A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea. Apesar de relativa alta prevalência, possui poucas informações referentes ao perfil cognitivo de seus portadores. Em literatura atual seus portadores são descritos com moderado prejuízo na cognição social em termos de reconhecimento das emoções e expressão do afeto, além de variável nível de inteligência. Em virtude da raridade de pesquisas na área psicológica acerca desta síndrome e, tomando por base recentes estudos, o presente estudo buscou esclarecer o perfil cognitivo de portadores da síndrome de Noonan decorrente de mutação do gene PTPN11, visando a contribuir para o estabelecimento de seu fenótipo comportamental. Foram estudadas 19 pessoas com a síndrome, de ambos os sexos, diagnosticadas clínica e laboratorialmente. A avaliação psicológica foi realizada por meio das escalas Wechsler de inteligência, pelo teste Figuras Complexas de Rey e pelo Teste Wisconsin de Classificação de Cartas. Os resultados obtidos indicaram uma variação entre inteligência normal a retardo mental leve, além de inflexibilidade mental e resposta não adaptada ao feedback ambiental. A avaliação aferiu presença de prejuízos em categorização e, ainda, falha no planejamento do ato motor (praxia) como responsável pelos escores rebaixados em memória episódica visuo-construtiva gráfica. Estes resultados sugerem a necessidade de ampliação de estudos que correlacionem aspectos cognitivos nas mais variadas patologias genéticas / Noonan syndrome is an autosomal dominant genetically heterogeneous disorder. Although relatively high prevalence, there are few information about the cognitive profile of people with the syndorme. Current literature describes moderately impaired social cognition in terms of emotion recognition and emotion affection, besides a variable level of intelligence. Because of rarely researches about psychological area in this syndrome and, based on recent studies, the present study looked for clarify the cognitive profile of people with Noonan syndrome with mutation in the PTPN11 gene, trying to contribute for the establishment of a phenotypic behavior. 19 persons with the syndrome were studied, both male and female, diagnosticaded clinical and laboratorilly. Psychological assessment was realized by using Wechsler intelligence Scales, Rey Complex Figure Test and Wisconsin Card Sorting Test. The results indicated a variation of normal intelligence to mild mental retardation, besides inflexibility and not adapted responses using environmental feedback. The assessment checked the presence of lacked in categories achieved and, even, fault in planning of motor act (praxis) as responsible for low scores in graphic visuoconstruction episodic memory. These results suggest the necessity of expansion of studies which correlated cognitive aspects in the most variables genetic pathologics

Familial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the LDL receptor. Heterozygous FH is among the most common inborn errors of metabolism and remains as the best example of an inherited defect causing premature coronary artery disease (CAD). This thesis describes the physical and biochemical characteristics of heterozygous FH in a large cohort consisting of 208 women and 156 men. The influence of both genetic and environmental factors on the clinical expression of FH were investigated to better understand the phenotypic variation within FH and thus improve the prediction and treatment of CAD in affected individuals. The general incidence of CAD in this population was lower compared to previous reports but the differences between the sexes were expected. It was shown that men had a much higher frequency of CAD (31%) compared to women (13%) despite having lower concentrations of total and LDL cholesterol. In addition, the average age of onset of coronary symptoms was delayed in females, 55 years compared to 48 years for males. A greater risk of developing CAD for men was associated with low levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglyceride levels and the presence of hypertension. In order to efficiently assess the influence of the co-inheritance of the apolipoprotein E polymorphism in this large FH population, a novel apo E phenotyping procedure was developed. Phenotypes were determined directly from plasma which was neuraminidase treated, delipidated and focused in polyacrylamide minigels. The accuracy of this method was confirmed by making a comparison to the established procedure of phenotyping by isoelectric focusing of delipidated VLDL. The low cost, speed and simplicity of the minigel methodology provided ideal conditions to phenotype a large patient population. The frequencies of the ɛ2, ɛ3 and ɛ4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relationship between apo E4 and the concentration of any of the parameters in the plasma lipid profile. However, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. From this study, it is evident that the mutant FH gene exerts its effect within a system of interacting environmental and polygenic factors that are known to modify atherosclerotic risk. It has been established that the dissimilarity in the frequency of CAD between men and women is related to differences between the impact of known risk factors and the incidence of CAD. Therefore, the importance of the influence of these risk factors and the differences between men and women should be emphasized when treating and predicting the development of CAD in patients with FH. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Please read the abstract in the section 00front of this document / Dissertation (MSc (Chemical Pathology))--University of Pretoria, 2005. / Chemical Pathology / unrestricted

In silico prioritization of undiscovered associations can help find causal genes of newly discovered diseases. Some existing methods are based on known associations, and side information of diseases and genes. We exploit the possibility of using a neural network model, Neural inductive matrix completion (NIMC), in disease-gene prediction. Comparing to the state-of-the-art inductive matrix completion method, using neural networks allows us to learn latent features from non-linear functions of input features. Previous methods use disease features only from mining text. Comparing to text mining, disease ontology is a more informative way of discovering correlation of dis- eases, from which we can calculate the similarities between diseases and help increase the performance of predicting disease-gene associations. We compare the proposed method with other state-of-the-art methods for pre- dicting associated genes for diseases from the Online Mendelian Inheritance in Man (OMIM) database. Results show that both new features and the proposed NIMC model can improve the chance of recovering an unknown associated gene in the top 100 predicted genes. Best results are obtained by using both the new features and the new model. Results also show the proposed method does better in predicting associated genes for newly discovered diseases.

Thesis (M.Sc. Agriculture (Animal Production)) -- University of Limpopo, 2020 / Stillbirth is a trait of high economic importance in dairy cattle and is increasingly being included in dairy cattle breeding objectives worldwide. In South Africa, however, there is limited information on stillbirth that can be used to improve this trait genetically. Currently, there are no estimated breeding values (EBVs) for any measures of calving performance produced under the national genetic evaluation programme. The current study was, therefore, conducted to assess the incidence of stillbirth and estimate the genetic and environmental influences on maternal effects for stillbirth in South African Holstein cattle, to enable estimation of breeding values for the trait. Data used in the study comprised 13 143 calving records of 7 723 Holstein cows, from 41 herds, participating in the National Dairy Animal Recording and Improvement Scheme during the period 2014 to 2018. Incidence of stillbirth was determined using the PROC FREQ procedure and environmental effects were tested by the General Linear Models (GLM) procedure of Statistical Analysis System (SAS 9.4, 2016). Maternal heritability of stillbirth was estimated by the Restricted Maximum Likelihood (REML) procedure, using the ASReml software (Gilmour et al., 2018). The analyses were carried out using a threshold animal model and a repeatability animal model, where the latter considered stillbirth in different parities as repeated measures of the same trait. Environmental effects significantly influencing stillbirth (p<0.05) were herd-year season of calving, dam parity and calf sex, and these were included in the model for variance component estimation. Estimates of maternal heritability effects from the threshold animal model were 0.12±0.04, 0.15±0.08 and 0.14±0.06 for parities 1 to 3, respectively. The repeatability animal model gave a heritability estimate of 0.09±0.03 and a repeatability of 0.18±0.03. The moderate estimates of maternal heritability indicate scope for reducing incidence of stillbirth by selectively breeding cows that are less genetically predisposed to calving dead calves. Stillbirth in different parities should not be considered as the same trait, as indicated by the low repeatability estimate. Results of the current study estimate genetic parameters that are required to compute accurate estimated breeding values (EBVs) for stillbirth, which will enable South African Holstein farmers to select for reduced stillbirths, thus improving calving performance / National Research Foundation (NRF), University of Limpopo (UL) and Department of Agriculture Forestry and Fisheries (DAFF)

In the mammalian brain, information is believed to be encoded at the cellular level through alterations in synaptic weights. Furthermore, changes in synaptic strength are correlated with structural changes at dendritic spines, such as growth and shrinkage, which may serve to shape inputs into functional domains and increase the computational power of neurons. Neuroanatomical alterations in dendritic spines have been described in humans with intellectual disability, further supporting the relationship between neuronal structure and function. Fragile X Syndrome (FXS) is the most common single-gene neurodevelopmental disorder, and a hallmark feature of this disorder is the increased density of long spines in several brain regions including the hippocampus. Identification of FXS spines as filopodia-like has led to the theory that these spines are immature, and that altered spine development underlies the cognitive dysfunction in this disorder. However, the functional capacity of the long spines observed in FXS is not well understood. For my thesis work, I used two photon imaging, glutamate uncaging and electrophysiology to perform a high-resolution characterization of dendritic spine structure, function, and plasticity in the hippocampus of the FXS mouse model in order to determine what gives rise to these alterations and how this contributes to the observed neuronal dysfunction in this disorder. From my dissertation research, I find that while Fmr1 KO neurons have region-specific alterations in both dendrite and spine morphology, the functional responses of single synapses in FXS mutant neurons are grossly normal. FXS spines respond proportionally to increased levels of glutamate release, and the linear relationship between structure and function is preserved at these synapses. In addition, structural plasticity, both growth and shrinkage, at single inputs is similar in magnitude to control neurons following synaptic potentiation and depression, respectively. However, upon more detailed examination of structural plasticity, either at single or multiple inputs, I find several deficits. First, following structural plasticity, I observe aberrant heterosynaptic plasticity in Fmr1 KO neurons, where unstimulated mutant spines located in close proximity to activated spines become significantly larger compared to neighboring spines in control neurons, which showed no significant change in size. Next, competition for mGluR-LTD does not occur in Fmr1 KO neurons, leading to an increase in spines that undergo spine shrinkage. I conclude from this work that while spine morphology is altered in FXS, spines develop with functional synapses that have the capacity to express bidirectional forms of structural plasticity. However, these spines undergo abnormal structural plasticity across stimulated inputs, leading to the expression of aberrant heterosynaptic structural plasticity. As activity is integrated across a dendritic branch, such excess plasticity observed in Fmr1 KO neurons could contribute to the altered spine morphology as well as cognitive dysfunction observed in FXS.

Indiana University-Purdue University Indianapolis (IUPUI) / Glycogen is a highly branched polymer of glucose that functions to store glucose residues for future metabolic use. Skeletal muscle and liver comprise the largest glycogen reserves and play critical roles in maintaining whole body glucose homeostasis. In addition to glucose, glycogen contains small amounts of covalent phosphate of unknown function, origin and structure. Evidence to support the involvement of glycogen associated phosphate in glycogen metabolism comes from patients with Lafora Disease. Lafora disease is an autosomal recessive, fatal form of progressive myoclonus epilepsy. Approximately 90% of cases of Lafora disease are caused by mutations in either the EPM2A or EPM2B genes that encode, respectively, a dual specificity phosphatase called laforin and an E3 ubiquitin ligase called malin. Lafora patients accumulate intracellular inclusion bodies, known as Lafora bodies that are primarily composed of poorly branched, insoluble glycogen-like polymers. We have shown that laforin is a glycogen phosphatase capable of releasing phosphate from glycogen in vitro and that this activity is dependent on a functional carbohydrate binding domain. In studies of laforin knockout mice, we observed a progressive change in the properties and structure of glycogen that paralleled the formation of Lafora bodies. Glycogen isolated from these mice showed increased glycogen phosphate, up to 6-fold (p< 0.001) compared to WT, providing strong evidence that laforin acts as a glycogen phosphatase in vivo. Furthermore we have demonstrated that glycogen synthase introduces phosphate into glycogen during synthesis by transferring the beta-phosphate of UDP-glucose into the polymer and that laforin is capable of releasing the phosphate incorporated by glycogen synthase. Analysis of mammalian glycogen revealed the presence of covalently linked phosphate at the 2 hydroxyl and the 3 hydroxyl of glucose residues in the polysaccharide, providing the first direct evidence of the chemical nature of the phosphate linkage. We envision a glycogen damage/repair process, analogous to errors during DNA synthesis that are subsequently repaired. We propose that laforin action parallels that of DNA repair enzymes and Lafora disease results from the inability of the phosphatase to repair damaged glycogen, adding another biological polymer to the list of those prone to errors by their respective polymerizing enzymes.

Indiana University-Purdue University Indianapolis (IUPUI) / The information gained from sequencing of the human genome has begun to transform human biology and genetic medicine. The discovery of functionally important genetic variation lies at the heart of these endeavors, and there has been substantial progress in understanding the common patterns of single-nucleotide polymorphism (SNP) in humans- the most frequent type of variation in humans. Although more than 99% of human DNA sequences are the same across the population, variations in DNA sequence have a major impact on how we humans respond to disease; to environmental entities such as bacteria, viruses, toxins, and chemicals; and drugs and other therapies and thus studying differences between our genomes is vital. This makes SNPs as well other genetic variation data of great value for biomedical research and for developing pharmaceutical products or medical diagnostics. The goal of the project is to link genetic variation data to biological pathways and networks data, and also to clinical data for creating a framework for translational and systems biology studies. The study of the interactions between the components of biological systems and biological pathways has become increasingly important. It is known and accepted by scientists that it as important to study different biological entities as interacting systems, as in isolation. This project has ideas rooted in this thinking aiming at the integration of a genetic variation dataset with biological pathways dataset. Annotating genetic variation data with standardized disease notation is a very difficult yet important endeavor. One of the goals of this research is to identify whether informatics approaches can be applied to automatically annotate genetic variation data with a classification of diseases.

The increasing transparence of the human genome has profound implications for how we understand health and illness and perceive our biological and social relatedness to others. Presymptomatic testing for adult onset conditions, in particular, creates the novel situation in which some individuals know in advance of impending illness while others learn that they have escaped such a fate. How families at risk for one adult onset condition — Huntington Disease (HD) — communicate about such information is the topic of this dissertation. HD is often described as a 'genetic time bomb'. It is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. There is no effective prevention or cure but with the advent of predictive testing in 1987 it became possible for at risk individuals to learn if they had inherited the mutation associated with HL\ Empirical studies on predictive testing for HD focus primarily on the individual psychological impacts of the test; few studies consider how families understand and attempt to manage genetic information in their everyday lives. This dissertation begins to address these lacunae by examining the stories that test candidates and their families tell about hereditary risk and predictive testing. These stories derive from a prospectively designed study which includes 102 in-depth, at-home interviews conducted in the pre and post-results period with 16 test candidates and 33 family members. Focusing on three narrative 'moments', the dissertation explores how study participants storied their experiences of: 1) learning about the family history of HD, 2) deciding to request the predictive test and, 3) making sense of an informative result. Drawing upon a social constructionist approach, the analysis emphasizes the processual nature of predictive testing as well as the significance of interpersonal communication in producing and reproducing the social realities in which genetic information acquires a particular salience. Given the recent proliferation of genetic tests as well as the absence of an adequate popular discourse on embodied risk, the research underscores lay actors' abilities to reframe existing clinical schema in order to interpret and manage hereditary risk in an intersubjectively meaningful way.

The increasing transparence of the human genome has profound implications for how we understand health and illness and perceive our biological and social relatedness to others. Presymptomatic testing for adult onset conditions, in particular, creates the novel situation in which some individuals know in advance of impending illness while others learn that they have escaped such a fate. How families at risk for one adult onset condition — Huntington Disease (HD) — communicate about such information is the topic of this dissertation. HD is often described as a 'genetic time bomb'. It is an autosomal dominant neuropsychiatric disorder characterized by mid-life onset, involuntary movements, cognitive impairment, and depression. There is no effective prevention or cure but with the advent of predictive testing in 1987 it became possible for at risk individuals to learn if they had inherited the mutation associated with HL\ Empirical studies on predictive testing for HD focus primarily on the individual psychological impacts of the test; few studies consider how families understand and attempt to manage genetic information in their everyday lives. This dissertation begins to address these lacunae by examining the stories that test candidates and their families tell about hereditary risk and predictive testing. These stories derive from a prospectively designed study which includes 102 in-depth, at-home interviews conducted in the pre and post-results period with 16 test candidates and 33 family members. Focusing on three narrative 'moments', the dissertation explores how study participants storied their experiences of: 1) learning about the family history of HD, 2) deciding to request the predictive test and, 3) making sense of an informative result. Drawing upon a social constructionist approach, the analysis emphasizes the processual nature of predictive testing as well as the significance of interpersonal communication in producing and reproducing the social realities in which genetic information acquires a particular salience. Given the recent proliferation of genetic tests as well as the absence of an adequate popular discourse on embodied risk, the research underscores lay actors' abilities to reframe existing clinical schema in order to interpret and manage hereditary risk in an intersubjectively meaningful way. / Arts, Faculty of / Anthropology, Department of / Graduate