by Lan Chen. / "June 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Introdução: A doença de Parkinson é uma enfermidade neurodegenerativa decorrente da perda de neurônios dopaminérgicos na substância negra, principalmente, e em outras regiões cerebrais. Caracteriza-se clinicamente por tremor, rigidez, bradicinesia e instabilidade postural. O tratamento é sintomático e consiste essencialmente na reposição da dopamina deficiente. A etiologia da doença de Parkinson ainda não é conhecida, mas os recentes avanços da Neurologia trouxeram novos conhecimentos acerca dos mecanismos fisiopatológicos envolvidos. Disfunção mitocondrial, estresse oxidativo e degradação de proteínas são alguns dos processos celulares que foram relacionados à degeneração dos neurônios dopaminérgicos. O campo da genética da doença de Parkinson tem recebido atenção especial na última década, graças à descoberta de vários genes associados ao desenvolvimento da doença. Um fator de risco genético recentemente descrito é a presença de mutações no gene da glicocerebrosidase, uma enzima lisossomal cuja deficiência resulta na doença de Gaucher. Apesar de a maioria dos estudos já publicados terem confirmado esta associação, um trabalho mais recente da Noruega não encontrou significância estatística ao analisar a presença destas mutações em pacientes com doença de Parkinson, tornando o assunto ainda controverso. Objetivo: Pesquisar a presença de mutações da glicocerebrosidase em pacientes com diagnóstico de doença de Parkinson no Brasil, acompanhados no ambulatório de Distúrbios do Movimento do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e correlacionar tais achados com estudos recém-publicados que analisaram esta associação em outras populações em âmbito mundial, além de descrever possíveis características dos pacientes portadores de mutações que os diferenciem de não portadores. Métodos: Foram incluídos no estudo 65 pacientes com o diagnóstico de doença de Parkinson e idade de início da doença inferior ou igual a 55 anos e 267 controles sem a doença, emparelhados para sexo e idade. Foi realizada análise genética de material obtido a partir de raspagem da mucosa oral destes indivíduos, tendo sido pesquisadas as três mutações da glicocerebrosidase mais comuns na população brasileira: N370S, L444P e G377S. Resultados: Em dois dos 65 pacientes e em nenhum dos 267 controles foram identificadas mutações no gene da glicocerebrosidase. Os dois pacientes carreadores de mutações (L444P em um e L444P + E326K em outro) apresentavam quadro clínico indistinguível dos demais pacientes com doença de Parkinson não portadores das mutações. Conclusões: Foi observada uma associação estatisticamente significativa (P=0,0379, teste exato de Fisher) entre doença de Parkinson e mutações da glicocerebrosidase na nossa população. A prevalência de mutações da glicocerebrosidase neste grupo de pacientes foi maior do que a esperada para a população geral, porém menor do que a encontrada em estudos internacionais previamente publicados. Espera-se que a identificação desta nova associação permita uma maior compreensão dos mecanismos subjacentes à doença de Parkinson e que em um futuro próximo possa propiciar o desenvolvimento de novas estratégias terapêuticas. / Introduction: Parkinson\'s disease is a neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra, primarily, and in other brain regions. It is clinically characterized by tremor, rigidity, bradykinesia and postural instability. Treatment is symptomatic and consists essentially in replacing the deficient dopamine. The etiology of Parkinson\'s disease remains unknown, but recent advances in Neurology have provided data concerning the pathophysiological mechanisms involved. Mithocondrial dysfunction, oxidative stress and protein degradation are some of the cellular processes that have been linked to dopaminergic neurons degeneration. The field of genetics in Parkinson\'s disease has gained special attention in the past decade, thanks to the discovery of several genes associated with the development of the disease. A recently described genetic risk factor for Parkinson\'s disease is the presence of glucocerebrosidase gene mutations. Glucocerebrosidase is a lysosomal enzyme which is deficient in Gaucher disease. Although most studies published to date have confirmed such association, a recent article from Norway could not find statistical significance when Parkinson\'s disease patients were analyzed for glucocerebrosidase mutations, generating controversy. Objective: To search for glucocerebrosidase mutations in Parkinson\'s disease patients in Brazil, followed at the Movement Disorders Division at Hospital das Clínicas, University of São Paulo Medical School, and correlate these findings with recently published studies which evaluated this association in other populations worldwide, besides describing possible features of patients carrying the mutations that may help differentiating them from non-carriers. Methods: Sixty five patients diagnosed with Parkinson’s disease, with disease onset before age 55, and 267 age and sex-matched controls were included in the study. DNA analysis of the three most common glucocerebrosidase mutations in the Brazilian population, N370S, L444P and G377S, was performed utilizing samples obtained from mouth mucus. Results: Glucocerebrosidase gene mutations were identified in two of the 65 Parkinson\'s disease patients and in none of the 267 controls. The two patients who were carriers of mutations (one of them had L444P and the other L444P+E326K) had a clinical picture indistinguishable from the other Parkinson\'s disease non-carriers patients. Conclusion: A statistically significant association (P=0,0379, Fisher\'s exact test) between Parkinson\'s disease and glucocerebrosidase mutations was observed in our population. The prevalence of glucocerebrosidase mutations was higher than expected for the general population, though lower than reported in previous international studies. It is expected that the finding of this association will allow a better understanding of Parkinson\'s disease mechanisms and that in a near future it may help providing the development of new therapeutic strategies.

Bibliography: leaves 118-132. This thesis examines the structure and gene expression of barley yellow dwarf viruses (BYDVs)-PAV in order to gain a better understanding of the interaction between the virus and the Yd2 resistance gene. The protein products of open reading frame (ORF)3, ORF4 and ORF5 are expressed in bacterial cells, in order to characterise the BYDV-PAV virion-associated proteins. The effect of the Yd2 resistance gene on the expression of the BYDV-PAV viral proteins in infected cells is also studied.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease which results from the degeneration of upper and lower motor neurons in the brainstem, spinal cord and motor cortex. Tragically there is no treatment to prevent ALS. The drug Riluzole acts to delay progression, but only by a month or so in this disease that has a survival length of three to five years. The identification of genes that are mutated in patients with ALS would help devise novel therapeutic strategies as much remains to be discovered about the genetics of ALS. Familial forms of the disease account for only 5-10% of patients. Among these familial cases, about 15-20% are caused by mutations in the zinc/copper superoxide dismutase gene, but the genetic basis of the remaining familial cases and the many sporadic cases continues to be largely unknown. / Altogether, the results presented in this thesis came from the use of several strategies to establish the genetic cause of ALS and the related motor neuron disorders like hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS). A concerted and collaborative effort was put forth to identify the gene causative for ALS3 on chromosome 18. In addition, a recently reported locus has been confirmed on chromosome 9p for patients that present both ALS and frontotemporal dementia. The major finding involves the discovery of eight mutations in the TARDBP gene in nine patients with sporadic and familial ALS. Furthermore, a large association study evaluated the role of common polymorphisms in the paraoxonase gene cluster in susceptibility to the development of ALS. In the analysis of upper motor neuron diseases, mutations in a novel gene, KIAA0196, were identified for the HSP locus SPG8 on chromosome 8. Finally, the first locus for PLS was discovered on the p-arm of chromosome 4 following genome scan analysis of a large Quebec family with PLS. / These genetic discoveries all contributed novel advances to the field of motor neuron disorders. As more is elucidated regarding the biochemical function of these the proteins encoded by these genes, a more comprehensive picture of ALS and other motor neuron disorders will hopefully emerge.

Bibliography: leaves 118-132. / iv, 132 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / This thesis examines the structure and gene expression of barley yellow dwarf viruses (BYDVs)-PAV in order to gain a better understanding of the interaction between the virus and the Yd2 resistance gene. The protein products of open reading frame (ORF)3, ORF4 and ORF5 are expressed in bacterial cells, in order to characterise the BYDV-PAV virion-associated proteins. The effect of the Yd2 resistance gene on the expression of the BYDV-PAV viral proteins in infected cells is also studied. / Thesis (Ph.D.)--University of Adelaide, Dept. of Plant Science, 1997

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Introdução: A doença de Parkinson é uma enfermidade neurodegenerativa decorrente da perda de neurônios dopaminérgicos na substância negra, principalmente, e em outras regiões cerebrais. Caracteriza-se clinicamente por tremor, rigidez, bradicinesia e instabilidade postural. O tratamento é sintomático e consiste essencialmente na reposição da dopamina deficiente. A etiologia da doença de Parkinson ainda não é conhecida, mas os recentes avanços da Neurologia trouxeram novos conhecimentos acerca dos mecanismos fisiopatológicos envolvidos. Disfunção mitocondrial, estresse oxidativo e degradação de proteínas são alguns dos processos celulares que foram relacionados à degeneração dos neurônios dopaminérgicos. O campo da genética da doença de Parkinson tem recebido atenção especial na última década, graças à descoberta de vários genes associados ao desenvolvimento da doença. Um fator de risco genético recentemente descrito é a presença de mutações no gene da glicocerebrosidase, uma enzima lisossomal cuja deficiência resulta na doença de Gaucher. Apesar de a maioria dos estudos já publicados terem confirmado esta associação, um trabalho mais recente da Noruega não encontrou significância estatística ao analisar a presença destas mutações em pacientes com doença de Parkinson, tornando o assunto ainda controverso. Objetivo: Pesquisar a presença de mutações da glicocerebrosidase em pacientes com diagnóstico de doença de Parkinson no Brasil, acompanhados no ambulatório de Distúrbios do Movimento do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo e correlacionar tais achados com estudos recém-publicados que analisaram esta associação em outras populações em âmbito mundial, além de descrever possíveis características dos pacientes portadores de mutações que os diferenciem de não portadores. Métodos: Foram incluídos no estudo 65 pacientes com o diagnóstico de doença de Parkinson e idade de início da doença inferior ou igual a 55 anos e 267 controles sem a doença, emparelhados para sexo e idade. Foi realizada análise genética de material obtido a partir de raspagem da mucosa oral destes indivíduos, tendo sido pesquisadas as três mutações da glicocerebrosidase mais comuns na população brasileira: N370S, L444P e G377S. Resultados: Em dois dos 65 pacientes e em nenhum dos 267 controles foram identificadas mutações no gene da glicocerebrosidase. Os dois pacientes carreadores de mutações (L444P em um e L444P + E326K em outro) apresentavam quadro clínico indistinguível dos demais pacientes com doença de Parkinson não portadores das mutações. Conclusões: Foi observada uma associação estatisticamente significativa (P=0,0379, teste exato de Fisher) entre doença de Parkinson e mutações da glicocerebrosidase na nossa população. A prevalência de mutações da glicocerebrosidase neste grupo de pacientes foi maior do que a esperada para a população geral, porém menor do que a encontrada em estudos internacionais previamente publicados. Espera-se que a identificação desta nova associação permita uma maior compreensão dos mecanismos subjacentes à doença de Parkinson e que em um futuro próximo possa propiciar o desenvolvimento de novas estratégias terapêuticas. / Introduction: Parkinson\'s disease is a neurodegenerative disorder due to the loss of dopaminergic neurons in the substantia nigra, primarily, and in other brain regions. It is clinically characterized by tremor, rigidity, bradykinesia and postural instability. Treatment is symptomatic and consists essentially in replacing the deficient dopamine. The etiology of Parkinson\'s disease remains unknown, but recent advances in Neurology have provided data concerning the pathophysiological mechanisms involved. Mithocondrial dysfunction, oxidative stress and protein degradation are some of the cellular processes that have been linked to dopaminergic neurons degeneration. The field of genetics in Parkinson\'s disease has gained special attention in the past decade, thanks to the discovery of several genes associated with the development of the disease. A recently described genetic risk factor for Parkinson\'s disease is the presence of glucocerebrosidase gene mutations. Glucocerebrosidase is a lysosomal enzyme which is deficient in Gaucher disease. Although most studies published to date have confirmed such association, a recent article from Norway could not find statistical significance when Parkinson\'s disease patients were analyzed for glucocerebrosidase mutations, generating controversy. Objective: To search for glucocerebrosidase mutations in Parkinson\'s disease patients in Brazil, followed at the Movement Disorders Division at Hospital das Clínicas, University of São Paulo Medical School, and correlate these findings with recently published studies which evaluated this association in other populations worldwide, besides describing possible features of patients carrying the mutations that may help differentiating them from non-carriers. Methods: Sixty five patients diagnosed with Parkinson’s disease, with disease onset before age 55, and 267 age and sex-matched controls were included in the study. DNA analysis of the three most common glucocerebrosidase mutations in the Brazilian population, N370S, L444P and G377S, was performed utilizing samples obtained from mouth mucus. Results: Glucocerebrosidase gene mutations were identified in two of the 65 Parkinson\'s disease patients and in none of the 267 controls. The two patients who were carriers of mutations (one of them had L444P and the other L444P+E326K) had a clinical picture indistinguishable from the other Parkinson\'s disease non-carriers patients. Conclusion: A statistically significant association (P=0,0379, Fisher\'s exact test) between Parkinson\'s disease and glucocerebrosidase mutations was observed in our population. The prevalence of glucocerebrosidase mutations was higher than expected for the general population, though lower than reported in previous international studies. It is expected that the finding of this association will allow a better understanding of Parkinson\'s disease mechanisms and that in a near future it may help providing the development of new therapeutic strategies.

Objective: Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett's oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. Design: We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). Results: We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Conclusion: Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.

No description available.

As doenças autoimunes da tireoide (DAIT) representadas, principalmente pela doença de Graves (DG) e tireoidite de Hashimoto (TH), apresentam causas multifatoriais, incluindo fatores genéticos e ambientais. Diversos genes estão envolvidos, entre eles CTLA4, PTPN22 e mais recentemente IFIH1, principalmente quando associados a diabetes mellitus tipo 1 (DM1). OBJETIVOS: Determinar a frequência alélica e genotípica dos polimorfismos: -318C/T, A49G e CT60 do CTLA4, R620W do PTPN22 e A946T do IFIH1 em pacientes pediátricos portadores de DG, TH e DM1 associado a TH e em uma população controle normal, e determinar a associação com características clínicas e laboratoriais. MATERIAL E MÉTODOS: Foram estudados 142 pacientes menores de 21 anos ao diagnóstico. Os dados clínicos e laboratoriais foram obtidos em prontuário. A genotipagem foi realizada por PCR em tempo real de todos os polimorfismos. Dados clínicos e laboratoriais como sexo, idade de início, bócio, anticorpos anti-GAD, IA2 e IAA e níveis de TRAb e anti-TPO foram analisados. RESULTADOS: Sessenta e dois pacientes foram diagnosticados com DG, com idade média ao diagnóstico (IMD) de 10,8 ± 4,4 anos, sendo 43 do sexo feminino; TH esteve presente em 44 pacientes, sendo 37 meninas, com IMD de 10,3 (± 2,9 anos); e 36 pacientes com DM1 associado a TH, sendo 21 meninas, com IMD de 6,2 (± 4,0 anos) no momento do diagnóstico de DM1 e de 11,6 (± 4,6 anos) ao diagnóstico de TH. O grupo controle foi constituído por 81 indivíduos sem diabetes, função tireoidiana normal e ausência de anticorpos antitireoidianos. Todos os polimorfismos estavam em equilíbrio de Hardy-Weinberg. O polimorfismo -318C/T não esteve associado com nenhum dos grupos. O alelo de risco G do polimorfismo A49G foi mais frequente em pacientes com TH (p=0,047) e o genótipo patogênico (AG e GG) foi mais frequente em pacientes com DG (p=0,049). O alelo de risco G do polimorfismo CT60 foi mais frequente apenas em pacientes com DG (p=0,035). O alelo de risco T do polimorfismo R620W foi mais frequente em pacientes com DM1 associado a TH (p=0,043). O alelo de risco T do polimorfismo A946T foi mais frequente em pacientes com DM1 associado a TH (p=0,009), assim como o genótipo patogênico (CT e TT) quando comparado ao grupo controle (p=0,007). Quando agrupamos todas as DAIT, observamos associação com A49G (p=0,024) e R620W (p=0,047). Quando agrupamos apenas pacientes com TH, encontramos diferença no A49G (p=0,018) e no A946T (p=0,041). O polimorfismo CT60 foi associado com menor duração da terapia medicamentosa no grupo DG (p=0,004), mas não com os níveis de TRAb ou presença de bócio. No DM1 com HT, o alelo de risco do A49G foi mais frequentemente encontrado no sexo masculino (p=0,04); R620W foi relacionado com a presença de bócio (p=0,03), enquanto A946T foi associado com níveis de anti-TPO mais baixos (p=0,047). Os níveis de anti-GAD, IA2 e Resumo IAA não foram associados aos polimorfismos. CONCLUSÃO: Encontramos associações genéticas diferentes entre os pacientes com DAIT, sugerindo que as crianças possuem provavelmente padrões genéticos distintos, apesar do menor tempo de exposição a fatores ambientais / Autoimmune thyroid diseases (AITD) represented by Graves\' disease (GD) and Hashimoto\'s thyroiditis (HT), have multifactorial causes, including genetic and environmental factors. Several genes are involved, including CTLA4, PTPN22 and more recently IFIH1, especially when associated with type 1 diabetes (T1D). OBJECTIVES: To determine the allelic and genotypic frequencies of the polymorphisms: -318C/T, A49G and CT60 of CTLA4, R620W of PTPN22 and A946T of IFIH1 in pediatric patients with GD, HT and T1D associated with HT and in a control population and determine association with clinical and laboratory features. MATERIAL AND METHODS: We studied 142 patients under 21 years at diagnosis. Clinical and laboratory data were obtained from medical records. Genotyping was performed by real time PCR for all polymorphisms. Clinical and laboratory data were analyzed, such as gender, age of onset, goiter, anti-GAD, IA2 and IAA levels and TRAb and anti-TPO levels. RESULTS: Sixty-two patients were diagnosed with GD, with mean age at diagnosis (MAD) of 10.8 ± 4.4 years, 43 females; HT was present in 44 patients, 37 girls, MAD 10.3 (± 2.9 years) and type 1 diabetes associated with HT was present in 36 patients, 21 girls, MAD 6.2 (± 4.0 years) at diagnosis of T1D and 11.6 (± 4.6 years) at diagnosis of HT. Control group consisted of 81 subjects without diabetes, normal thyroid function and absence of antithyroid antibodies. All polymorphisms were in Hardy-Weinberg equilibrium. The polymorphism -318C/T was not associated with any of the groups. The risk allele G of A49G polymorphism was more frequent in patients with HT (p=0.047) and the pathogenic genotype (AG and GG) was more frequent in patients with GD (p=0.049). The risk allele G of CT60 polymorphism was more frequent only in patients with GD (p=0.035). The risk allele T of R620W polymorphism was more frequent in patients with T1D associated with HT (p=0.043). The risk allele T of A946T polymorphism was more frequent in patients with T1D associated with HT (p=0.009), as well as the pathogenic genotype (CT and TT) compared to control group (p=0.007). When all AITD is grouped, we observed association with A49G (p=0.024) and R620W (p=0.047). Only when patients with HT are grouped, we found differences in A49G (p=0.018) and A946T (p=0.041). CT60 polymorphism was associated with a shorter duration of drug therapy on GD group (p=0.004), but no association with TRAb levels or presence of goiter were found. In T1D with HT, the risk allele of A49G was more often found in males (p=0.04); R620W was associated with presence of goiter (p=0.03), while A946T was associated with anti-TPO levels (p=0.047). The anti-GAD, IAA and IA2 levels were not associated with any polymorphisms. CONCLUSION: We found different genetic associations among patients with AITD, suggesting that children are likely to have distinct genetic background, despite shorter exposure to environmental factors