Causative molecular mechanisms of Autism Spectrum Disorder in patients with dystrophinopathy

Abstract

Dystrophinopathies are neuromuscular diseases caused by pathogenic variants in DMD gene, and comprised, mostly, by Duchenne Muscular Dystrophy (DMD) and Becker Muscular Dystrophy (BMD). Three independent, tissue-specific promoters, located at the 5' end of DMD gene, are responsible for the production of the long dystrophin isoforms (Dp427m, Dp427p and Dp427c), while four internal promoters regulate the short isoforms (Dp260, Dp140, Dp116, Dp71, and Dp40). In addition to muscle impairment, patients with DMD/BMD have a high prevalence of neurodevelopmental disorders and other psychiatric conditions, such as intellectual disability (ID) (12-30%) and Autism Spectrum Disorder (ASD) (10-20%). Although alterations in the short isoforms of dystrophin (Dp140 and Dp71) explain, in part, the increased risk for ID, the molecular mechanisms associated with the manifestation of ASD, in a proportion of patients with dystrophinopathy, are still unknown. Recently, genotype-phenotype correlation analyzes of patients with DMD/BMD have suggested a possible association between the long isoform (Dp427) loss-of-function, and the neurodevelopmental alterations observed in these patients. On the other hand, several studies have demonstrated the relevance of rare variants in the genetic background of affected individuals, for the manifestation and clinical variability of neuropsychiatric diseases, compatible with a polygenic or oligogenic inheritance model. From this perspective, it is possible that, in addition to the main pathogenic variant in DMD gene, other genetic factors are contributing to the development of ASD in these individuals. Thus, the main objective of this study is to investigate whether in DMD/DMB patients with dystrophin Dp427 deficiency, other molecular factors in the genome are contributing to the manifestation of autism. Therefore, we will use patient-specific neural progenitor cells (NPCs), derived from induced pluripotent stem cells (iPSCs), as an in vitro model. The characterization of gene and protein expression levels of dystrophin, in NPCs, will be performed, as well as their transcriptional profile. Thus, through functional studies, we intend to contribute to a wider understanding of the molecular mechanisms and the relevance of other risk variants of the genome in the etiology of ASD, in patients diagnosed with dystrophinopathy.