and found that BBS-null mice were hyperphagic, had low locomotor activity, and had elevated circulating levels of the hormone leptin. The effect of exogenous leptin on body weight and food intake was attenuated in BBS mice, which suggests that leptin resistance may contribute to hyperleptinemia. In other mouse models of obesity, leptin resistance may be selective rather than systemic; although mice became resistant to leptin's anorectic effects, the ability to increase renal sympathetic nerve activity (SNA) was preserved. Although all 3 of the BBS mouse models were similarly resistant to leptin, the sensitivity of renal SNA to leptin was maintained in Bbs4 -/- and Bbs6 -/- mice, but not in Bbs2 -/- mice. Consequently, Bbs4 -/- and Bbs6 -/- mice had higher baseline renal SNA and arterial pressure and a greater reduction in arterial pressure in response to ganglionic blockade. Furthermore, we found that BBS mice had a decreased hypothalamic expression of proopiomelanocortin, which suggests that BBS genes play an important role in maintaining leptin sensitivity in proopiomelanocortin neurons.

Topics: Animals; Bardet-Biedl Syndrome; Blood-Brain Barrier; Body Weight; Disease Models, Animal; Electrocardiography; Gene Expression Regulation; Group II Chaperonins; Hypertension; Leptin; Magnetic Resonance Imaging; Mice; Mice, Knockout; Microtubule-Associated Proteins; Molecular Chaperones; Obesity; Organ Size; Proteins

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.

Topics: Aging; Animals; Anxiety; Bardet-Biedl Syndrome; Female; Insulin; Introns; Leptin; Liver; Male; Mice; Mice, Inbred C57BL; Microtubule-Associated Proteins; Mutagenesis, Insertional; Obesity; Penetrance; Phenotype; Retina; Social Dominance

McKusick-Kaufman syndrome (MKS) is an autosomal recessive disorder characterized by post-axial polydactyly, congenital heart defects and hydrometrocolpos, a congenital structural abnormality of female genitalia. Mutations in the MKKS gene have also been shown to cause some cases of Bardet-Biedl syndrome (BBS) which is characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities and hypogenitalism with secondary features of hypertension and diabetes. Although there is overlap in clinical features between MKS and BBS, MKS patients are not obese and do not develop retinopathy or have learning disabilities. To further explore the pathophysiology of BBS and the related disorder MKS, we have developed an Mkks(-/-) mouse model. This model shows that the absence of Mkks leads to retinal degeneration through apoptosis, failure of spermatozoa flagella formation, elevated blood pressure and obesity. The obesity is associated with hyperphagia and decreased activity. In addition, neurological screening reveals deficits in olfaction and social dominance. The mice do not have polydactyly or vaginal abnormalities. The phenotype of the Mkks(-/-) mice closely resembles the phenotype of other mouse models of BBS (Bbs2(-/-) and Bbs4(-/-)). These observations suggest that the complete absence of MKKS leads to BBS while the MKS phenotype is likely to be due to specific mutations.

Topics: Abnormalities, Multiple; Alleles; Animals; Bardet-Biedl Syndrome; Blood Pressure; Disease Models, Animal; Genes, Recessive; Humans; Leptin; Male; Mice; Mice, Knockout; Models, Genetic; Obesity; Phenotype; Proteins; Retinal Degeneration; Social Dominance; Sperm Tail; Syndrome