P.57 - Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) has a high incidence of learning and behavioural problems and comorbidity with neurodevelopmental disorders such as autism-spectrum disorders, attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and dyslexia. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across healthy human brain development, using transcriptomic data from Allen Human Brain and BrainSpan atlases. Specific results were verified using transcription start sites usage data from the FANTOM5 project, epigenomic marks from the Roadmap Epigenomic Consortium, and ex vivo qPCR experiments. We show a clear distinction between isoforms based on the expression levels through life from fetal to adult human brain with higher expression levels in the hippocampus and amygdala compared to cerebellum. The Dp140 isoform was expressed in the cerebral cortex only in fetal life stages, while in the cerebellum it was also expressed post-natally. Moreover, the Purkinje isoform Dp427p was virtually absent throughout development in humans, which we experimentally validated. Using spatio-temporal co-expression analysis, we found a strong association between dystrophin isoforms and genes implicated in neurodevelopmental disorders associated to the DMD phenotype such as autism or ADHD. Additionally, we identified relevant functional associations of the different isoforms. For example, genes strongly co-expressed with the Dp140 isoform were associated with axon guidance and neuron differentiation during early development. This work shows that dystrophin isoforms play an important role in the development and function of the human brain. Studying the functional relationship between dystrophin isoforms and their related genes may further elucidate the pathophysiology of the cognitive phenotype of DMD.