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.
Highlights
The X-linked neuromuscular disorder, Duchenne muscular dystrophy (DMD), is one of the most common fatal genetic disorders diagnosed in childhood
There is a reported increase in epilepsy in patients with Duchenne compared with the general population (Table 1) and other brain-related comorbidities such as attention deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD) are more prevalent in patients who have both DMD and epilepsy compared with non-epilepsy Duchenne patients [17]
During nerve growth factor (NGF)-induced PC12 cell differentiation, Dp71f Δ71 relocates from the cytoplasm to neuritic processes such as the growth cone and Dp71dΔ71 appears to relocate almost entirely to the nucleus where it binds the nuclear matrix during the late stages of neuronal differentiation in PC12 cells (Fig. 5) [127, 155], are Dystrophin protein 71 (Dp71) levels upregulated but there is a differential subcellular localisation of Dp71 isoforms during neuronal differentiation
Summary
The X-linked neuromuscular disorder, Duchenne muscular dystrophy (DMD), is one of the most common fatal genetic disorders diagnosed in childhood It is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Characterised by the progressive loss of muscle strength and function [1], cognitive impairment and neuropsychiatric symptoms are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain. Distal DMD mutations affecting the expression of these shorter variants are linked to cognitive impairment [5,6,7,8,9,10,11]. We review the gene expression and RNA processing of Dp71 and its function(s) and discuss how the absence and/or alteration of Dp71 likely contributes to the neuropathophysiology of DMD
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