Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.

Single-transcript multiplex in situ hybridisation reveals unique patterns of dystrophin isoform expression in the developing mammalian embryo

“…Expression of dp71 is found within epithelial and endothelial cell populations, and within cell-dense regions such as the growth tips and the interzonal mesenchyme of the developing limbs, or the germinal layers of the mesencephalic roof and cerebellar primordium. Shared features here are proliferation and mobility: cells in the process of migrating or multiplying to line tissue surfaces, or to expand developing tissue territories (others have suggested similar roles for this isoform 79 , 80 ). Finally, dp140 is highly expressed in the brain as expected (enriched in the diencephalon and within the germinal layer of the cerebellar primoridium, but also present within the developing telencephalon), and is found at specific locations in the kidney.…”

“…Mitosis is also heavily-dependent upon orchestrated microtubule activity 92 : a process potentially complicated by the presence of abundant membrane-localized microtubule recruiting domains found in dp427, dp260 and dp140 but not dp71. Dp71 is however thought to interact with microtubules via DAGC binding partners, and a role for this short isoform in mitosis itself has been proposed 93 , suggesting the situation may be more nuanced (particularly given the number of reported dp71 splice variants 80 ). We further note that dp427 is transiently expressed in activated muscle satellite cells, apparently playing a role in asymmetric cell division 94 .…”

First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

“…They consist in combinations of single or multiple exon skipping involving exons 71 to 74 and exon 78, with the isoforms lacking exon 71 and/or exon 78 being by far the most represented [ 12 , 13 , 16 , 41 , 42 , 43 ]. In Dp71, the splice isoforms determine the differential subcellular localization and various cellular functions of the short dystrophin isoform in the brain [ 44 , 45 ]. Transcripts spliced out for exon 78 produce a protein with an elongated C-term region by replacing the last 13 amino acids in the protein with an evolutionary conserved sequence of 31 new residues encoding the ancestral alternative amphipathic C-terminal α-helix.…”

Computational cognitive modeling and validation of Dp140 induced alteration of working memory in Duchenne Muscular Dystrophy

“…Full length dystrophin (Dp427; based on their length in kiloDaltons) is expressed in the tissue specific manner from three proximal promoters in the muscle, brain and purkinje cells whereas short dystrophin isoforms (Dp260, Dp140, Dp116 Dp71 and Dp40) are expressed in various organs from distant upstream promoters 8 . Dp140, Dp71 and an alternatively spliced short isoform Dp40 are reported to be expressed in the various brain regions including cerebral cortex, cerebellum, hippocampal dentate gyrus 9 – 11 . Human DMD brain studies have also reported deficiency of dystrophin in the post synaptic densities (PSD) of brain 9 .…”