Responsável: Astrid Vicente
Financiamento e data: Molecular genetics and functional genomics of Autism Spectrum Disorders - Fundação para a Ciência e Tecnologia, PTDC/SAU-GMG/64519/2006 (2007-2010). €199,940; Estudo de factores imunológicos e de neuroprotecção em pacientes com autismo - Comissão de Fomento da Investigação em Cuidados de Saúde (2007-2009). €5,000
Resumo: Autism is a chronic disorder that in most cases represents a permanent and complete disability, with patients requiring social, medical and economic support all their lives. Available treatment can improve specific behaviours in some patients, but does not represent a cure. The understanding of the etiology of this disease will thus be fundamental for the development of effective therapies and prevention for this disease.
Although genetic factors have been known to increase susceptibility to autism for quite some time, so far the identification of specific genes has been hindered by the complexity of the disease, for which multiple genes and environmental factors are thought to contribute. Given the probable heterogeneity of autism, we favour an approach directed at the characterization of disease-associated traits, which is expected to facilitate the identification of susceptibility loci and the definition of impaired biological pathways. It also provides an opportunity to identify biomarkers that may prove useful for early detection of autism and therefore impact on both drug development and early intervention. To contribute to a better understanding of autism, we have established a research program integrating the clinical and molecular genetics field. A population sample of autistic patients and close relatives, currently reaching over 300 families, has been collected with extensive clinical information, psychometric profiling and biochemical data. In this population we have been addressing a variety of questions, ranging from the prevalence of autism in Portugal to the role of hyperserotonemia, neuroinflammation, mitochondrial dysfunction and specific candidate genes in disease etiology. Some intriguing observations suggested new research perspectives and directions. Specifically, we identified in autistic patients a highly significant increase in plasma Brain-derived Neurotrophic Factor (BDNF), which was strongly correlated with abnormally high platelet serotonin (5-HT), suggesting an interaction of the serotonergic, glutamatergic and BDNF cellular pathways in autism etiology. Further, we identified main effects and interactions among serotonergic genes associated with risk for hyperserotonemia and autism, indicative of a common genetic architecture underlying the two traits. Because BDNF is an important neuroprotective molecule which is able to cross the Blood Brain Barrier (BBB), we also hypothesize that the increased BDNF levels may reflect an ongoing neuroinflammatory process in autism. The existence of mitochondrial disease in some autistic patients was also suggested by the finding of an unexpected high frequency of mitochondrial disorder markers, namely hyperlactacidemia and increased lactate/pyruvate ratio. What is known about the function and dysfunction of these systems in the Central Nervous System (CNS) clearly supports the possibility of an involvement in autism pathophysiology, and reinforces the need of further studies.
In the present project, we will seek to explain these observations in our population sample. Our strategy will be hypothesis driven, as we will extend, replicate and follow up on identified autism-associated traits and genetic variation. For this purpose, we plan to extend the current biobank and complete phenotypic assessment of patients and relatives, improving our power to detect genetic associations. We will explore the neuroinflammatory hypothesis by assessing specific inflammatory markers in patients and relatives. We will also quantify markers of mitochondrial dysfunction in additional patients. Selected candidate genes will be tested for association with autism and endophenotypes, and previous association findings will be followed-up by fine-mapping with dense marker genotyping, sequencing and variant identification procedures. The implementation of a gene-gene interaction discovery strategy is expected to increase power to detect genetic liabilities that may not be detected by testing independent gene effects on the phenotype. As specific gene variants are identified, the emphasis is shifting from purely genetic strategies to functional analysis of associated genetic variants in cell lines and animal models. We will therefore investigate the impact of genetic variants and gene interactions previously associated with increased risk for hyperserotonemia in serotonin function, using an appropriate neuronal cell line expressing the full serotonergic phenotype.
Institutional Partners: Instituto Gulbenkian de Ciência, Hospital Pediátrico de Coimbra