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

Doorenweerd, N.; Mahfouz, Ahmed; Putten, Maaike van; Kaliyaperumal, Rajaram; Hoen, Peter A.C. ‘t; Hendriksen, Jos G.M.; Aartsma‐Rus, Annemieke; Verschuuren, Jan J.; Niks, Erik H.; Reinders, Marcel J. T.; Kan, Hermien E.; Lelieveldt, Boudewijn P. F.

doi:10.1038/s41598-017-12981-5

Cited by 138 publications

(148 citation statements)

References 71 publications

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“…Our findings form a valuable basis for further investigations to evaluate whether changes in the amount or activity of the identified RBPs contribute to splicing of the DMD gene in different cells, tissues or developmental stages. This is of particular interest regarding the cerebral dystrophin isoforms, which play a crucial role in the development and function of the human brain and are coexpressed with genes implicated in neurodevelopmental disorders [ 53 ]. DMD affects the central nervous system in about one-third of cases, mostly due to distal mutations affecting the expression of the shorter cerebral isoforms (Dp140, Dp71) [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

Miro

Bougé

Murauer

et al. 2020

IJMS

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The Duchenne muscular dystrophy (DMD) gene has a complex expression pattern regulated by multiple tissue-specific promoters and by alternative splicing (AS) of the resulting transcripts. Here, we used an RNAi-based approach coupled with DMD-targeted RNA-seq to identify RNA-binding proteins (RBPs) that regulate splicing of its skeletal muscle isoform (Dp427m) in a human muscular cell line. A total of 16 RBPs comprising the major regulators of muscle-specific splicing events were tested. We show that distinct combinations of RBPs maintain the correct inclusion in the Dp427m of exons that undergo spatio-temporal AS in other dystrophin isoforms. In particular, our findings revealed the complex networks of RBPs contributing to the splicing of the two short DMD exons 71 and 78, the inclusion of exon 78 in the adult Dp427m isoform being crucial for muscle function. Among the RBPs tested, QKI and DDX5/DDX17 proteins are important determinants of DMD exon inclusion. This is the first large-scale study to determine which RBP proteins act on the physiological splicing of the DMD gene. Our data shed light on molecular mechanisms contributing to the expression of the different dystrophin isoforms, which could be influenced by a change in the function or expression level of the identified RBPs.

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Section: Discussionmentioning

confidence: 99%

First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

Miro

Bougé

Murauer

et al. 2020

IJMS

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“…For years, the main brain regions with dystrophin expression were considered to be the cortex, hippocampus, amygdala and cerebellum. Recently, the Allen Brain Atlas adult human brain and developing brain datasets were mined for DMD gene expression and DMD exon expression [13] . In the adult dataset, the six donor brains (five male, one female, aged 24-57, mean age 42 years) were segmented into 363 to 946 brain regions (3702 samples in total) [14] .…”

Section: Dystrophin Expression In the Human Brainmentioning

confidence: 99%

Combining genetics, neuropsychology and neuroimaging to improve understanding of brain involvement in Duchenne muscular dystrophy - a narrative review

Doorenweerd

2020

Neuromuscular Disorders

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Duchenne muscular dystrophy is a multifactorial disease including a cognitive phenotype. It is caused by mutations in the X-chromosomal DMD gene from which dystrophin is synthesized. Multiple isoforms of dystrophin have been identified. The full length dystrophin isoform Dp427 m is expressed predominantly in muscle. Other isoforms include: Dp427 c , Dp427 p , Dp260, Dp140, Dp116, Dp71 and Dp40. The majority of these isoforms are expressed in brain and several hypotheses exist on their role in subtypes of neurons and astrocytes. However, their function in relation to cognition remains unclear. Unlike progressive muscle wasting, cognitive involvement is not seen in all DMD patients and the severity varies greatly. To achieve a better understanding of brain involvement in DMD, a multidisciplinary approach is required. Here, we review the latest findings on dystrophin isoform expression in the brain; specific DMD-associated learning and behavioural difficulties; and imaging and spectroscopy findings relating to brain structure, networks, perfusion and metabolism. The main challenge lies in determining links between these different findings. If we can determine which factors play a role in the differentiation between severe and minor cognitive problems in DMD in the near future, we can both provide better advise for the patients and also develop targeted therapeutic interventions.

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“…Dp260 is highly present in the retina, and its lack is associated with electroretinogram anomalies [ 42 , 43 , 44 ]. Dp140 is expressed in the brain, retina, and kidneys where it appears to be involved in brain development and blood flow regulation [ 45 , 46 , 47 ]. Dp116 is produced in Schwann cells, however, its role in this context is poorly understood [ 48 ].…”

Section: Dystrophin—from Gene To Proteinmentioning

confidence: 99%

Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine

D’Amario

Gowran

Canonico

et al. 2018

JCM

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Duchenne’s muscular dystrophy is an X-linked neuromuscular disease that manifests as muscle atrophy and cardiomyopathy in young boys. However, a considerable percentage of carrier females are often diagnosed with cardiomyopathy at an advanced stage. Existing therapy is not disease-specific and has limited effect, thus many patients and symptomatic carrier females prematurely die due to heart failure. Early detection is one of the major challenges that muscular dystrophy patients, carrier females, family members and, research and medical teams face in the complex course of dystrophic cardiomyopathy management. Despite the widespread adoption of advanced imaging modalities such as cardiac magnetic resonance, there is much scope for refining the diagnosis and treatment of dystrophic cardiomyopathy. This comprehensive review will focus on the pertinent clinical aspects of cardiac disease in muscular dystrophy while also providing a detailed consideration of the known and developing concepts in the pathophysiology of muscular dystrophy and forthcoming therapeutic options.

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

Cited by 138 publications

References 71 publications

First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

First Identification of RNA-Binding Proteins That Regulate Alternative Exons in the Dystrophin Gene

Combining genetics, neuropsychology and neuroimaging to improve understanding of brain involvement in Duchenne muscular dystrophy - a narrative review

Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine

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