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Background: Individuals with a phenotype of early-onset severe obesity associated with intellectual disability can have molecular diagnoses ranging from monogenic to complex genetic traits. Severe overweight is the major sign of a syndromic physical appearance and predicting the influence of a single gene and/or polygenic risk profile is extremely complicated among the majority of the cases. At present, considering rare monogenic bases as the principal etiology for the majority of obesity cases associated with intellectual disability is scientifically poor. The diversity of the molecular bases responsible for the two entities makes the appliance of the current routinely powerful genomics diagnostic tools essential. Objective: Clinical investigation of these difficult-to-diagnose patients requires pediatricians and neurologists to use optimized descriptions of signs and symptoms to improve genotype correlations. Methods: The use of modern integrated bioinformatics strategies which are conducted by experienced multidisciplinary clinical teams. Evaluation of the phenotype of the patient’s family is also of importance. Results: The next step involves discarding the monogenic canonical obesity syndromes and considering infrequent unique molecular cases, and/or then polygenic bases. Adequate management of the application of the new technique and its diagnostic phases is essential for achieving good cost/efficiency balances. Conclusion: With the current clinical management, it is necessary to consider the potential coincidence of risk mutations for obesity in patients with genetic alterations that induce intellectual disability. In this review, we describe an updated algorithm for the molecular characterization and diagnosis of patients with a syndromic obesity phenotype.

The objective is to determine whether variability in the MSRA gene, related to obesity and several psychiatric conditions, may be relevant for psychopathological symptoms common in Anorexia Nervosa (AN) and/or for the susceptibility to the disorder. A total of 629 women (233 AN patients and 396 controls) were genotyped for 14 tag-SNPs. Psychometric evaluation was performed with the EDI-2 and SCL-90R questionnaires. Genetic associations were carried out by logistic regression controlling for age and adjusting for multiple comparisons (FDR method). Two tag-SNPs, rs11249969 and rs81442 (with a pairwise r2 value of 0.41), were associated with the global EDI-2 score, which measures EDI-related psychopathology (adjusted FDR-q = 0.02 and 0.04, respectively). Moreover, rs81442 significantly modulated all the scales of the SCL-90R test that evaluates general psychopathology (FDR-q values ranged from 4.1E-04 to 0.011). A sliding-window analysis using adjacent 3-SNP haplotypes revealed a proximal region of the MSRA gene spanning 187.8 Kbp whose variability deeply affected psychopathological symptoms of the AN patients. Depression was the symptom that showed the strongest association with any of the constructed haplotypes (FDR-q = 3.60E−06). No variants were found to be linked to AN risk or anthropometric parameters in patients or controls. Variability in the MSRA gene locus modulates psychopathology often presented by AN patients.

The endocannabinoid system plays a key role in eating behavior regulating appetite and reward mechanisms, but the impact of its genetic variability has been scarcely studied in Anorexia Nervosa (AN). We aimed to analyze the association of genetic variants in cannabinoid receptors with the risk for AN and with psychiatric comorbidities that are commonplace in these patients. We screened 221 AN patients and 396 controls for 14 tag-SNPs in the CNR1 and CNR2 genes, coding for cannabinoids receptors CB1 and CB2, respectively. Patients were diagnosed according to DSM-5 criteria and interviewed with the SCL-90R and the EDI-2 inventories to identify AN-coupled and general psychopathology. None of the tag-SNPs was significantly related to AN risk. However, the rs806369-TT genotype and haplotype rs806368/rs1049353/rs806369 of CNR1 were respectively associated with lower weight (mean difference = − 4.92 kg, FDR-q = 0.044) and BMI (FDR-q = 0.042) in AN patients. CNR1 rs806374-TT and CNR2 rs3003335-AA and rs6658703-GG genotypes correlated with higher scores in the Positive Symptom Distress Index (PSDI, FDR-q = 0.011 and 0.009, respectively). These three genotypes were also linked to increased Hostility in the patients (FDR-q

Exposure to environmental chemicals can produce effects on the endocrine system through epigenetic mechanisms. These can considerably decrease or increase the sensitivity of multiple hormones depending on the dose, route, or time of exposure. The exposure of endocrine disrupting chemicals (EDCs) during the in utero period could be a critical window, altering the epigenome profile. Recently, several researchers suggest a role of EDCs in the obesity epidemic. In this brief review, we focused on how four EDCs (bisphenol A, dichlorodiphenyltrichloroethane, di-(2-ethylhexyl) phthalate and tributyltin) may underlay transgenerational epigenetic effects. We also discuss the adipogenesis signaling pathway and the impact of exposure to individual or mixtures of EDCs on the developing endocrine system. Understanding the molecular determinants of epigenetic memory across generations will provide essential insight into how environmental exposure can affect the health of individuals, as well as subsequent generations.

The objective is to determine whether variability in the MSRA gene, related to obesity and several psychiatric conditions, may be relevant for psychopathological symptoms common in Anorexia Nervosa (AN) and/or for the susceptibility to the disorder. A total of 629 women (233 AN patients and 396 controls) were genotyped for 14 tag-SNPs. Psychometric evaluation was performed with the EDI-2 and SCL-90R questionnaires. Genetic associations were carried out by logistic regression controlling for age and adjusting for multiple comparisons (FDR method). Two tag-SNPs, rs11249969 and rs81442 (with a pairwise r2 value of 0.41), were associated with the global EDI-2 score, which measures EDI-related psychopathology (adjusted FDR-q = 0.02 and 0.04, respectively). Moreover, rs81442 significantly modulated all the scales of the SCL-90R test that evaluates general psychopathology (FDR-q values ranged from 4.1E-04 to 0.011). A sliding-window analysis using adjacent 3-SNP haplotypes revealed a proximal region of the MSRA gene spanning 187.8 Kbp whose variability deeply affected psychopathological symptoms of the AN patients. Depression was the symptom that showed the strongest association with any of the constructed haplotypes (FDR-q = 3.60E-06). No variants were found to be linked to AN risk or anthropometric parameters in patients or controls. Variability in the MSRA gene locus modulates psychopathology often presented by AN patients.

MC4R gene is a hypothalamic satiety control mediator in which mutations cause a monogenic form of obesity. The aim of this study was to perform a genetic screening to identify variations in the entire region of MC4R gene. A total of 236 unrelated and severely obese patients (BMI ≥ 40 kg/m2) with Spanish ancestry and severe overweight familiar history have been enrolled into the study. Seven MC4R gene variants were identified in the heterozygous state in 21 patients. Coding variants p.Thr101Ile and p.Ala259Asp are new and variants p.Ser30Phe, p.Val103Ile and p.Ile251Leu were previously described. Two variants have been also observed in the promoter region of the MC4R gene; the c.-24G>A mutation, described for the first time, and the known c.-178A>C variant. Both in silico and family segregation analysis confirm the correlation between novel identified mutations in MC4R gene and obesity development. The correlation between the four variants (c.-24G>A, p.Thr101Ile, p.Ala259Asp and p.Ser30Phe) and the obesity phenotype, therefore, allows the conclusion that all of the four mutations cause a monogenic form of obesity.

Our aim was to determine whether variability in the fat mass obesity (FTO) gene locus, consistently related to obesity, affects the risk of eating disorders (ED) and/or the psychopathology displayed by these patients. We analyzed 26 tag-single nucleotide polymorphisms (SNPs) that capture FTO variability in 352 ED patients [233 with Anorexia Nervosa (AN) and 119 with binge-eating] and 396 controls. Psychopathological symptoms and traits were evaluated by the Eating Disorders Inventory Test 2 (EDI-2) and Symptoms Checklist 90 Revised (SCL-90R) questionnaires. No associations were found for ED risk. The rs7205987 CC genotype correlated with higher scores in all but one of the EDI-2 scales in the AN group. Associations with Bulimia (p = 0.0019) and Interoceptive Awareness (p = 0.00007) retained significance after False Discovery Rate (FDR) correction for multiple testing. A 3-SNP sliding window analysis showed that FTO haplotypes were again highly associated with Interoceptive Awareness (rs9921255/rs6499662/rs7205987 haplotype; FDR-q = 0.04), Bulimia (rs1125338/rs2192872/rs708258; FDR-q = 0.00037), and Maturity Fears (rs708258/rs12599672/rs11076017; FDR-q = 0.041). In addition, a distal region of the gene between rs9924877 (position 53947509) and rs2192872 (54040715) was linked to Anxiety, Depression and Phobic Anxiety in AN patients, with FDR-q values ranging from 0.023 to 0.045. The results suggest that the FTO gene might be an important locus regarding traits and psychopathological symptoms often displayed by AN patients.

Several BMI associated-loci conferring susceptibility to obesity have been identified. Summarizing all these risk-associated variations into a genetic risk-score (GRS) may improve predictive power and cumulative effect on obesity risk. In this study, we investigate the reproducibility in two independent samples of the association and weighted GRS previously proposed for six SNPs as predictors for obesity susceptibility. A case-control study was performed using one sample comprising 346 unrelated Portuguese children [6–12 years-old; 191 controls and 155 obese], and a second sample comprising 332 unrelated Spanish adults [18–60 years-old; 217 controls and 115 obese]. Polymorphisms located on FTO, TFAP2B, SEC16B, ETV5, and SH2B1 genes were genotyped by allelic discrimination TaqMan assays. After Bonferroni corrections we found nominal significant associations of the rs17817449 FTO polymorphism with BMI (p = 0.023), Z-score (p = 0.009), weight (p = 0.020), and waist circumference (p = 0.022) in the Portuguese children. A nominal association was also observed with risk of obesity (p = 0.027). The same polymorphism was found significantly associated with obesity (p = 0.0005) in Spanish adults. Nominal association with risk of obesity was also found for rs7634510 ETV5 polymorphism (p = 0.011). No further associations were observed for the other polymorphisms. Our results failed to replicate a previously proposed GRS predicting high susceptibility to childhood obesity. Nonetheless, we highlight the role of the rs17817449 FTO polymorphism on obesity in both Portuguese and Spanish samples, as well as the rs7634510 ETV5 polymorphism in adults.

Reduced genetic variability in isolated populations promotes the prevalence of long contiguous stretches of homozygosity (LCSH) that may carry deleterious mutations, manifesting recessive syndromes such as Alstrom syndrome (OMIM # 203800), caused principally by mutations in exons 8, 10, and 16 and deletions/insertions along the ALMS1 gene. Here, Sanger sequencing of these exons and whole-genome copy-number variants/single-nucleotide polymorphisms (SNPs) microarray were used to characterize ALMS1 gene in a 19-year-old Pakistani female with Alstrom syndrome. Sequencing did not reveal pathogenic alterations but described a set of homozygous polymorphisms. The microarray revealed these SNPs were included in an 8.24 Mb LCSH in 2p12.2p13 that contained a homozygous deletion including exons 13-16 of ALMS1 gene. Therefore, reduced genetic variability in Pakistani population enhanced the inheritance of the homozygous deletion causing Alstrom syndrome. The comparison of the deletion with known deletions spanning exons 13-16, described on Middle Eastern patients, suggested a fixation of the deletion in a specific haplotype.

OBJECTIVES To investigate whether objectively measured physical activity (PA) modulates the association between the FTO rs9939609 polymorphism and obesity variables in a sample of Portuguese children. METHODS A total of 440 children (213 girls and 227 boys) aged 3 to 11 years were observed. Genotyping was performed using TaqMan assay. Body mass index (BMI), BMI Z scores, waist circumference (WC), and waist-to-height ratio (WHtR) were calculated. PA was estimated in 399 children by accelerometry. RESULTS Linear regression, in the additive model, showed that the rs9939609 minor A-allele significantly associated with BMI (P = .029), BMI Z score (P = .017), WC (P = .016), and WHtR (P = .019). Logistic regression, in the additive model, showed a marginally significant association between the A-allele and overweight/obesity (odds ratio [OR]: 1.372; P = .049). When stratified by sex, rs9939609 showed marginal or significant associations with BMI (P = .08), BMI Z score (P = .07), WC (P = .005), WHtR (P = .02), and overweight/obesity (OR: 1.529; P = .064) in girls but not in boys (P > .05). Significant interactions were not found between the FTO polymorphism and PA (inactive vs active groups of children) for BMI (P = .461), BMI Z score (P = .387), WC (P = .757), or WHtR (P = .621). CONCLUSIONS Findings of the present study highlight the association between FTO rs9939609 and obesity or body fat indices in girls but not in boys. PA was not found to mediate the impact of FTO genetic variation on risk of obesity.

Syndromic monogenic obesity is a rare and severe early-onset form of obesity. It is characterized by intellectual disability, congenital malformations, and/or dysmorphic facies. The diagnosis of patients is challenging due to the genetic heterogenicity of this condition. However, the use of microarray technology in combination with public databases has been successful on genotype–phenotype correlations, especially for body mass index (BMI) alteration. In this study, the relationship between copy number variations (CNVs) detected by microarray mapping on 16p region and BMI alterations in syndromic patients were assessed. In order to achieve this goal, 680 unrelated Spanish children with intellectual disability were included. 16p region was characterized by using microarray platforms. All detected variants were classified as: (I) one previously non-described 10-Mb duplication in 16p13.2p12.3 region considered causal of intellectual disability and severe overweight, and (II) eleven 16p11.2 CNVs of low prevalence but with recurrence in syndromic patients with severe BMI alteration (nine proximal and two distal). Proximal 16p11.2 CNVs have a dose-dependent effect: underweight in carriers of duplication and obesity in carriers of deletion. KCTD13 was identified as a possible candidate gene for BMI alteration on proximal syndromes, whereas SH2B1 gene was identified as candidate for distal syndromes. The results shown in this paper suggest that syndromic patients could constitute a reliable model to evaluate hypothalamic satiety and obesity disorders as well as generate a wide expectation for primary prevention of comorbidities. Furthermore, 16p13.2p12.3 showed to be an important region on the regulation of body fatness.

The object of our study is the form of education in its relation to the right form. The methodology used is the analysis of social forms through the historical materialist dialectic of Karl Marx. We are not interested in taking the forms of education and law as generic, abstract, idealistic, and immutable expressions, but that which is specifically derived from the present mode of production, its unfolding and finishing in capitalist society. Education and law how and while forms. The education form and the right form, approximate and distinct, of the other social interactions, as well as of the other. And for that: the philosophy of the concepts of the form education and the right form. In order to understand the theory of social forms it is necessary to cross the debate of historical materialism. In this way, the exposition of education and law as a specific moment of general sociability accompanies the debate of social totality composed of forms that are both approximate and distinct. Because they are components of all forms, they dialogue with each other without losing themselves as uniforms. That is why forms can be discernible when they are realized in the totality, reflecting themselves as components of something greater, that organizes them and allows them fruition. It follows that the totality of the social being is greater than the sum of its parts. The forms are distinguishable by being examined by the methodological view of the contraposition. The form reflects the whole into parts, ensuring that it is a specific moment of something more complex and multiply shaped. In the interaction of these complexes, always under the dictates of the forces of production, certain forms approximate one to another more than the medium. Our research interests the proximity between the forms of education and law, both because education is externalized in the form of a law, and the educational debate, in our political reality, is located very much in the institutional political scope. And the peak of this suffocation caused to education by law is expressed in the proposals for intervention, or capture of education by the political agenda of the dominant social economic forces, which carry the debate of education from the pedagogical area to the authority of the alleged neutrality of the law. Under this domain, education begins to respond in an official way to the interests of the pedagogical science debate, assuming subordination to the dictates of imposed legality. The sum of the lawful and illicit of the law covers education and shapes it in a way to exhaust the more accurate methodological debate, leaving as a structure of mechanistic education mediation between the supposedly legal and pertinent, regulated by law and normativity, and the subjective, using punishment as the imprisonment of criticism for intellectual development. The terminology 'school without party' is only its latest manifestation. Instead of criticizing it directly we point out the fundamentals that allow the strength of such proposals and their propagation. We thus move the debate to the stage of real overcoming of the problematic, which is - the end of the right form as a presupposition of the end of the constriction of legality over education form. O objeto de nosso estudo é a forma educação em sua relação com a forma direito. A metodologia utilizada é a análise das formas sociais por meio da dialética materialista histórica de Karl Marx. Não nos interessa tomar as formas educação e direito enquanto expressões genéricas, abstratas, idealistas e imutáveis, mas aquilo que lhes são especificamente derivação do atual modo de produção, seus desdobramentos e acabamentos na sociedade capitalista. Educação e direito como e enquanto forma. A forma educação e a forma direito, aproximadas e distintas, tanto das demais interações sociais, como uma da outra. E para tanto: a filosofia dos conceitos da forma educação e da forma direito. Para se compreender a teoria das formas sociais é necessário perpassar o debate do materialismo histórico. Desta maneira, a exposição da educação e do direito enquanto momento específico da sociabilidade geral acompanha o debate da totalidade social composta por formas ao mesmo tempo aproximadas e distintas. Por serem componentes do todo as formas dialogam entre si sem se perderem como uniformes. Por isso as formas podem ser discerníveis ao se realizarem na totalidade, refletindo-se como componentes de algo maior, que as organiza e as permite fruição. Donde se conclui que a totalidade do ser social é maior que a soma de suas partes. As formas são distinguíveis ao serem perscrutadas pelo olhar metodológico da contraposição. A forma reflete o todo em partes, garantindo ser um específico momento de algo mais complexo e multiplamente conformado. Na interação desses complexos, sempre sob o ditame das forças de produção, determinadas formas aproximam-se umas das outras mais que a mediania. À nossa pesquisa interessa a proximidade existente entre as formas educação e direito, tanto por ser a educação externalizada na forma de lei, como o debate educacional, na nossa atualidade política, estar localizado sobremaneira no âmbito político institucional. E o cume desse sufoco causado à educação pelo direito se expressa nas propostas de intervenção, ou captura da educação pela agenda política das forças econômicas sociais dominantes, que transportam o debate da educação desde a área pedagógica à autoridade da pretensa neutralidade da lei. Sob esse domínio a educação passa a responder de modo oficial à interesses alheados do debate da ciência pedagógica, assumindo subordinação aos ditames da legalidade imposta. A soma do lícito e do ilícito do direito reveste a educação e a molda de maneira a esgotar o debate metodológico mais acurado, deixando como estrutura da educação mecanicista mediação entre o supostamente legal e pertinente, regulado pelo direito e pela normatividade, e o subjetivo, utilizando da punição como aprisionamento da crítica em prol do desenvolvimento intelectual. A terminologia ‘escola sem partido’ é apenas sua mais recente manifestação. Ao invés de criticá-la diretamente apontamos os fundamentos que permitem a força de tais propostas e sua propagação. Deslocamos, assim, o debate para o palco da real superação da problemática, qual seja – o fenecimento da forma direito como pressuposto do fim da constrição da legalidade por sobre a forma educação.

It is well-known that obesity is a complex multifactorial and heterogeneous condition with an important genetic component. Recently, major advances in obesity research emerged concerning the molecular mechanisms contributing to the obese condition. This review outlines several studies and data concerning the genetics and other important factors in the susceptibility risk to develop obesity. Based in the genetic etiology three main categories of obesity are considered: monogenic, syndromic, and common obesity. For the monogenic forms of obesity, the gene causing the phenotype is clearly identified, whereas for the common obesity the loci architecture underlying the phenotype is still being characterized. Given that, in this review we focus mainly in this obesity form, reviewing loci found until now by genome-wide association studies related with the susceptibility risk to develop obesity. Moreover, we also detail the obesity-related loci identified in children and in different ethnic groups, trying to highlight the complexity of the genetics underlying the common obese phenotype. Importantly, we also focus in the evolutionary hypotheses that have been proposed trying to explain how natural selection favored the spread of genes that increase the risk for an obese phenotype and how this predisposition to obesity evolved. Other factors are important in the obesity condition, and thus, we also discuss the epigenetic mechanisms involved in the susceptibility and development of obesity. Covering all these topics we expect to provide a complete and recent perspective about the underlying mechanisms involved in the development and origin of obesity. Only with a full understanding of the factors and mechanisms contributing to obesity, it will be possible to provide and allow the development of new therapeutic approaches to this condition.

Background: Obesity is a global health problem mainly attributed to lifestyle changes such as diet, low physical activity or socioeconomics factors. However, several evidences consistently showed that genetics contributes significantly to the weight-gain susceptibility. Sources of data: A systematic literature search of most relevant original, review and meta-analysis, restricted to English was conducted in PubMed, Web of Science and Google scholar up to May 2017 concerning the contribution of genetics and environmental factors to obesity. Areas of agreement: Several evidences suggest that obesogenic environments contribute to the development of an obese phenotype. However, not every individual from the same population, despite sharing the same obesogenic environment, develop obesity. Areas of controversy: After more than 10 years of investigation on the genetics of obesity, the variants found associated with obesity represent only 3% of the estimated BMI-heritability, which is around 47-80%. Moreover, genetic factors per se were unable to explain the rapid spread of obesity prevalence. Growing points: The integration of multi-omics data enables scientists having a better picture and to elucidate unknown pathways contributing to obesity. Areas timely for developing research: New studies based on case-control or gene candidate approach will be important to identify new variants associated with obesity susceptibility and consequently unveiling its genetic architecture. This will lead to an improvement of our understanding about underlying mechanisms involved in development and origin of the actual obesity epidemic. The integration of several omics will also provide insights about the interplay between genes and environments contributing to the obese phenotype. Fundacao para a Ciencia e a Tecnologia (FCT) [UID/ANT/00283/2013] FCT [SFRH/BPD/109043/2015] FCT, Portugal French Muscular Dystrophy Association, France Fundacao para a Ciencia e a Tecnologia (FCT) [UID/ANT/00283/2013] FCT [SFRH/BPD/109043/2015] FCT, Portugal French Muscular Dystrophy Association, France info:eu-repo/semantics/publishedVersion

Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease. * Abbreviation : SCA : spinocerebellar ataxia

Introduction TFAP2B and KCTD15 are obesity‐related genes that interact to regulate feeding behavior. We hypothesize that variability in these loci, isolated or in combination, could also be related to the risk of eating disorders (ED) and/or associated psychological traits. Methods We screened 425 participants (169 ED patients, 75 obese subjects, and 181 controls) for 10 clinically relevant and tag single‐nucleotide polymorphisms (SNPs) in KCTD15 and TFAP2B by the Sequenom MassARRAY platform and direct sequencing. Psychometric evaluation was performed with EDI‐2 and SCL‐90R inventories. Results The KCTD15 rs287103 T variant allele was associated with increased risk of bulimia nervosa (BN) (OR = 4.34 [1.47–29.52]; p = .003) and with scores of psychopathological scales of these patients. Haplotype *6 in KCTD15 was more frequent in controls (OR = 0.40 [0.20–0.80], p = .009 for anorexia nervosa), while haplotype *4 in TFAP2B affected all three scales of the SCL‐90R inventory in BN patients (p ≤ .01). Epistasis analyses revealed relevant interactions with body mass index of BN patients (p

Summary We screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population. A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants. Ten MC4R gene mutations were identified in the heterozygous state in 10 patients. Mutations p.R147G and p.G323E are new and mutations p.R7H, p.G32E, p.H76R, p.V103I, p.S127L, p.T150I, p.I251L and p.G252S were previously described. A new dinucleotide insertion -77_-76insTA in the promoter region of the LEPR gene was found in the heterozygous state in one patient. The new p.R147G and the previously published p.R7H, p.S127L, p.T150I and p.G252S MC4R mutations, cosegregate with obesity in our patients and were predicted to be deleterious. For the novel MC4R p.G323E and LEPR -77_-76insTA gene mutations, the genotype-phenotype correlation and bioinformatic analysis did not clarify whether these mutations are indeed implicated in obesity.

Aim The -13910C>T single nucleotide polymorphism located upstream of the lactase gene (LCT) was found tightly associated with lactase persistence in European populations. Recently, it was also associated with body mass index (BMI) and obesity in European adults. The aim of this study was to test the association of -13910C>T polymorphism with obesity-related traits and risk of obesity in children. Methods We genotyped 580 Portuguese children (6–12-year-olds) for the -13910C>T polymorphism using TaqMan probes by real-time PCR. Anthropometric measurements were assessed in all children. Obesity was defined according to the International Obesity Task Force (IOTF) cut-offs and abdominal obesity using the sex and age-specific ≥90th waist circumference percentile. Results We found indication for an association between the-13910*T allele and children abdominal obesity (odds ratio [OR] = 1.41; 95% confidence intervals [CI]: 1.03–1.94; p = 0.030). Under the dominant model, the indicative association was observed between the LCT-13910 CT/TT genotypes and abdominal obesity, remaining significant after adjustment for age and gender (OR = 1.65; 95% CI: 1.04–2.60; p = 0.029). No association was detected with the risk of obesity (p = 0.350). Conclusion Our results suggest that the -13910C>T polymorphism may predispose to abdominal obesity in Portuguese children. The association with BMI or risk of obesity, previously observed in adults, was not confirmed.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is a fatal, dominant neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Clinical manifestations include cerebellar ataxia and pyramidal signs culminating in severe neuronal degeneration. Currently, there is no therapy able to modify disease progression. In the present study, we aimed at investigating one of the most severely affected brain regions in the disorder--the cerebellum--and the behavioral defects associated with the neuropathology in this region. For this purpose, we injected lentiviral vectors encoding full-length human mutant ataxin-3 in the mouse cerebellum of 3-week-old C57/BL6 mice. We show that circumscribed expression of human mutant ataxin-3 in the cerebellum mediates within a short time frame--6 weeks, the development of a behavioral phenotype including reduced motor coordination, wide-based ataxic gait, and hyperactivity. Furthermore, the expression of mutant ataxin-3 resulted in the accumulation of intranuclear inclusions, neuropathological abnormalities, and neuronal death. These data show that lentiviral-based expression of mutant ataxin-3 in the mouse cerebellum induces localized neuropathology, which is sufficient to generate a behavioral ataxic phenotype. Moreover, this approach provides a physiologically relevant, cost-effective and time-effective animal model to gain further insights into the pathogenesis of MJD and for the evaluation of experimental therapeutics of MJD.

Obesity is a major public health concern, with a complex etiology that involves the interaction of several natural and unnatural factors. It is now well established that obesity has a genetic component and, with the advent of Genome-Wide Association Studies (GWAS) approach, more than 55 loci have been found associated with at least one obesity-related trait. However, according to an estimate, it is only 1–3 % of the total putative heritability of the variance in BMI. It is, furthermore, suggested that part of the missing heritability of the obesity could be due to rare genetic variants, copy number variations, epigenetic factors, and also some other variants still remain to be discovered. The interactions between environmental factors and genes are another potential explanation for the unexplained heritability of obesity. The purpose of this chapter is to provide a comprehensive overview of the genetics contribution in the common obesity etiology, and the interaction between our genes and the changes in lifestyle factors.

Ferroportin is a transmembrane protein responsible for iron export from enterocytes and macrophages. Mutation c.744G → T (Q248H), located in exon 6 of the ferroportin gene SLC40A1, is found as a polymorphism in populations of African origin. This mutation has been extensively analysed in African-Americans, but poorly studied in native African populations.To increase information about Q248H mutation frequency in native sub-Saharan populations examining three West African populations.Samples from S. Tomé e Príncipe (n = 115), Angola (n = 156) and Republic of Guinea (n = 170) were analysed for Q248H mutation and for two polymorphisms, IVS1( - 24)G → C and microsatellite (CGG)(n), using standard molecular methodology.The estimated frequencies of Q248H allele were 2.2% in S. Tomé e Príncipe, 3.5% in Angola and 4.1% in Republic of Guinea. Analysis of polymorphisms IVS1( - 24)G → C and (CGG)(n) showed mutation allele c.744T to be strongly associated with haplotype IVS1( - 24)G/(CGG)(7).This study confirmed the presence of Q248H mutation at polymorphic frequencies in three native sub-Saharan populations. Analysis of two additional markers in the same gene support a single origin of the mutant allele c.744T in the haplotype background IVS1( - 24)G/(CGG)(7).

Machado-Joseph disease is a progressive neurodegenerative disorder associated with the polyQ-expanded ataxin-3 (encoded by ATXN3), for which no therapy is available. With the aim of clarifying the mechanism of neurodegeneration, we hypothesized that the abnormally long polyQ tract would interact aberrantly with ataxin-2 (encoded by ATXN2), another polyQ protein whose function has recently been linked to translational regulation. Using patient's samples and cellular and animal's models we found that in Machado-Joseph disease: (i) ataxin-2 levels are reduced; and (ii) its subcellular localization is changed towards the nucleus. Restoring ataxin-2 levels by lentiviral-mediated overexpression: (i) reduced mutant ataxin-3 levels; and (ii) rescued behaviour defects and neuropathology in a transgenic mouse model of Machado-Joseph disease. Conversely (i) mutating the ataxin-2 motif that enables binding to its natural interactor and translation activator poly(A)-binding protein; or (ii) overexpressing poly(A)-binding protein, had opposite effects, increasing mutant ataxin-3 translation and aggregation. This work suggests that in Machado-Joseph disease, mutant ataxin-3 drives an abnormal reduction of ataxin-2 levels, which overactivates poly(A)-binding protein, increases translation of mutant ataxin-3 and other proteins and aggravates Machado-Joseph disease. Re-establishment of ataxin-2 levels reduces mutant ataxin-3 and alleviates Machado-Joseph disease pathogenesis opening a new avenue for therapeutic intervention in this and potentially other polyQ disorders.

We aimed to determine whether variability in the melanocortin-4 receptor (MC4R) gene, predisposing to hyperphagia and obesity, may also be present in nonobese patients with binge-eating behavior or be related to anthropometric or psychopathological parameters in these patients. The coding region of the MC4R gene was sequenced in nonobese patients with binge-eating behavior diagnosed with bulimia nervosa or binge-eating disorder (n=77); individuals with severe early-onset obesity (n=170); and lean women with anorexia nervosa (n=20). A psychometric evaluation (Eating Disorders Inventory-2 and Symptom Checklist 90 Revised inventories) was carried out for all the patients with eating disorders. In the obesity group, 10 different variants were identified, whereas in the binge-eating patients, only two individuals with bulimia nervosa were found to carry the I251L polymorphism, which did not correlate with weight, BMI, or psychopathological features. We found no evidence that mutations in the MC4R gene are associated with binge-eating behavior in nonobese eating disorder patients.

Background SNRPN, which codes for the RNA-binding SmN protein, is a candidate gene for Prader-Willi syndrome. One characteristic of this neuroendocrine disorder is hyperphagia resulting in extreme obesity later in life. In the present study, we aimed to assess whether variability within this gene could be implicated in obesity susceptibility. Methods A case–control study was performed including 265 unrelated patients with nonsyndromic and early-onset severe obesity, belonging to high-risk obesity families from Spanish ancestry; 184 healthy control individuals were included representative of the same genetic background and sex-matched. Forty-nine single nucleotide polymorphisms (SNPs) spanning the entire SNRPN gene were selected and genotyped using the Sequenom MassARRAY platform (Sequenom Inc., San Diego, CA, USA). Results The four SNPs, rs12905653, rs752874, rs1391516 and rs2047433, were found to be nominally associated with obesity (p

Epigenetic refers to the study of heritable changes in gene expression that do not modify DNA sequence. The underlying main epigenetic mechanisms comprise DNA methylation, histone modifications and the non-coding micro RNAs (miRNAs). These mechanisms are responsible for maintaining the patterns of gene expression during cellular differentiation. Moreover, there is a link between genetic and epigenetic mechanisms, in which some single nucleotide polymorphisms can interact with nutrients and other bioactive food components. This nutrient-gene interaction can lead to the modulation of gene expression in response to the nutritional factors. When we eat, we introduce some bioactive dietary components that can modify patterns of gene expression thus influencing the phenotype. There is considerable evidence that the pre- or the conception stage strongly influence the risk of developing obesity in later life. In this chapter, we review epigenetic mechanisms involved in the susceptibility and development of obesity. We have collected some of the most recent results on epiobesogenic genes and some nutrients involved in epigenetic changes. Further understanding on how these genes and nutrients act may help toward personalized treatment for obesity-related co-morbidities based on individual needs.

The Genome-Wide Association Studies (GWAS) approach have help to found numerous genes for common traits and diseases, including the susceptibility to develop common obesity. Following the discovery of the first locus, by GWAS in 2007, more than 35 loci have been found associated with the increase of body mass index (BMI). However, all these loci explain only a small proportion of the heritability of common obesity (explaining ~ 1–2 % of the variance in BMI). Most of obesity susceptible genes found by GWAS have been performed in Caucasian adults. Several studies appear to replicate these findings in children and other ethnic groups, but our knowledge about the genetic of common obesity remains limited. The major part of these studies only assesses the genetic risk locus alone. However, the design of a combined genetic score could be a better tool to determine the susceptibility of obesity. In this chapter we report loci associated with obesity, which were found by GWAS.

At least 52 genetic loci were associated with obesity-related traits. However, little is known about the genetic basis of obesity among children. This study aims to test whether 10 polymorphisms in obesity-related genes methionine sulfoxide reductase A (MSRA), transcription factor AP-2 beta (TFAP2B), melanocortin 4 receptor (MC4R), neurexin 3 (NRXN3), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), transmembrane protein 18 (TMEM18), homolog of S. cerevisiae Sec16 (SEC16B), homeobox B5 (HOXB5) and olfactomedin 4 (OLFM4) are associated with the risk of obesity in Portuguese children. A total of 730 children aging from 6 to 12 years old, recruited randomly from public schools in Portugal, were analysed. Anthropometric measurements were obtained and children were classified into three phenotypic groups, normal weight (n=256), overweight (n=320) and obese (n=154), according to the International Obesity Task Force cutoffs. Polymorphisms were genotyped by allelic discrimination TaqMan assays. The MC4R rs12970134 polymorphism was nominally associated with body mass index (BMI) (P=0.035), BMI Z-score (P=0.043) and waist circumference (P=0.020), and borderline associated with weight (P=0.053). Near nominal associations were also found for the PPARGC1A rs8192678 polymorphism with weight (P=0.061), and for the MSRA rs545854 polymorphism with BMI (P=0.055) and BMI Z-score (P=0.056). Furthermore, logistic regression showed that MC4R rs12970134 and TFAP2B rs987237 were nominally, respectively, associated (P=0.029) and borderline associated (P=0.056) with the obese phenotype. This study highlighted the possible association of MC4R, PPARGC1A, MSRA and TFAP2B polymorphisms with several obesity-related traits in a sample of Portuguese children. The two significant associated TFAP2B rs987237 and MC4R rs12970134 polymorphisms showed an opposite direction of effect to that in the original reports.

Machado-Joseph disease or Spinocerebellar ataxia type 3 is a progressive fatal neurodegenerative disorder caused by the polyglutamine-expanded protein ataxin-3. Recent studies demonstrate that RNA interference is a promising approach for the treatment of Machado-Joseph disease. However, whether gene silencing at an early time-point is able to prevent the appearance of motor behavior deficits typical of the disease when initiated before onset of the disease had not been explored. Here, using a lentiviral-mediated allele-specific silencing of mutant ataxin-3 in an early pre-symptomatic cerebellar mouse model of Machado-Joseph disease we show that this strategy hampers the development of the motor and neuropathological phenotypic characteristics of the disease. At the histological level, the RNA-specific silencing of mutant ataxin-3 decreased formation of mutant ataxin-3 aggregates, preserved Purkinje cell morphology and expression of neuronal markers while reducing cell death. Importantly, gene silencing prevented the development of impairments in balance, motor coordination, gait and hyperactivity observed in control mice. These data support the therapeutic potential of RNA interference for Machado-Joseph disease and constitute a proof of principle of the beneficial effects of early allele-specific silencing for therapy of this disease.

We screened for mutations in the MC4R and LEPR genes and investigated the genotype-phenotype correlation in obese individuals belonging to families with evident hereditary patterns of severe and early-onset obesity among the Iberian population. A total of 202 unrelated and severely obese patients since childhood, were enrolled in the study. Bidirectional sequencing of the MC4R gene was carried out in all patients; the LEPR gene was sequenced in 15 individuals based on additional clinical signals. Segregation analysis and/or genotype-phenotype description was performed for subjects with the new mutations and with presumably functional variants. Ten MC4R gene mutations were identified in the heterozygous state in 10 patients. Mutations p.R147G and p.G323E are new and mutations p.R7H, p.G32E, p.H76R, p.V103I, p.S127L, p.T150I, p.I251L and p.G252S were previously described. A new dinucleotide insertion -77_-76insTA in the promoter region of the LEPR gene was found in the heterozygous state in one patient. The new p.R147G and the previously published p.R7H, p.S127L, p.T150I and p.G252S MC4R mutations, cosegregate with obesity in our patients and were predicted to be deleterious. For the novel MC4R p.G323E and LEPR -77_-76insTA gene mutations, the genotype-phenotype correlation and bioinformatic analysis did not clarify whether these mutations are indeed implicated in obesity.

The - 13910CT polymorphism has been associated with lactase persistence (LP) in European populations.To assess - 13910CT genotypes across Portugal and in adult individuals with unspecific gastrointestinal complaints associated with milk consumption.This study genotyped - 13910CT in the general population from Northern (n = 64), Central (n = 70) and Southern (n = 65) Portugal and in 40 subjects with gastrointestinal symptoms. Additionally, the concordance was evaluated between breath-hydrogen test and - 13910CT genotypes in 65 samples.An overall frequency of 0.349 for the LP - 13910*T allele was estimated in the general population, with a noticeable decrease in the South (0.269) compared with North (0.383) and Centre (0.393). Among the symptomatic group, the frequency of the - 13910*T allele (0.363) was not significantly different from the general population. A 94% concordance was found between the breath-hydrogen and the molecular tests.This study suggests that (i) the distribution of the LP polymorphism is not uniform across the country, (ii) genotyping - 13910CT is a good diagnostic tool for lactase status in the Portuguese population and (iii) self-reported gastrointestinal complaints are not good predictors of the LP status, implying that a significant part of those complaints may not be related to hypolactasia.

Childhood obesity is a major public health issue in developed countries, and frequently proceeds into adulthood. The aim of this study was to estimate the prevalence of obesity and abdominal fat distribution in 6-12 years old children from the central region of Portugal, providing new data about trends on prevalence, epidemiology and evolution in obesity.Weight, height and waist circumference were measured in a random representative sample of 1,433 children (747 girls and 686 boys) from public schools in 2011. International Obesity Task Force (IOTF) cut-offs were used to define overweight and obesity. Abdominal obesity was estimated using the sex and age-specific = 90th waist circumference percentile and waist-to-height ratio cut-off.The prevalence of overweight and obesity among children was 33.0%; 10.7% were obese. Overweight was significantly higher in boys than in girls (p = 0.044), whereas no gender differences was found in obesity (10.6 % in boys and 10.7% in girls, p = 0.571). The prevalence of abdominal obesity based on waist circumference was similar in girls and boys (3.8% vs. 3.9% respectively; p = 0.924), but significantly higher in boys than in girls based on waist-to-height ratio (28.1% vs. 19.4%, respectively; p = 0.009). Comparison with previous studies showed a slightly increase in overweight/obesity in children of central Portugal in the last 10 years, reaching values of 40.0% prevalence in the 7-9 years old.In conclusion, this study shows a very high prevalence of overweight/obesity and abdominal obesity among Portuguese children, following the trend of other southern European countries. Thus, it is of the utmost importance the development of preventive and treatment strategies.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein - ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD.

BackgroundSeveral studies have reported an association between single nucleotide polymorphisms in the first intron of the FTO gene and body mass index (BMI) or obesity. However, this association has not yet been studied among the Portuguese population. This study aims to assess the association of three FTO polymorphisms (rs1861868, rs1421085 and rs9939609) with obesity-related outcomes in a sample of Portuguese children.MethodsWe examined a total of 730 children, 256 normal-weight (55.9% girls), 320 overweight (45.3% girls) and 154 obese (53.2% girls), aging from 6 to 12-years-old, recruited randomly from public schools in the central region of Portugal. DNA samples were genotyped for the three polymorphisms by allelic discrimination TaqMan assay. Association of the FTO polymorphisms with several anthropometric traits was investigated. Additionally, we tested association with the risk of obesity using overweight and obese vs. normal-weight children.ResultsWe found significant associations of rs9939609 and rs1421085 polymorphisms with weight, BMI, BMI Z-score, waist circumference and hip circumference, even after age and gender adjustment (p0.05). Haplotype analyses identified two combinations (ACA and GCA) associated with a higher risk of obesity (OR 1.53; 95% CI, 1.06-2.22; p = 0.023; OR 1.73; 95% CI, 1.06-2.87; p = 0.030, respectively).ConclusionsThis study provides the first evidence for the association of FTO polymorphisms with anthropometric traits and risk of obesity in Portuguese children.

Background: Childhood obesity is a major public health issue in developed countries, and frequently proceeds into adulthood. The aim of this study was to estimate the prevalence of obesity and abdominal fat distribution in 6-12 years old children from the central region of Portugal, providing new data about trends on prevalence, epidemiology and evolution in obesity. Methods: Weight, height and waist circumference were measured in a random representative sample of 1,433 children (747 girls and 686 boys) from public schools in 2011. International Obesity Task Force (IOTF) cut-offs were used to define overweight and obesity. Abdominal obesity was estimated using the sex and age-specific ≥ 90th waist circumference percentile and waist-to-height ratio cut-off. Results: The prevalence of overweight and obesity among children was 33.0%; 10.7% were obese. Overweight was significantly higher in boys than in girls (p = 0.044), whereas no gender differences was found in obesity (10.6 % in boys and 10.7% in girls, p = 0.571). The prevalence of abdominal obesity based on waist circumference was similar in girls and boys (3.8% vs. 3.9% respectively; p = 0.924), but significantly higher in boys than in girls based on waist-to-height ratio (28.1% vs. 19.4%, respectively; p = 0.009). Comparison with previous studies showed a slightly increase in overweight/obesity in children of central Portugal in the last 10 years, reaching values of 40.0% prevalence in the 7-9 years old. Conclusion: In conclusion, this study shows a very high prevalence of overweight/obesity and abdominal obesity among Portuguese children, following the trend of other southern European countries. Thus, it is of the utmost importance the development of preventive and treatment strategies.