Precise mapping of 17 deletion breakpoints within the central hotspot deletion region (introns 50 and 51) of the DMD gene

Esposito, Gabriella; Tremolaterra, Maria Roberta; Marsocci, Evelina; Tandurella, Igor Cm; Fioretti, Tiziana; Savarese, Maria Flavia; Carsana, Antonella

doi:10.1038/jhg.2017.84

Cited by 16 publications

(17 citation statements)

References 34 publications

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“…The reason for the high rate of deletion and low rate of small mutation might be that the patients enrolled in our hospital were mainly deletions and duplications. In addition, we found that deletions preferentially clustered in one hot-spot region that located between exon 43-55 of DMD gene which was in agreement with previous studies in other populations [22,23]. Likewise, two hot spot regions were located for duplications, which were exon 8-11 and exon 51.…”

Section: Discussionsupporting

confidence: 92%

Prenatal diagnosis of Duchenne muscular dystrophy and cytogenetic analysis in 303 Chinese families

Yao

Hao

et al. 2020

Preprint

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Background: Duchenne muscular dystrophy (DMD) has showed a wide spectrum of mutations in the dystrophin gene including exon deletions, duplications and small mutations. This retrospective study was to supply information of the DMD mutational spectrum in 303 Chinese families and further offer 5-year clinical experience of DMD genetic counselling and prenatal diagnosis.Methods: In this retrospective study, 305 pregnancies in 303 pregnant women who has a birth history of DMD patients underwent prenatal diagnosis using multiplex ligation-dependent probe amplification (MLPA) followed by Sanger sequencing between 2014 and 2018. Karyotype analysis was performed to exclude fetal abnormal karyotype.Results: The detection rate of DMD gene mutation in 303 probands was 97.7% with 7 families having a negative genetic diagnosis. The mutational spectrum comprised of large arrangements in 288/303 (95.0%) and small mutations in 8/303 (2.6%). 204 pregnant women did carrier testing among whom, 108 mothers had the same mutation as family proband. Of the 305 pregnancies underwent prenatal diagnosis, 55 of 173 male fetuses were affected. We also performed karyotype analysis and found 3 abnormal karyotypes of trisomy 21. We even found a fetus with DMD gene mutation and trisomy 21 in a same fetus by further analysis.Conclusions: The distribution and mutation profile of 303 probands and 305 fetuses were demonstrated. Given the large samples provided in this study, the information is essential for genetic counselling and prenatal diagnosis in DMD families in China.

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Section: Discussionsupporting

confidence: 92%

Prenatal diagnosis of Duchenne muscular dystrophy and cytogenetic analysis in 303 Chinese families

Yao

Hao

et al. 2020

Preprint

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“…This is also an interesting finding since mechanisms underlining deletion and duplication events are different indeed. Deletions seem to be frequently related to micro-homology in breakpoint regions, mainly due to the presence of short tandem repeats, interspersed repeat elements which can predispose to deletion events (Esposito et al, 2017) or (as already mentioned above) due to an aberrant firing replication fork. Duplications are known to arise from either homologous (such as Alu-Alu) recombination or nonhomologous recombination, which is mediated by topoisomerases activity.…”

Section: Dmd Deletions and Duplications: Frequency Distribution Topmentioning

confidence: 97%

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Neri¹,

Rossi²,

Trabanelli³

et al. 2020

Front. Genet.

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in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein d o m a i n , w i t h e ff e c t s on p o p u l a t i o n ge n e t i c c h a r a c t e r i s t i c s a n d ne w personalized therapies.

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“…Effective treatments are limited for DMD patients, and research for genetic-based therapies is ongoing [7]. As a consequence, the analysis of the DMD gene is of utmost importance for the identification of the underlying molecular defect, because it can confirm the clinical diagnosis, reveal patients' genotype, address patients to the most opportune therapeutic options, and allow the identification of carrier females and the application of prenatal tests [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

Esposito

Carsana

2019

JCM

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Duchenne and Becker muscular dystrophies (DMD/BMD) result in progressive weakness of skeletal and cardiac muscles due to the deficiency of functional dystrophin. Respiratory failure is a leading cause of mortality in DMD patients; however, improved management of the respiratory symptoms have increased patients’ life expectancy, thereby also increasing the clinical relevance of heart disease. In fact, the prevalence of cardiomyopathy, which significantly contributes to mortality in DMD patients, increases with age and disease progression, so that over 95% of adult patients has cardiomyopathy signs. We here review the current literature featuring the metabolic alterations observed in the dystrophic heart of the mdx mouse, i.e., the best-studied animal model of the disease, and discuss their pathophysiological role in the DMD heart. It is well assessed that dystrophin deficiency is associated with pathological alterations of lipid metabolism, intracellular calcium levels, neuronal nitric oxide (NO) synthase localization, and NO and reactive oxygen species production. These metabolic stressors contribute to impair the function of the cardiac mitochondrial bulk, which has a relevant pathophysiological role in the development of cardiomyopathy. In fact, mitochondrial dysfunction becomes more severe as the dystrophic process progresses, thereby indicating it may be both the cause and the consequence of the dystrophic process in the DMD heart.

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Precise mapping of 17 deletion breakpoints within the central hotspot deletion region (introns 50 and 51) of the DMD gene

Cited by 16 publications

References 34 publications

Prenatal diagnosis of Duchenne muscular dystrophy and cytogenetic analysis in 303 Chinese families

Prenatal diagnosis of Duchenne muscular dystrophy and cytogenetic analysis in 303 Chinese families

The Genetic Landscape of Dystrophin Mutations in Italy: A Nationwide Study

Metabolic Alterations in Cardiomyocytes of Patients with Duchenne and Becker Muscular Dystrophies

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