Brain involvement in Duchenne muscular dystrophy: a role for dystrophin isoform Dp71 in cell migration and proliferation

Amanda Ash, Leah Booth-Wynne, Karen Anthony

Research output: Contribution to journalAbstractResearchpeer-review

Abstract

Intelligence of individuals with Duchenne muscular dystrophy (DMD) is lower than the general population. Cognitive impairment, epilepsy, autism and attention deficit hyperactivity disorder are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain; yet central nervous system involvement in DMD has been largely ignored. The most predominant dystrophin isoform in the brain is the smaller Dp71 isoform expressed in neurons and glia. Distal DMD mutations affecting Dp71 expression are linked to cognitive impairment. The function(s) of Dp71 and how its absence can lead to cognitive and behavioural symptoms are not well understood. We are modelling the loss of Dp71 both endogenously in DMD patient-derived fibroblasts (which, in controls, naturally express Dp71) and with siRNA in neuronal and glial cell lines. Four patient fibroblast cell lines, each harbouring a different DMD gene mutation that naturally results in the loss of Dp71 are being studied. Accompanying clinical data confirms these patients display cognitive and/or behavioural symptoms, which is severe for two individuals. Our preliminary findings highlight a role for Dp71 in cell migration and proliferation; alterations in these processes are associated with psychiatric disorders prevalent in DMD such as autism. We will present would healing and proliferation assay data exploring these role(s) and discuss potential molecular mechanisms behind the cognitive and behavioural symptoms observed in DMD. The high risk of neuropsychiatric syndromes in Duchene warrants early intervention to achieve the best possible quality of life; our findings have significant potential to inform ongoing drug development in this area.
Original languageEnglish
JournalNeuromuscular Disorders
Volume27
Issue numberSupp 2
Early online date2 Oct 2017
DOIs
Publication statusPublished - 2 Oct 2017

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Dystrophin
Duchenne Muscular Dystrophy
Cell Movement
Protein Isoforms
Cell Proliferation
Brain
Behavioral Symptoms
Neurobehavioral Manifestations
Autistic Disorder
Neuroglia
Distal Myopathies
Fibroblasts
Cell Line
Mutation
Attention Deficit Disorder with Hyperactivity
Intelligence
Small Interfering RNA
Psychiatry
Epilepsy
Central Nervous System

Keywords

  • Duchenne muscular dystrophy
  • neuromuscular disorders
  • dystrophin
  • Dp71
  • Duchenne

Cite this

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title = "Brain involvement in Duchenne muscular dystrophy: a role for dystrophin isoform Dp71 in cell migration and proliferation",
abstract = "Intelligence of individuals with Duchenne muscular dystrophy (DMD) is lower than the general population. Cognitive impairment, epilepsy, autism and attention deficit hyperactivity disorder are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain; yet central nervous system involvement in DMD has been largely ignored. The most predominant dystrophin isoform in the brain is the smaller Dp71 isoform expressed in neurons and glia. Distal DMD mutations affecting Dp71 expression are linked to cognitive impairment. The function(s) of Dp71 and how its absence can lead to cognitive and behavioural symptoms are not well understood. We are modelling the loss of Dp71 both endogenously in DMD patient-derived fibroblasts (which, in controls, naturally express Dp71) and with siRNA in neuronal and glial cell lines. Four patient fibroblast cell lines, each harbouring a different DMD gene mutation that naturally results in the loss of Dp71 are being studied. Accompanying clinical data confirms these patients display cognitive and/or behavioural symptoms, which is severe for two individuals. Our preliminary findings highlight a role for Dp71 in cell migration and proliferation; alterations in these processes are associated with psychiatric disorders prevalent in DMD such as autism. We will present would healing and proliferation assay data exploring these role(s) and discuss potential molecular mechanisms behind the cognitive and behavioural symptoms observed in DMD. The high risk of neuropsychiatric syndromes in Duchene warrants early intervention to achieve the best possible quality of life; our findings have significant potential to inform ongoing drug development in this area.",
keywords = "Duchenne muscular dystrophy, neuromuscular disorders, dystrophin, Dp71, Duchenne",
author = "Amanda Ash and Leah Booth-Wynne and Karen Anthony",
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language = "English",
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journal = "Neuromuscular Disorders",
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Brain involvement in Duchenne muscular dystrophy: a role for dystrophin isoform Dp71 in cell migration and proliferation. / Ash, Amanda; Booth-Wynne, Leah; Anthony, Karen.

In: Neuromuscular Disorders, Vol. 27, No. Supp 2, 02.10.2017.

Research output: Contribution to journalAbstractResearchpeer-review

TY - JOUR

T1 - Brain involvement in Duchenne muscular dystrophy: a role for dystrophin isoform Dp71 in cell migration and proliferation

AU - Ash, Amanda

AU - Booth-Wynne, Leah

AU - Anthony, Karen

PY - 2017/10/2

Y1 - 2017/10/2

N2 - Intelligence of individuals with Duchenne muscular dystrophy (DMD) is lower than the general population. Cognitive impairment, epilepsy, autism and attention deficit hyperactivity disorder are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain; yet central nervous system involvement in DMD has been largely ignored. The most predominant dystrophin isoform in the brain is the smaller Dp71 isoform expressed in neurons and glia. Distal DMD mutations affecting Dp71 expression are linked to cognitive impairment. The function(s) of Dp71 and how its absence can lead to cognitive and behavioural symptoms are not well understood. We are modelling the loss of Dp71 both endogenously in DMD patient-derived fibroblasts (which, in controls, naturally express Dp71) and with siRNA in neuronal and glial cell lines. Four patient fibroblast cell lines, each harbouring a different DMD gene mutation that naturally results in the loss of Dp71 are being studied. Accompanying clinical data confirms these patients display cognitive and/or behavioural symptoms, which is severe for two individuals. Our preliminary findings highlight a role for Dp71 in cell migration and proliferation; alterations in these processes are associated with psychiatric disorders prevalent in DMD such as autism. We will present would healing and proliferation assay data exploring these role(s) and discuss potential molecular mechanisms behind the cognitive and behavioural symptoms observed in DMD. The high risk of neuropsychiatric syndromes in Duchene warrants early intervention to achieve the best possible quality of life; our findings have significant potential to inform ongoing drug development in this area.

AB - Intelligence of individuals with Duchenne muscular dystrophy (DMD) is lower than the general population. Cognitive impairment, epilepsy, autism and attention deficit hyperactivity disorder are prevalent. Mounting evidence links these symptoms to the loss of dystrophin in the brain; yet central nervous system involvement in DMD has been largely ignored. The most predominant dystrophin isoform in the brain is the smaller Dp71 isoform expressed in neurons and glia. Distal DMD mutations affecting Dp71 expression are linked to cognitive impairment. The function(s) of Dp71 and how its absence can lead to cognitive and behavioural symptoms are not well understood. We are modelling the loss of Dp71 both endogenously in DMD patient-derived fibroblasts (which, in controls, naturally express Dp71) and with siRNA in neuronal and glial cell lines. Four patient fibroblast cell lines, each harbouring a different DMD gene mutation that naturally results in the loss of Dp71 are being studied. Accompanying clinical data confirms these patients display cognitive and/or behavioural symptoms, which is severe for two individuals. Our preliminary findings highlight a role for Dp71 in cell migration and proliferation; alterations in these processes are associated with psychiatric disorders prevalent in DMD such as autism. We will present would healing and proliferation assay data exploring these role(s) and discuss potential molecular mechanisms behind the cognitive and behavioural symptoms observed in DMD. The high risk of neuropsychiatric syndromes in Duchene warrants early intervention to achieve the best possible quality of life; our findings have significant potential to inform ongoing drug development in this area.

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KW - neuromuscular disorders

KW - dystrophin

KW - Dp71

KW - Duchenne

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JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

IS - Supp 2

ER -