Patients lacking Dp140 and/or Dp71 have a particularly high incidence of neurodevelopmental disorders. Patients with distal DMD mutations affecting the expression of all DMD gene products have lower FSIQ scores than those with mutations that result in only the absence of full-length dystrophin. Full-scale intelligent quotients (FSIQ) are consistently reported at one standard deviation below the normal population mean and levels of intellectual disability within Duchenne cohorts vary between approximately 19 and 35% (Table (Table1, 1, ). Whilst most individuals with DMD are not intellectually disabled, the risk of cognitive impairment is higher than for the general population. We then 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.Įmotional, Behavioural and Neurodevelopmental Observations We first describe the ‘DMD neuropsychiatric syndrome’ coined by Ricotti and the abnormalities observed in the DMD brain. Here, we provide a detailed update on Dp71 and review the accumulating evidence linking its loss to the neuropathophysiology of Duchenne. (Fig.1) 1) and our understanding of the function(s) of Dp71 has increased. In light of this and the fact that 100% of individuals with mutations affecting Dp71 have intellectual disability, we limit the focus of this review to Dp71.Īs many as 14 isoforms of Dp71 have now been described (Fig. In contrast, our knowledge of Dp71 has expanded rapidly, there are mouse models devoid of Dp71 and the literature has become complex. There is limited information on Dp140, likely due to its restricted expression pattern. Thus, it is not entirely clear which, if any, single DMD gene product is responsible for the CNS phenotype. The risk and severity of cognitive disability are associated with a cumulative loss of distal DMD gene products. Dp140 and Dp71 are both heavily implicated. Distal DMD mutations affecting the expression of these shorter variants are linked to cognitive impairment. The most predominant in the brain is the Dp71 variant expressed in neurones and glia, except during foetal development where Dp140, also expressed throughout the CNS, dominates. Dystrophin protein variants (Dp) are named based on their length in kilodaltons and are produced through unique promoter usage, alternative splicing and/or alternative polyadenylation signals. Unlike skeletal muscle, the central nervous system (CNS) sees the expression of a large variety of DMD transcripts implicated in diverse cellular processes. Mounting evidence links these symptoms to the loss of dystrophin in the brain. Although characterised by the progressive loss of muscle strength and function, cognitive impairment and neuropsychiatric symptoms are also prevalent. It is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. The X-linked neuromuscular disorder, Duchenne muscular dystrophy (DMD), is one of the most common fatal genetic disorders diagnosed in childhood. 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. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. 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. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. We then review the gene expression, RNA processing and functions of Dp71. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. However, unlike in skeletal muscle in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. 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. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Duchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin.
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