Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) display developmental delays, cognitive impairment, excessive hunger, obesity, and various behavioral abnormalities. Current PWS treatments are limited to strict supervision of food intake and growth hormone therapy, highlighting the need for new therapeutic strategies. Brain-derived neurotrophic factor (BDNF) functions downstream of hypothalamic feeding circuitry and has roles in energy homeostasis and behavior. In this preclinical study, we assessed the translational potential of hypothalamic adeno-associated virus (AAV)-BDNF gene therapy as a therapeutic for metabolic dysfunction in the Magel2-null mouse model of PWS. To facilitate clinical translation, our BDNF vector included an autoregulatory element allowing for transgene titration in response to the host's physiological needs. Hypothalamic BDNF gene transfer prevented weight gain, decreased fat mass, increased lean mass, and increased relative energy expenditure in female Magel2-null mice. Moreover, BDNF gene therapy improved glucose metabolism, insulin sensitivity, and circulating adipokine levels. Metabolic improvements were maintained through 23 weeks with no adverse behavioral effects, indicating high levels of efficacy and safety. Male Magel2-null mice also responded positively to BDNF gene therapy, displaying improved body composition, insulin sensitivity, and glucose metabolism. Together, these data suggest that regulating hypothalamic BDNF could be effective in the treatment of PWS-related metabolic abnormalities.

The N-terminal domain of the Schaaf-Yang syndrome protein MAGEL2 likely has a role in RNA metabolism.

MAGEL2 encodes the L2 member of the melanoma-associated antigen gene (MAGE) protein family, truncating mutations of which can cause Schaaf-Yang syndrome, an autism spectrum disorder. MAGEL2 is also inactivated in Prader-Willi syndrome, which overlaps clinically and mechanistically with Schaaf-Yang syndrome. Studies to date have only investigated the C-terminal portion of the MAGEL2 protein, containing the MAGE homology domain that interacts with RING-E3 ubiquitin ligases and deubiquitinases to form protein complexes that modify protein ubiquitination. In contrast, the N-terminal portion of the MAGEL2 protein has never been studied. Here, we find that MAGEL2 has a low-complexity intrinsically disordered N-terminus rich in Pro-Xn-Gly motifs that is predicted to mediate liquid-liquid phase separation to form biomolecular condensates. We used proximity-dependent biotin identification (BioID) and liquid chromatography-tandem mass spectrometry to identify MAGEL2-proximal proteins, then clustered these proteins into functional networks. We determined that coding mutations analogous to disruptive mutations in other MAGE proteins alter these networks in biologically relevant ways. Proteins identified as proximal to the N-terminal portion of MAGEL2 are primarily involved in mRNA metabolic processes and include three mRNA N 6-methyladenosine (m6A)-binding YTHDF proteins and two RNA interference-mediating TNRC6 proteins. We found that YTHDF2 coimmunoprecipitates with MAGEL2, and coexpression of MAGEL2 reduces the nuclear accumulation of YTHDF2 after heat shock. We suggest that the N-terminal region of MAGEL2 may have a role in RNA metabolism and in particular the regulation of mRNAs modified by m6A methylation. These results provide mechanistic insight into pathogenic MAGEL2 mutations associated with Schaaf-Yang syndrome and related disorders.

Regulation of autism-relevant behaviors by cerebellar-prefrontal cortical circuits.

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

The necdin interactome: evaluating the effects of amino acid substitutions and cell stress using proximity-dependent biotinylation (BioID) and mass spectrometry.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of function of a set of imprinted genes on chromosome 15q11-15q13. One of these genes, NDN, encodes necdin, a protein that is important for neuronal differentiation and survival. Loss of Ndn in mice causes defects in the formation and function of the nervous system. Necdin is a member of the melanoma-associated antigen gene (MAGE) protein family. The functions of MAGE proteins depend highly on their interactions with other proteins, and in particular MAGE proteins interact with E3 ubiquitin ligases and deubiquitinases to form MAGE-RING E3 ligase-deubiquitinase complexes. Here, we used proximity-dependent biotin identification (BioID) and mass spectrometry (MS) to determine the network of protein-protein interactions (interactome) of the necdin protein. This process yielded novel as well as known necdin-proximate proteins that cluster into a protein network. Next, we used BioID-MS to define the interactomes of necdin proteins carrying coding variants. Variant necdin proteins had interactomes that were distinct from wildtype necdin. BioID-MS is not only a useful tool to identify protein-protein interactions, but also to analyze the effects of variants of unknown significance on the interactomes of proteins involved in genetic disease.

A MAGEL2-deubiquitinase complex modulates the ubiquitination of circadian rhythm protein CRY1.

MAGEL2 encodes the L2 member of the MAGE (melanoma antigen) protein family. Protein truncating mutations in MAGEL2 cause Schaaf-Yang syndrome, and MAGEL2 is one of a small set of genes deleted in Prader-Willi syndrome. Excessive daytime sleepiness, night-time or early morning waking, and narcoleptic symptoms are seen in people with Prader-Willi syndrome and Schaaf-Yang syndrome, while mice carrying a gene-targeted Magel2 deletion have disrupted circadian rhythms. These phenotypes suggest that MAGEL2 is important for the robustness of the circadian rhythm. However, a cellular role for MAGEL2 has yet to be elucidated. MAGEL2 influences the ubiquitination of substrate proteins to target them for further modification or to alter their stability through proteasomal degradation pathways. Here, we characterized relationships among MAGEL2 and proteins that regulate circadian rhythm. The effect of MAGEL2 on the key circadian rhythm protein cryptochrome 1 (CRY1) was assessed using in vivo proximity labelling (BioID), immunofluorescence microscopy and ubiquitination assays. We demonstrate that MAGEL2 modulates the ubiquitination of CRY1. Further studies will clarify the cellular role MAGEL2 normally plays in circadian rhythm, in part through ubiquitination and regulation of stability of the CRY1 protein.

Disentangling ingestive behavior-related phenotypes in Prader-Willi syndrome: Integrating information from nonclinical studies and clinical trials to better understand the pathophysiology of hyperphagia and obesity.

Prader-Willi syndrome (PWS) is a rare genetic form of hyperphagia leading to severe obesity, accompanied by endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes on chromosome 15q11-q13, and mice with gene-targeted mutations in one or more of these PWS genes recapitulate PWS-like phenotypes. In addition to evaluating the potential effectiveness of a therapeutic for the treatment of PWS, animal models can be used to elucidate the deficiencies in appetitive and energy balance pathways that lead to hyperphagia and obesity. Various therapeutics have been tested for their effects on ingestive behavior, hyperphagia, and obesity in clinical trials for PWS, with encouraging preliminary results on small groups of participants with PWS. Here, we summarize ingestive behavior-related therapeutics tested in PWS animal models and summarize published data from clinical trials that have evaluated the effect of therapeutics on ingestive behavior in individuals with PWS. We then discuss strategies to accelerate the discovery and translation of therapies into clinical practice in PWS.

Preclinical Testing in Translational Animal Models of Prader-Willi Syndrome: Overview and Gap Analysis.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing endocrine, musculoskeletal, and neurological dysfunction. PWS is caused by the inactivation of contiguous genes, complicating the development of targeted therapeutics. Clinical trials are now underway in PWS, with more trials to be implemented in the next few years. PWS-like endophenotypes are recapitulated in gene-targeted mice in which the function of one or more PWS genes is disrupted. These animal models can guide priorities for clinical trials or provide information about efficacy of a compound within the context of the specific disease. We now review the current status of preclinical studies that measure the effect of therapeutics on PWS-like endophenotypes. Seven categories of therapeutics (oxytocin and related compounds, K+-ATP channel agonists, melanocortin 4 receptor agonists, incretin mimetics and/or GLP-1 receptor agonists, cannabinoids, ghrelin agents, and Caralluma fimbriata [cactus] extract) have been tested for their effect on endophenotypes in both PWS animal models and clinical trials. Many other therapeutics have been tested in clinical trials, but not preclinical models of PWS or vice versa. Fostering dialogs among investigators performing preclinical validation of animal models and those implementing clinical studies will accelerate the discovery and translation of therapies into clinical practice in PWS.

Clinical and genetic analysis of children with a dual diagnosis of Tourette syndrome and autism spectrum disorder.

Gilles de la Tourette Syndrome (TS) is a neurodevelopmental disorder that causes children to make repeated, brief involuntary movements or sounds. TS can be co-morbid with other neurodevelopmental disorders, including autism spectrum disorder (ASD). Clusters of biologically related genes have been associated with neurodevelopmental disorders, suggesting shared pathologies. However, the genetic contribution to TS remains poorly defined. We asked whether children with both TS and ASD differed clinically from children with ASD alone, and identified potentially deleterious genetic events in children with TS and ASD. We compared clinical data from 119 children with ASD and TS to 2603 children with ASD, all from the Simons Simplex Collection. We performed gene set enrichment analysis on de novo genetic events in children with both TS and ASD to identify candidate genes and pathways, and compared these genes and pathways with those previously identified in TS. Children with TS and ASD were diagnosed at an older age, had higher IQ scores, and had more restricted and repetitive behavior than children with ASD but not TS. Gene Ontology analysis revealed that proteins important for specific biological pathways, including regulation of calcium ion-dependent exocytosis, basement membrane organization, and visual behavior and learning, and specific cellular pathways, including basal lamina and ciliary transition zone, are enriched among genes with de novo mutations in children with TS and ASD. Clinical and genetic analysis of cohorts of affected children can help to determine the underlying pathophysiology of TS and other neurodevelopmental disorders.

ROHHAD and Prader-Willi syndrome (PWS): clinical and genetic comparison.

BACKGROUND: Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands. RESULTS: Detailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands. CONCLUSIONS: ROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.

Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome.

Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of the benzothiadiazine derivative diazoxide demonstrated improved metabolic parameters and decreased fat mass in obese children and adults with PWS. We tested whether chronic diazoxide administration can reduce fat mass and improve metabolism in mice lacking MAGEL2, a gene inactivated in PWS. Magel2-null and wild-type control mice were rendered obese by high fat diet feeding, then provided diazoxide while being maintained on a high fat diet. Treatment of obese mice with diazoxide reduced weight and body fat, lowered blood glucose and improved endurance capacity. Treatment with diazoxide partially normalizes obesity in children and adults with PWS and in a PWS mouse model, demonstrating that the biological pathways impacted by diazoxide may be rational pharmacological targets in PWS and other disorders diseases associated with obesity.

Genetic analysis of very obese children with autism spectrum disorder.

Autism spectrum disorder (ASD) is defined by the triad of deficits in social interactions, deficits in communication, and repetitive behaviors. Common co-morbidities in syndromic forms of ASD include intellectual disability, seizures, and obesity. We asked whether very obese children with ASD had different behavioral, physical and genetic characteristics compared to children with ASD who were not obese. We found that very obese children with ASD had significantly poorer scores on standardized behavioral tests. Very obese boys with ASD had lower full scale IQ and increased impairments with respect to stereotypies, communication and social skills. Very obese girls with ASD had increased impairments with respect to irritability and oppositional defiant behavior. We identified genetic lesions in a subset of the children with ASD and obesity and attempted to identify enriched biological pathways. Our study demonstrates the value of identifying co-morbidities in children with ASD as we move forward towards understanding the biological processes that contribute to this complex disorder and prepare to design customized treatments that target the diverse genetic lesions present in individuals with ASD.

The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways.

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.

OBJECTIVE: Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. METHODS: We studied eCB 'tone' in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. RESULTS: Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. CONCLUSIONS: Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS.

Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes.

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.

Sleeve gastrectomy leads to weight loss in the Magel2 knockout mouse.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia, obesity, cardiopulmonary diseases, and increased mortality. Although successful weight loss improves health in PWS, few treatments cause sustained weight loss in obese patients let alone obese individuals with PWS. OBJECTIVES: The present study uses the Magel2 knockout (KO) mouse, an animal model of PWS, to conduct a preclinical study on the efficacy of sleeve gastrectomy (SG) in PWS. SETTING: Academic research laboratory, United States. METHODS: We performed sham or SG surgeries in 24- to 28-week-old male Magel2 KO and wild-type littermate control mice (WT) who had been maintained on a high-fat diet for 10 weeks. We monitored weight, food intake, and fat and lean mass pre- and postoperatively. Fasting glucose, glucose tolerance, and counter-regulation were measured postoperatively. RESULTS: Magel2 KO animals had similar recovery and mortality rates compared with WT. SG resulted in similar weight loss, specifically loss of fat but not lean mass, in both Magel2 KO and WT mice. SG also resulted in significantly lower fasting glucose levels and a reduction in fat intake in both Magel2 KO and WT mice. We also found that Magel2 KO mice failed to increase their food intake in response to the glucoprivic agent 2-deoxy-D-glucose, suggesting impaired glucose counter-regulation, but this occurred regardless of surgical status. All results were considered significant when P< .05. CONCLUSION: We find in this mouse model of PWS, SG is a well-tolerated, effective strategy for weight and fat loss.

Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist.

BACKGROUND AND PURPOSE: α- and ß-melanocyte-stimulating hormones (MSH) are derived from pro-opiomelanocortin (POMC) and are the natural agonist ligands of the melanocortin 4 receptor, a key regulator of energy homeostasis. Recent rodent and human data have implicated the MAGEL2 gene, which may regulate activation of POMC neurons, as a significant contributor to the metabolic symptoms observed in Prader-Willi Syndrome (PWS). Firstly, patients with protein truncating mutations in MAGEL2 exhibit numerous clinical characteristics of PWS. Secondly, Magel2-null mice may not normally activate MC4 receptors, as they are defective in the activation of their POMC neurons and hence may fail to normally release the POMC-derived MC4 receptor agonist ligands α- and ß-MSH. Magel2-null mice represent a tractable animal model for the metabolic and appetitive imbalance seen in patients with PWS. EXPERIMENTAL APPROACH: We tested a dose titration of the MC4 receptor agonist setmelanotide, in development for rare monogenic forms of obesity, in Magel2-null mice. KEY RESULTS: We show that Magel2-null mice are hypersensitive to the appetite suppressing and metabolic effects of setmelanotide. CONCLUSION AND IMPLICATIONS: Setmelanotide may be a useful investigational hormone/neuropeptide replacement therapy for PWS and rare monogenic forms of obesity exhibiting impaired function of POMC neurons.

Dopamine pathway imbalance in mice lacking Magel2, a Prader-Willi syndrome candidate gene.

The etiology of abnormal eating behaviors, including binge-eating disorder, is poorly understood. The neural circuits modulating the activities of the neurotransmitters dopamine and serotonin are proposed to be dysfunctional in individuals suffering from eating disorders. Prader-Willi syndrome is a neurodevelopmental disorder that causes extreme food seeking and binge-eating behaviors together with reduced satiety. One of the genes implicated in Prader-Willi syndrome, Magel2, is highly expressed in the regions of the brain that control appetite. Our objective was to examine behaviors relevant to feeding and the neural circuits controlling feeding in a mouse model of Prader-Willi syndrome that lacks expression of the Magel2 gene. We performed behavioral tests related to dopaminergic function, measuring cocaine-induced hyperlocomotion, binge eating, and saccharin-induced anhedonia in Magel2-deficient mice. Next, we analyzed dopaminergic neurons in various brain regions and compared these findings between genotypes. Finally, we examined biochemical markers in the brain under standard diet, high-fat diet, and withdrawal from a high-fat diet conditions. We identified abnormal behaviors and biomarkers reflecting dopaminergic dysfunction in mice lacking Magel2. Our results provide a biological framework for clinical studies of dopaminergic function in children with Prader-Willi syndrome, and may also provide insight into binge-eating disorders that occur in the general population. (PsycINFO Database Record

Progressive postnatal decline in leptin sensitivity of arcuate hypothalamic neurons in the Magel2-null mouse model of Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a multigene disorder associated with neonatal failure to thrive, developmental delay and endocrine abnormalities suggestive of hypothalamic dysfunction. Children with PWS typically develop overt hyperphagia and obesity ∼8 years of age, later than children with other genetic forms of obesity. This suggests a postnatal developmental or degenerative component to PWS-associated obesity. De novo inactivating mutations in one PWS candidate gene, MAGEL2, have been identified in children with features of PWS. Adult mice lacking Magel2 are insensitive to the anorexic effect of leptin treatment, and their hypothalamic pro-opiomelanocortin (POMC) neurons fail to depolarize in response to leptin. However, it is unclear whether this leptin insensitivity is congenital, or whether normal leptin sensitivity in neonatal Magel2-null mice is lost postnatally. We used in vitro cytosolic calcium imaging to follow the postnatal development of leptin responses in POMC neurons in these mice. Leptin caused an activation of POMC neurons in wild-type acute hypothalamic slice preparations at all ages, reflecting their normal leptin-invoked depolarization. Normal leptin responses were found in Magel2-null mice up to 4 weeks of age, but the proportion of leptin-responsive POMC neurons was reduced in 6-week-old Magel2-null mice. The number of α-melanocyte-stimulating hormone immunoreactive fibers in the paraventricular hypothalamic nucleus was also reduced in mutant mice at 6 weeks of age. A similar progressive loss of leptin sensitivity caused by loss of MAGEL2 in children with PWS could explain the delayed onset of increased appetite and weight gain in this complex disorder.

Evaluation of melanoma antigen (MAGE) gene expression in human cancers using The Cancer Genome Atlas.

Melanoma antigen (MAGE) cancer-testis (CT) (or cancer-germline) genes are frequently over-expressed in cancer. However, the types of cancer in which the MAGE genes are over-expressed and the effect of over-expression on outcomes have been difficult to ascertain, and their relevance to progression is unclear. We queried transcriptomic and survival data from 26 cancer studies through the cBio Cancer Genomics Portal (www.cbioportal.org) to investigate dysregulation of 34 MAGE genes in cancer. MAGE genes are dysregulated in many cancers. Up to 44% of samples had over-expression of 22 Type 1 MAGE, which are not expressed in most normal tissues, or dysregulation of 12 Type 2 MAGE genes, which are expressed in normal tissues. Dysregulation of specific MAGE genes correlated with reduced overall survival in four cancer types (brain low grade gliomas, renal clear cell carcinomas, head and neck squamous cell carcinomas, and uterine corpus endometrioid carcinomas), with weaker correlations in four additional cancer types. This study demonstrates (1) the value of cancer-germline antigen expression profiling as a complement to mutation analysis for prognosis in cancer; (2) that over-expression of MAGE genes in a subset of cancers is associated with reduced survival; and (3) that patterns of MAGE expression could inform individualized treatment in cancer.

Hyperphagia: current concepts and future directions proceedings of the 2nd international conference on hyperphagia.

OBJECTIVE: Hyperphagia is a central feature of inherited disorders (e.g., Prader-Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. DESIGN AND METHODS: International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. RESULTS: The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. CONCLUSIONS: This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.