Duchenne Muscular Dystrophy from Brain to Muscle: The Role of Brain Dystrophin Isoforms in Motor Functions

Wijekoon, Nalaka; Gonawala, Lakmal; Ratnayake, Pyara; Amaratunga, Dhammika; Hathout, Yetrib; Mohan, Chandra; Steinbusch, Harry W. M.; Dalal, Ashwin; Hoffman, Eric P.; de Silva, K. Ranil D.

doi:10.3390/jcm12175637

Cited by 6 publications

(3 citation statements)

References 55 publications

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“…This evaluation prompted their enrollment in the molecular diagnostic program, which provides genetic confirmation at no cost. The authors have previously addressed the relationship between age, mutation pattern and CPK levels in this patient cohort in a comprehensive manner, as documented in Wijekoon et al, 2023 [ 105 ]. Therefore, further discussion on this topic will not be included in the present paper.…”

Section: Discussionmentioning

confidence: 99%

Title-molecular diagnostics of dystrophinopathies in Sri Lanka towards phenotype predictions: an insight from a South Asian resource limited setting

Wijekoon,

Gonawala,

Ratnayake

et al. 2024

Eur J Med Res

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Background The phenotype of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) patients is determined by the type of DMD gene variation, its location, effect on reading frame, and its size. The primary objective of this investigation was to determine the frequency and distribution of DMD gene variants (deletions/duplications) in Sri Lanka through the utilization of a combined approach involving multiplex polymerase chain reaction (mPCR) followed by Multiplex Ligation Dependent Probe Amplification (MLPA) and compare to the international literature. The current consensus is that MLPA is a labor efficient yet expensive technique for identifying deletions and duplications in the DMD gene. Methodology Genetic analysis was performed in a cohort of 236 clinically suspected pediatric and adult myopathy patients in Sri Lanka, using mPCR and MLPA. A comparative analysis was conducted between our findings and literature data. Results In the entire patient cohort (n = 236), mPCR solely was able to identify deletions in the DMD gene in 131/236 patients (DMD-120, BMD-11). In the same cohort, MLPA confirmed deletions in 149/236 patients [DMD-138, BMD -11]. These findings suggest that mPCR has a detection rate of 95% (131/138) among all patients who received a diagnosis. The distal and proximal deletion hotspots for DMD were exons 45–55 and 6–15. Exon 45–60 identified as a novel in-frame variation hotspot. Exon 45–59 was a hotspot for BMD deletions. Comparisons with the international literature show significant variations observed in deletion and duplication frequencies in DMD gene across different populations. Conclusion DMD gene deletions and duplications are concentrated in exons 45–55 and 2–20 respectively, which match global variation hotspots. Disparities in deletion and duplication frequencies were observed when comparing our data to other Asian and Western populations. Identified a 95% deletion detection rate for mPCR, making it a viable initial molecular diagnostic approach for low-resource countries where MLPA could be used to evaluate negative mPCR cases and cases with ambiguous mutation borders. Our findings may have important implications in the early identification of DMD with limited resources in Sri Lanka and to develop tailored molecular diagnostic algorithms that are regional and population specific and easily implemented in resource limited settings.

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Section: Discussionmentioning

confidence: 99%

Title-molecular diagnostics of dystrophinopathies in Sri Lanka towards phenotype predictions: an insight from a South Asian resource limited setting

Wijekoon,

Gonawala,

Ratnayake

et al. 2024

Eur J Med Res

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“…This reduces the diagnostic usefulness of GFAP as a specific biomarker of muscular dystrophy-related changes in the central nervous system but does not limit its general suitability as an astrogliosis marker protein. Proteomics suggests nevertheless that neuronal disturbances and reactive astrogliosis might play a central role in the molecular pathogenesis of brain abnormalities in dystrophinopathy [ 371 ] that may lead to mental retardation, behavioral problems, cognitive impairments, emotional disturbances, attention deficit, impaired language, memory deficiencies and altered coordination in DMD [ 377 , 378 , 379 ].…”

Section: The Pathoproteomic Profiling Of Duchenne Muscular Dystrophymentioning

confidence: 99%

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

Dowling,

Trollet,

Negroni

et al. 2024

Proteomes

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This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.

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“…A fraction of Dp71 is expressed in neuronal synapses [5], but the majority is detected in perivascular astrocytes throughout the forebrain, as well as in radial glial cells in the retina (Müller glial cells) and cerebellum (Bergmann glial cells) [6][7][8]. Converging evidence of the medical importance of DMD underscores the critical involvement of Dp71 at the glial-vascular interface in composing the blood-brain and blood-retinal barriers (BBBs and BRBs) [9][10][11], suggesting that glial dysfunction is a core mechanism underlying cognitive dysfunction in the most severely affected DMD patients. As other dystrophins, Dp71 is a critical component of a multiprotein transmembraneous complex that bridges proteins of the extracellular matrix to cytoskeleton's actin and signaling proteins.…”

Section: Introductionmentioning

confidence: 99%

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

Vacca,

Zarrouki,

Izabelle

et al. 2024

Cells

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A deficiency in the shortest dystrophin-gene product, Dp71, is a pivotal aggravating factor for intellectual disabilities in Duchenne muscular dystrophy (DMD). Recent advances in preclinical research have achieved some success in compensating both muscle and brain dysfunctions associated with DMD, notably using exon skipping strategies. However, this has not been studied for distal mutations in the DMD gene leading to Dp71 loss. In this study, we aimed to restore brain Dp71 expression in the Dp71-null transgenic mouse using an adeno-associated virus (AAV) administrated either by intracardiac injections at P4 (ICP4) or by bilateral intracerebroventricular (ICV) injections in adults. ICP4 delivery of the AAV9-Dp71 vector enabled the expression of 2 to 14% of brain Dp71, while ICV delivery enabled the overexpression of Dp71 in the hippocampus and cortex of adult mice, with anecdotal expression in the cerebellum. The restoration of Dp71 was mostly located in the glial endfeet that surround capillaries, and it was associated with partial localization of Dp71-associated proteins, α1-syntrophin and AQP4 water channels, suggesting proper restoration of a scaffold of proteins involved in blood–brain barrier function and water homeostasis. However, this did not result in significant improvements in behavioral disturbances displayed by Dp71-null mice. The potential and limitations of this AAV-mediated strategy are discussed. This proof-of-concept study identifies key molecular markers to estimate the efficiencies of Dp71 rescue strategies and opens new avenues for enhancing gene therapy targeting cognitive disorders associated with a subgroup of severely affected DMD patients.

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Duchenne Muscular Dystrophy from Brain to Muscle: The Role of Brain Dystrophin Isoforms in Motor Functions

Cited by 6 publications

References 55 publications

Title-molecular diagnostics of dystrophinopathies in Sri Lanka towards phenotype predictions: an insight from a South Asian resource limited setting

Title-molecular diagnostics of dystrophinopathies in Sri Lanka towards phenotype predictions: an insight from a South Asian resource limited setting

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

AAV-Mediated Restoration of Dystrophin-Dp71 in the Brain of Dp71-Null Mice: Molecular, Cellular and Behavioral Outcomes

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