Esquizofrenia e síndrome da deleção 22q11.2: Caracterização de genes relevantes
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Data
2011-02-22
Autores
Ota, Vanessa Kiyomi Arashiro [UNIFESP]
Orientadores
Smith, Marilia de Arruda Cardoso [UNIFESP]
Tipo
Dissertação de mestrado
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Introdução: A esquizofrenia é o transtorno mental mais grave e incapacitante entre os distúrbios psiquiátricos. Ela é uma doença complexa e com fenótipo heterogêneo. Dentre os fatores genéticos que parecem ter um papel na etiologia da esquizofrenia está a deleção 22q11.2. Objetivos: Investigar alterações cromossômicas, polimorfismos dos genes UFD1L e ZDHHC8, mutações no gene TBX1 e variações no número de cópias na esquizofrenia e na síndrome da deleção 22q11.2, e correlacionar com achados de avaliações genético-clínicas, psiquiátricas, neuropsicológicas e de neuroimagem. Métodos: Um total de 200 portadores de esquizofrenia, 200 indivíduos controles e 10 portadores do fenótipo clínico da síndrome da deleção 22q11.2, mas sem a deleção, participaram do presente estudo. Os pacientes com esquizofrenia foram estudados por citogenética clássica e Multiplex Ligation-dependent probe amplification. Os polimorfismos rs5992403 (gene UFD1L) e rs175174 (gene ZDHHC8) foram investigados em pacientes com esquizofrenia e controles por meio de PCR em tempo real com sonda TaqMan. Outros polimorfismos do gene UFD1L foram analisados, rs5746744 e rs1547931, por Restriction Fragment Length Polymorphism. Mutações no gene TBX1 foram investigadas em portadores do fenótipo clínico da síndrome da deleção 22q11.2, mas sem a deleção, por meio de sequenciamento genômico. As variações no número de cópias foram analisadas por meio da metodologia de array em pools. Os pacientes com esquizofrenia também foram avaliados por testes neuropsicológicos e por neuroimagem estrutural. Resultados: Todos os cariótipos estudados foram normais. Foi encontrada um paciente com a deleção de 1,5 megabases na região 22q11.2. Os polimorfismos rs5992403 (UFD1L) e rs175174 (ZDHHC8) foram associados com a idade de acometimento da esquizofrenia. Além disso, todos os polimorfismos investigados parecem desempenhar um papel na morfologia cerebral e em habilidades cognitvas. Nenhuma mutação foi encontrada no gene TBX1, apenas polimorfismos, em portadores do fenótipo clínico da 22q11DS. Foram encontradas três regiões amplificadas em pools de DNAs de portadores de esquizofrenia: 1p36.32, 2q37.3 e 22q11.21. Conclusões: O estudo permitiu avaliar a participação de fatores genéticos em determinadas características da esquizofrenia, propiciando um melhor entendimento sobre a etiologia e fisiopatologia dessa doença complexa.
Background: Schizophrenia is a severe, persistent, debilitating and poorly understood psychiatric disorder. It is a complex disease with heterogeneous fenotype. Among the genetic factors that might have a role in schizophrenia, it is included 22q11.2 deletion. Objectives: We aimed to investigate chromosomal abnormalities, UFD1L and ZDHHC8 polymorphisms, TBX1 mutations and copy number variations in schizophrenia and 22q11.2 deletion syndrome and associate them with clinical genetics, psychiatric, neuropsychological and neuroimaging data. Methodology: A total of 200 schizophrenia patients, 200 healthy controls and 10 patients who have the 22q11.2 syndrome phenotype but no detectable deletion were selected. Schizophrenia patients were investigated through classical karyotyping by G-banding and Multiplex Ligationdependent probe amplification. UFD1L rs5992403 and ZDHHC8 rs175174 polymorphisms were genotyped in schizophrenia patients and healthy controls by Real Time PCR using TaqMan. UFD1L rs5746744 and rs1547931 polymorphisms were genotyped by Restriction Fragment Length Polymorphism. Tbx1 mutations were investigated in patients who have the 22q11.2 syndrome phenotype but no detectable deletion by sequencing. Affymetrix 6.0 microarrays in a pool of DNA samples was used to detect copy number variations. Schizophrenia patients were evaluated by neuropsychological tests and structural neuroimaging. Results: All karyotypes were normal. One patient presented a 1.5 megabases deletion in 22q11.2 region. UFD1L rs5992403 and ZDHHC8 rs175174 polymorphisms were associated with age at onset of schizophrenia. Moreover, all studied polymorphisms may have a role in brain morphology and cognition. No mutation, only polymorphisms, in TBX1 gene was found in 22q11.2 patients. Three regions were amplified in DNA pools of schizophrenia patients: 1p36.32, 2q37.3 e 22q11.21. Conclusion: This study evaluated the role of genetic factors in some schizophrenia fenotypes, providing a better understanding of its etiology and pathophysiology.
Background: Schizophrenia is a severe, persistent, debilitating and poorly understood psychiatric disorder. It is a complex disease with heterogeneous fenotype. Among the genetic factors that might have a role in schizophrenia, it is included 22q11.2 deletion. Objectives: We aimed to investigate chromosomal abnormalities, UFD1L and ZDHHC8 polymorphisms, TBX1 mutations and copy number variations in schizophrenia and 22q11.2 deletion syndrome and associate them with clinical genetics, psychiatric, neuropsychological and neuroimaging data. Methodology: A total of 200 schizophrenia patients, 200 healthy controls and 10 patients who have the 22q11.2 syndrome phenotype but no detectable deletion were selected. Schizophrenia patients were investigated through classical karyotyping by G-banding and Multiplex Ligationdependent probe amplification. UFD1L rs5992403 and ZDHHC8 rs175174 polymorphisms were genotyped in schizophrenia patients and healthy controls by Real Time PCR using TaqMan. UFD1L rs5746744 and rs1547931 polymorphisms were genotyped by Restriction Fragment Length Polymorphism. Tbx1 mutations were investigated in patients who have the 22q11.2 syndrome phenotype but no detectable deletion by sequencing. Affymetrix 6.0 microarrays in a pool of DNA samples was used to detect copy number variations. Schizophrenia patients were evaluated by neuropsychological tests and structural neuroimaging. Results: All karyotypes were normal. One patient presented a 1.5 megabases deletion in 22q11.2 region. UFD1L rs5992403 and ZDHHC8 rs175174 polymorphisms were associated with age at onset of schizophrenia. Moreover, all studied polymorphisms may have a role in brain morphology and cognition. No mutation, only polymorphisms, in TBX1 gene was found in 22q11.2 patients. Three regions were amplified in DNA pools of schizophrenia patients: 1p36.32, 2q37.3 e 22q11.21. Conclusion: This study evaluated the role of genetic factors in some schizophrenia fenotypes, providing a better understanding of its etiology and pathophysiology.
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Citação
OTA, Vanessa Kiyomi Arashiro. Esquizofrenia e síndrome da deleção 22q11.2: Caracterização de genes relevantes. 2011. 177 f. Dissertação (Mestrado) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2011.