Neurodevelopmental spectrum alterations are major yet unaddressed components of Duchenne and Becker muscular dystrophies (DMD/BMD). Patients frequently present anxiety, depression, attention-deficit or autism spectrum disorder (ASD), and deficits in executive and learning abilities; BMD shows milder but overlapping profiles. Robust genotype–phenotype correlations indicate that the severity of brain involvement increases with the number of dystrophin isoforms lost. We hypothesize that postnatal correction of dystrophin deficiency can mitigate cognitive and behavioral deficits in DMD and BMD conditions.
The two brain-expressed isoforms, Dp427 and Dp140, play complementary roles in neural circuit function. Dp427, expressed in subsets of oligodendrocytes and in hippocampal, cerebellar, prefrontal, amygdalar, and pontine neurons, anchors GABA-A receptors at inhibitory synapses; its loss impairs inhibitory control and heightens stress sensitivity and anxiety. Dp140, present in associative and limbic regions and co-expressed with ASD- and intellectual disability-related genes, contributes to glutamatergic neurotransmission, although its molecular partners remain incompletely defined. Combined loss of Dp427 and Dp140 are associated with more severe neurocognitive impairment, but mechanistic studies have been scarce.
To address this gap, we established a unified platform of three genome-edited rat lines deleted in distinct, clinically relevant combinations of Dp427 and Dp140. All lines were generated on the same outbred Sprague Dawley background, providing patient-like variability while ensuring isogenic comparability. We will present functional assays, PET imaging readouts, gut microbiota profiles and blood-based biochemical biomarkers that altogether define a unique disease trajectory signature for each line. Isoform distribution was mapped at cellular resolution across key brain regions and validated through molecular and histological approaches. Comparative analyses, including snRNA-seq of the hippocampus, identified vulnerable populations of neural cells, dysregulated pathways and intermediate molecular actors linking dystrophin isoforms to brain functions.
Through an integrative, multisystemic analysis in a translationally relevant model, this robust genetic platform identifies isoform-specific mechanisms and informs precision therapy development for neurodevelopmental spectrum alterations.