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

Abstract

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. 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 human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked genetic neuromuscular disorders characterized by severe and progressive muscle weakness. Mutations in the DMD gene result in absent/non-functional muscle dystrophin protein in DMD and shortened/partially functional protein in BMD.In addition to skeletal muscle pathology, DMD is characterized by cognitive and behavioural problems with 30% of boys with DMD showing cognitive impairment (IQ < 70) 1 and 40% having reading deficits similar to those observed in patients with phonological dyslexia 2-4 . Moreover, there is a higher incidence of attention-deficit/ hyperactivity disorder (ADHD) (32%), anxiety disorder (27%), autism spectrum disorders (ASD) (15%), epilepsy (6.3%), and obsessive-compulsive disorder (OCD) (4.8%) in patients with DMD [5][6][7] . The progressive nature of the

Genetic modifiers of respiratory function in Duchenne muscular dystrophy

“…The restrictive ventilatory defect in DMD is caused by the absence of full‐length dystrophin in the diaphragm and other respiratory muscles. While defects of short dystrophin isoforms have been associated with increased risk of intellectual disability and other central nervous system (CNS) manifestations of DMD, 28–30 they have not been clearly linked to more severe muscle weakness. A possible explanation is that while patients with very severe cognitive deficiencies are excluded from PFTs, because of insufficient cooperation, patients with subtler CNS issues due to Dp140/Dp71 defects still perform worse in PFTs, which are largely influenced by volition and effort.…”

Myogenesis modelled by human pluripotent stem cells uncovers Duchenne muscular dystrophy phenotypes prior to skeletal muscle commitment

“…It has been shown that the expression of Dp260 in mdx /utrnK/K mice can rescue the mdx phenotype (146), indicating overlapping functions between Dp427m and Dp260. On the other hand, it is now well established that a third of DMD patients display cognitive deficiencies – which might be correlated with mutations affecting Dp140 (147) – attesting that dystrophin can be involved in other cell functions.…”

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

“…Duchenne's muscular dystrophy), is important to consider as well as it is the top scoring upstream regulator pathway in Purkinje cells, and is also significant in granule cells. Dystrophin is an extremely large protein expressed from multiple promoters 208,209 and its loss in muscle causes Duchenne muscular dystrophy.…”