Analysis of dystrophin gene in Iranian Duchenne and Becker muscular dystrophies patients and identification of a novel mutation

Zamani, Gholamreza; Karami, Fatemeh; Mehdizadeh, Mahshid; Movafagh, Abolfazl; Nilipour, Yalda; Zamani, Mahdi

doi:10.1007/s10072-015-2290-2

Cited by 6 publications

(5 citation statements)

References 26 publications

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“…Exon 44 was the most frequently deleted single exon in the present study, while other studies reported exons 45 and 51. Among multiexon deletions in this study, exons 45–50 and exons 45–52 were the most commonly involved exons, which is consistent with the results of previous studies [ 29 , 30 ]. The largest deletion found in our study extended from exon 3 to exon 44 in the proximal part, while the largest deletion in previous studies was found in exons 8–47.…”

Section: Discussionsupporting

confidence: 93%

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Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy

et al. 2022

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Background Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy in the pediatric population. The manifestations of this disease include progressive muscle weakness, gait dysfunction, and motor impairment, leading to a loss of ambulation by the age of 13 years. Molecular diagnosis is the standard diagnostic tool for DMD. This study aimed to investigate disease progression and genetic patterns in Iranian ambulant boys and to find the correlation between genotypes and motor function phenotypes. Methods This study was performed on 152 DMD patients. Clinical history, including the disease phenotype, steroid therapy, and the North Star Ambulatory Assessment (NSAA) score, was taken for all the patients. Molecular diagnoses were confirmed by multiplex ligation-dependent probe amplification and next-generation sequencing tests. Results A total of 152 Iranian DMD patients were examined in this study. The mean age at the time of disease onset was 4.04 ± 2.00 years, and the mean age at diagnosis was 5.05 ± 2.08 years. The mean age of ambulation loss was 10.9 years. Contracture was reported in 38.9% of cases. In terms of age, the mean total NSAA score showed a peak at 4 years of age, with a mean NSAA score of 24. Annual changes in the NSAA score were determined for all cases, based on the mutation type and exon site. Deletion mutation was found in 79.1% of cases, duplication in 6.8%, nonsense in 12.8%, and splice site in 1.4%. The most common single exon deletion was exon 44 (5.3%), and the most common multiexon deletions were attributed to exons 45–50 and exons 45–52 (4.6%). The results did not indicate any correlation between the mutation type and age at the time of disease onset, loss of ambulation age, and wheelchair dependence; however, a significant association was found between contracture and mutation type. The results showed a significant difference in the NSAA score between the deletion and nonsense groups at the age of 3 years (P = 0.04). No significant correlation was found between the phenotype and exon site. Overall, 91.1% of the study population had a history of corticosteroid use, and 54.1% showed compliance with rehabilitation therapy. Conclusion This study demonstrated the phenotypes and mutational features of Iranian DMD boys and provided information regarding the natural motor history of the disease, disease progression, diagnosis, and status of DMD management in Iran. The present findings can promote the development of clinical trials and future advanced molecular therapies in Iran.

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Section: Discussionsupporting

confidence: 93%

“…Analysis of the distribution of mutation sites in 79 exons revealed that 47.4% of them were in the distal part, 35.5% were in the proximal part, and 1.3% were in both distal and proximal parts. Distal deletions constituted 57% of deletions in DMD, and their distribution was compatible with previous reports ([ 24 , 30 ], and [ 29 ]).…”

Section: Discussionsupporting

confidence: 92%

Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy

et al. 2022

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“…No novel mutations were identified in this study. In a study in Iranian DMD/BMD patients, 30.9 % of patients had single exon deletion, while group and contiguous exon deletions were identified in 41% of the patients [12]. The most numerous exon deletions included exons 45-50, and two exons 3-5 and 41-43 duplications (1.4 %) was observed in a BMD and a DMD patient, respectively [12].…”

Section: Discussionmentioning

confidence: 99%

Multiplex Ligation Dependent Probe Amplification Based Mutation Analysis of Dystrophin Gene in Nepalese Patients with Duchenne Muscular Dystrophy

Shrestha

Khatiwada³

et al. 2016

Nepal J Biotechnol

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Duchenne muscular dystrophy (DMD) is X-linked recessive neuromuscular disorders caused due to mutation in dystrophin gene, leading to progressive muscle weakness. This study was done to identify mutation in dystrophin gene in Nepalese patients with DMD using Multiplex Ligation Dependent Probe Amplification (MLPA) assay in Nepal. Twenty one patients from different regions of Nepal, who were clinically diagnosed as DMD were enrolled in the study. Peripheral blood samples were collected in EDTA vials, gDNA was extracted, and deletion mutation in the dystrophin gene was analysed using Multiplex Ligation Dependent Probe Amplification (MLPA) assay. Exon deletion mutation in the dystrophin gene was observed in 14 (66.6%) out of 21 DMD cases. The most common exon deletion was observed and confined in exon 7-14 and 45-53 of dystrophin gene. The location of deletion in dystrophin gene is apparently non-random with a preponderance found in the hot spot regions. Use of MLPA is useful in detecting copy number changes in DMD proband and suspected carriers in Nepal.

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“…Several isolated deletions of exon 49 of DMD have already been reported in the literature associated with both DMD and BMD phenotypes [ 18 , 19 , 20 , 21 , 22 , 23 ] ( Table S1 ). Notablythese reports did not include any specific phenotypic information about disease severity.…”

Section: Discussionmentioning

confidence: 99%

Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49

Abaji

Gorokhova

Silva

et al. 2022

Genes

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Exon skipping is a promising therapeutic approach. One important condition for this approach is that the exon-skipped form of the gene can at least partially perform the required function and lead to improvement of the phenotype. It is therefore critical to identify the exons that can be skipped without a significant deleterious effect on the protein function. Pathogenic variants in the DMD gene are responsible for Duchenne muscular dystrophy (DMD). We report for the first time a deletion of the in-frame exon 49 associated with a strikingly normal muscular phenotype. Based on this observation, and on previously known therapeutic approaches using exon skipping in DMD for other single exons, we aimed to extend the clinical use of exon skipping for patients carrying truncating mutations in exon 49. We first determined the precise genomic position of the exon 49 deletion in our patients. We then demonstrated the feasibility of skipping exon 49 using an in vitro AON (antisense oligonucleotide) approach in human myotubes carrying a truncating pathogenic variant as well as in healthy ones. This work is a proof of concept aiming to expand exon-skipping approaches for DMD exon 49.

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Analysis of dystrophin gene in Iranian Duchenne and Becker muscular dystrophies patients and identification of a novel mutation

Cited by 6 publications

References 26 publications

Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy

Characteristics of disease progression and genetic correlation in ambulatory Iranian boys with Duchenne muscular dystrophy

Multiplex Ligation Dependent Probe Amplification Based Mutation Analysis of Dystrophin Gene in Nepalese Patients with Duchenne Muscular Dystrophy

Novel Exon-Skipping Therapeutic Approach for the DMD Gene Based on Asymptomatic Deletions of Exon 49

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