Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human

Neri, Marcella; Torelli, Silvia; Brown, Susan C.; Ugo, I.; Sabatelli, Patrizia; Merlini, Luciano; Spitali, Pietro; Rimessi, Paola; Gualandi, Francesca; Sewry, Caroline A.; Ferlini, Alessandra; Muntoni, Francesco

doi:10.1016/j.nmd.2007.07.005

Cited by 147 publications

(106 citation statements)

References 33 publications

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“…The low efficiency of these methods raises the question of what are therapeutic levels of dystrophin. Studies involving female carriers of mutated dystrophin alleles suggested that levels slightly greater than 50% of normal are protective against skeletal muscle disease (127,538), although other studies of X-linked DCM patients report that levels as low as 30% of normal dystrophin expression can prevent significant skeletal muscle disease (637). The therapeutic threshold in the heart is complicated by the inability to obtain cardiac biopsies to determine the level of expression and by variability in the manifestation of cardiac disease in these patients (288,370,580,649).…”

Section: Dystrophin Gene Transfermentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Section: Dystrophin Gene Transfermentioning

confidence: 99%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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show abstract

“…On the other hand, recent study showed that there was no linear correlation between dystrophin levels and disease severity in patients with BMD [12]. If the dystrophin levels are greater than the threshold level (about 30%), then the structural characteristics of the internally deleted dystrophins, rather than the quantity of the dystrophin, could affect the phenotype [13]. Therefore, the structure modifications of dystrophin determined by the site of deletion in addition to its expression level modulate the severity of BMD [10].…”

Section: Discussionmentioning

confidence: 97%

Identification of two novel Duchenne muscular dystrophies mutations in patients with Becker muscular dystrophy

Kim

Seo

et al. 2017

J Genet Med

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JGMand may have near normal lives [2,3].The differential diagnosis of BMD and DMD in suspected cases is based on their clinical findings, muscle biopsy, and the mutations in DMD. Among these, positive staining for dystrophin in muscle biopsies is an important finding in the differential diagnosis [4,5]. However, since muscle biopsies are invasive procedures, the differential diagnosis of BMD and DMD is often dependent on the mutations in DMD gene identified in the patient. According to the mutation database or previous reports, each DMD mutation is classified as either a DMD-or BMDcausing mutation [6]. However, when a novel DMD mutation is identified, the differential diagnosis should be based on the muscle biopsy findings along with other clinical findings. IntroductionDuchenne and Becker muscular dystrophies (DMD, OMIM #310200 and BMD, OMIM #300376; respectively) are caused by mutations in DMD, the dystrophin-coding gene. These conditions are inherited in an X-linked recessive manner with a prevalence of 1 in 4,000 to 5,000 new born males [1].DMD and BMD are characterized by progressive muscular weakness. DMD is a severely disabling neuromuscular disease that leads to premature death of patients at approximately 19 years of age due to cardiac or respiratory failure. In contrast, BMD is a milder form with a later onset and slower rate of progression, and patients older than 16 years remain ambulatory www.e-kjgm.org Duchenne and Becker muscular dystrophies (DMD and BMD, respectively) are X-linked neuromuscular disorders characterized by progressive muscle weakness and severe skeletal muscle degeneration. BMD is a milder form with a later onset. Patients with BMD tend to survive much longer than those with DMD. The differentiation between DMD and BMD is important in the genetic counseling of affected patients and their families. Since muscle biopsies are invasive procedures, the differential diagnosis of BMD and DMD is often dependent on the mutation identified in the DMD gene in affected patients. However, when a novel DMD mutation is identified, the differential diagnosis should be based on muscle biopsy findings with other clinical findings. Here we describe two Korean patients with BMD confirmed by muscle biopsy and genetic testing. Two novel exonic deletions in the DMD gene were identified.

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“…In BMD muscles, the expression of mutated dystrophin is observed but with highly variable extents from less than 10 % to as high as 75% of the full length expression of normal muscles [14,15]. The direct correlation between dystrophin amount in BMD and clinical severity is not proven.…”

Section: Clinics Histopathology and Dystrophin In Dmd And Bmdmentioning

confidence: 99%

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

Rumeur¹

2015

Biomol Biomed

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Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects.

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Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human

Cited by 147 publications

References 33 publications

Designing Heart Performance by Gene Transfer

Designing Heart Performance by Gene Transfer

Identification of two novel Duchenne muscular dystrophies mutations in patients with Becker muscular dystrophy

Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

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