Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy

Michael Naidoo, Karen Anthony

Research output: Contribution to JournalArticle

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.
Original languageEnglish
Pages (from-to)1-20
Number of pages21
JournalMolecular Neurobiology
Early online date13 Dec 2019
DOIs
Publication statusE-pub ahead of print - 13 Dec 2019

Fingerprint

Dystrophin
Duchenne Muscular Dystrophy
Brain
Muscle
Genes
Dystrophin-Associated Protein Complex
Distal Myopathies
apo-dystrophin 1
Cell adhesion
Frameshift Mutation
Muscle Proteins
Gene expression
Genetic Association Studies
Protein Biosynthesis
DNA Repair
Cell Division
Synapses
Protein Isoforms
Repair
Skeletal Muscle

Keywords

  • Apo-dystrophin-1
  • Dp71
  • Duchenne muscular dystrophy
  • Dystrophin
  • Neurodevelopment

Cite this

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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.",
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Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy. / Naidoo, Michael; Anthony, Karen.

In: Molecular Neurobiology, 13.12.2019, p. 1-20.

Research output: Contribution to JournalArticle

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