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Investigation of epigenetic mechanisms in the etiology of Autism Spectrum Disorder in dystrophinopathies

Grant number: 23/01887-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2023
Effective date (End): May 31, 2027
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Maria Rita dos Santos e Passos Bueno
Grantee:Gabriele da Silva Campos
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID


Dystrophinopathies are X-linked genetic diseases, caused by pathogenic variants in the DMD gene, the most common form being Duchenne muscular dystrophy. Although the muscle signs of these diseases are widely investigated, at least 30% of individuals have neurodevelopmental disorders, such as ID and ASD, the latter presenting a frequency 20 times greater compared to the general population. In previous works, our group proposed that DMD deficiency contributes to the etiology of ASD. However, this mechanism, along with additional genetic variants that compose the individual's genetic background, seems insufficient to explain all cases. Since ASD is a multifactorial disorder that results from the interaction of genetic and environmental factors, a major challenge is to identify these factors, as well as to investigate the mechanisms through which they interact. In recent years, epigenetic marks have been identified as an gene-environment interaction interface; epigenetic marks such as DNA methylation can be modified in response to environmental conditions and are strongly influenced by the individual's genetic background. Therefore, this project aims to investigate the contribution of epigenetic factors to the etiology of ASD in individuals with dystrophinopathies, in addition to investigating whether these epigenetic changes result from a background of susceptibility to environmental insults. To this end, DNA methylation profile in peripheral tissue samples from individuals with dystrophinopathies (n=100, 50 with ASD and 50 neurotypical) and healthy controls (n=50) will be analyzed. Considering that inter-individual genetic differences lead to variation in response to environmental conditions, the response pattern of neural cells derived from iPSCs from individuals of the three groups (n=3 in each group) in the presence of a stressful environmental insult will also be investigated. The results of peripheral tissue and neural cells analysis will be compared, and compared with the current literature. This study can contribute to the elucidation of mechanisms of gene-environment interaction in neurodevelopment, as well as to the identification of predictive risk markers for the development of ASD. (AU)

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