Duchenne muscular dystrophy: A cerebellar disorder?

Cyrulnik, Shana E.; Hinton, Veronica J.

doi:10.1016/j.neubiorev.2007.09.001

Cited by 91 publications

(97 citation statements)

References 120 publications

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“…Cerebellar dysfunction has been suggested to underlie deficits in reading and verbal working memory as well as playing an role in ASD which are important components of the DMD cognitive deficit 46,47 . Our results rather emphasize the amygdala, involved in emotion regulation, and the hippocampus, involved in memory, based on their high expression of DMD and the supporting evidence of memory and emotion deficits in DMD from animal and neuropsychological studies in humans 5,26,48,49 .…”

Section: Discussionmentioning

confidence: 99%

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Doorenweerd

Mahfouz

Putten

et al. 2017

Neuromuscular Disorders

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Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.Duchenne (DMD) and Becker (BMD) muscular dystrophies are X-linked genetic neuromuscular disorders characterized by severe and progressive muscle weakness. Mutations in the DMD gene result in absent/non-functional muscle dystrophin protein in DMD and shortened/partially functional protein in BMD.In addition to skeletal muscle pathology, DMD is characterized by cognitive and behavioural problems with 30% of boys with DMD showing cognitive impairment (IQ < 70) 1 and 40% having reading deficits similar to those observed in patients with phonological dyslexia 2-4 . Moreover, there is a higher incidence of attention-deficit/ hyperactivity disorder (ADHD) (32%), anxiety disorder (27%), autism spectrum disorders (ASD) (15%), epilepsy (6.3%), and obsessive-compulsive disorder (OCD) (4.8%) in patients with DMD [5][6][7] . The progressive nature of the

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Section: Discussionmentioning

confidence: 99%

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Doorenweerd

Mahfouz

Putten

et al. 2017

Neuromuscular Disorders

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“…Some studies have reported that DMD patients have difficulties in tests requiring attention and verbal repetition, as well as deficits in speech processing and reading, suggesting DMD may be a cerebellar disorder [75,76] . Approximately one third of DMD patients show cognitive impairment [77,78] , in which the mutations in the dystrophin gene seem to alter the efficiency of the brain-cerebellum path, as well as change the neuronal and brain architecture, leading to cognitive deficits in these patients [75][76][77] . Modeling DMD in vitro will help disclose the neurological mechanism of this disease and even allow to correct the dystrophin deficit in the muscle.…”

Section: Dmdmentioning

confidence: 99%

Induced pluripotent stem cells for modeling neurological disorders

Russo

Cugola

Fernandes

et al. 2015

WJT

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“…Defects in DPC function and assembly cause several forms of muscular dystrophy (3), a group of genetic diseases affecting skeletal, smooth, and cardiac muscles, and in some cases involving the central nervous system. Indeed, many patients with muscular dystrophy suffer from cognitive impairment, learning disability, and neuropsychiatric disorders (4); the brain dysfunction is thought to be a non-progressive disorder that occurs early, probably during embryogenesis, whereas the muscle disease arises later and is progressive (5,6).…”

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confidence: 99%

The Interaction with HMG20a/b Proteins Suggests a Potential Role for β-Dystrobrevin in Neuronal Differentiation

Artegiani

Labbaye

Sferra

et al. 2010

Journal of Biological Chemistry

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␣ and ␤ dystrobrevins are cytoplasmic components of the dystrophin-associated protein complex that are thought to play a role as scaffold proteins in signal transduction and intracellular transport. In the search of new insights into the functions of ␤-dystrobrevin, the isoform restricted to non-muscle tissues, we performed a two-hybrid screen of a mouse cDNA library to look for interacting proteins. Among the positive clones, one encodes iBRAF/HMG20a, a high mobility group (HMG)-domain protein that activates REST (RE-1 silencing transcription factor)-responsive genes, playing a key role in the initiation of neuronal differentiation. We characterized the ␤-dystrobrevin-iBRAF interaction by in vitro and in vivo association assays, localized the binding region of one protein to the other, and assessed the kinetics of the interaction as one of high affinity. We also found that ␤-dystrobrevin directly binds to BRAF35/HMG20b, a close homologue of iBRAF and a member of a co-repressor complex required for the repression of neural specific genes in neuronal progenitors. In vitro assays indicated that ␤-dystrobrevin binds to RE-1 and represses the promoter activity of synapsin I, a REST-responsive gene that is a marker for neuronal differentiation. Altogether, our data demonstrate a direct interaction of ␤-dystrobrevin with the HMG20 proteins iBRAF and BRAF35 and suggest that ␤-dystrobrevin may be involved in regulating chromatin dynamics, possibly playing a role in neuronal differentiation.

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Duchenne muscular dystrophy: A cerebellar disorder?

Cited by 91 publications

References 120 publications

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Timing and localization of human dystrophin isoform expression provide insights into the cognitive phenotype of Duchenne muscular dystrophy

Induced pluripotent stem cells for modeling neurological disorders

The Interaction with HMG20a/b Proteins Suggests a Potential Role for β-Dystrobrevin in Neuronal Differentiation

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