Germinal Mosaicism in a Sample of Families with Duchenne/Becker Muscular Dystrophy with Partial Deletions in the DMD Gene

AbstractDystrophinopathies are a group of X-linked neuromuscular disorders resulting from mutations in DMD gene that encodes dystrophin. The clinical spectrum includes Duchenne muscular dystrophy, Becker muscular dystrophy, X-linked cardiomyopathy, and intellectual disability without involvement of skeletal muscle. Cognitive and behavioral problems are commonly seen among patients with dystrophinopathy. DMD gene is the largest human gene, consisting of 79 exons that produce dystrophin protein. Patients with genetic changes involving shorter dystrophin isoforms such as Dp140 and Dp71 are suggested to have higher rates of intellectual disability, attention-deficit/hyperactivity disorder, and other neuropsychiatric comorbidities. We describe three brothers who presented with prominent neurobehavioral deficits of varying degree, mild proximal weakness, and elevated serum creatine kinase due to a rare nonsense mutation, c.1702C > T; p.Gln568X, in exon 14 of DMD gene. Further studies are needed to better understand the effects of this rare mutation.

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Comprehensive genetic diagnosis of patients with Duchenne/Becker muscular dystrophy (DMD/BMD) and pathogenicity analysis of splice site variants in the DMD gene

Journal of Zhejiang University SCIENCE B ◽

10.1631/jzus.b1800541 ◽

2019 ◽

Vol 20 (9) ◽

pp. 753-765

Author(s):

Yan-mei Yang ◽

Kai Yan ◽

Bei Liu ◽

Min Chen ◽

Li-ya Wang ◽

...

Keyword(s):

Muscular Dystrophy ◽

Splice Site ◽

Genetic Diagnosis ◽

Becker Muscular Dystrophy ◽

Dmd Gene

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Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Journal of Personalized Medicine ◽

10.3390/jpm10040241 ◽

2020 ◽

Vol 10 (4) ◽

pp. 241

Author(s):

Kenji Rowel Q. Lim ◽

Quynh Nguyen ◽

Toshifumi Yokota

Keyword(s):

Muscular Dystrophy ◽

Neuromuscular Disease ◽

Becker Muscular Dystrophy ◽

Neuromuscular Disorder ◽

Test Results ◽

Disease Registry ◽

Reading Frame ◽

Negative Results ◽

Genetic Test Results ◽

Dmd Gene

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively.

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Clinicopathologic and molecular profiles of Duchenne and Becker muscular dystrophy

Paediatrica Indonesiana ◽

10.14238/pi59.5.2019.257-64 ◽

2019 ◽

Vol 59 (5) ◽

pp. 257-64

Author(s):

Ery Kus Dwianingsih ◽

Meydita Fuzia Putri Insani ◽

Linda Pratiwi ◽

Irianiwati Widodo ◽

Rusdy Ghazali Malueka

Keyword(s):

Muscular Dystrophy ◽

Muscle Biopsy ◽

Clinical Manifestations ◽

Becker Muscular Dystrophy ◽

High Serum ◽

Molecular Profile ◽

Molecular Profiles ◽

Weak Expression ◽

Dmd Gene ◽

Histopathological Grading

Background Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive diseases caused by mutations in the dystrophin (DMD) gene. To our knowledge, molecular analysis to differentiate between DMD and BMD has never been performed in Indonesia. Objective To elaborate the clinicopathologic and molecular profiles of DMD/BMD patients in Yogyakarta, Indonesia. Methods Eighteen muscle biopsy specimens of patients clinically suspected to have DMD/BMD were collected. Possible associations of clinical manifestations, histopathological grading, and immunohistochemistry (IHC) results were analyzed. Polymerase chain reaction (PCR) was performed to identify mutations in exon 52. Results. Positive Gower’s sign and high serum creatine kinase (CK) were observed in most patients. The IHC of dystrophin in two female patients suggested that they were manifesting carriers. Of the 16 male patients, 12 showed negative IHC staining, indicating DMD, while 4 patients demonstrated weak expression of dystrophin, indicating BMD. There was a significant association between high CK level and IHC results (P=0.005), indicating higher CK level in DMD patients. Histopathological grading of muscle biopsy was significantly associated with diagnosis of DMD/BMD using IHC (P=0.01), showing more severe tissue damage in DMD patients. None of the subjects had the single exon 52 deletion. Conclusion This is the first report of a clinicopathologic and molecular profile of DMD/BMD in an Indonesian population. Serum CK level and histopathological grading of muscle biopsy are useful in distinguishing DMD from BMD in settings where an IHC assay is not available.

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Exon skipping induced by nonsense/frameshift mutations in DMD gene results in Becker muscular dystrophy

Human Genetics ◽

10.1007/s00439-019-02107-4 ◽

2020 ◽

Vol 139 (2) ◽

pp. 247-255 ◽

Cited By ~ 2

Author(s):

Mariko Okubo ◽

Satoru Noguchi ◽

Shinichiro Hayashi ◽

Harumasa Nakamura ◽

Hirofumi Komaki ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Nonsense Mutation ◽

Frameshift Mutation ◽

Exon Skipping ◽

Becker Muscular Dystrophy ◽

Intronic Sequence ◽

Frameshift Mutations ◽

Dmd Gene ◽

Accurate Quantification

AbstractDuchenne muscular dystrophy (DMD) is caused by a nonsense or frameshift mutation in the DMD gene, while its milder form, Becker muscular dystrophy (BMD) is caused by an in-frame deletion/duplication or a missense mutation. Interestingly, however, some patients with a nonsense mutation exhibit BMD phenotype, which is mostly attributed to the skipping of the exon containing the nonsense mutation, resulting in in-frame deletion. This study aims to find BMD cases with nonsense/frameshift mutations in DMD and to investigate the exon skipping rate of those nonsense/frameshift mutations. We searched for BMD cases with nonsense/frameshift mutations in DMD in the Japanese Registry of Muscular Dystrophy. For each DMD mutation identified, we constructed minigene plasmids containing one exon with/without a mutation and its flanking intronic sequence. We then introduced them into HeLa cells and measured the skipping rate of transcripts of the minigene by RT-qPCR. We found 363 cases with a nonsense/frameshift mutation in DMD gene from a total of 1497 dystrophinopathy cases in the registry. Among them, 14 had BMD phenotype. Exon skipping rates were well correlated with presence or absence of dystrophin, suggesting that 5% exon skipping rate is critical for the presence of dystrophin in the sarcolemma, leading to milder phenotypes. Accurate quantification of the skipping rate is important in understanding the exact functions of the nonsense/frameshift mutations in DMD and for interpreting the phenotypes of the BMD patients.

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MLPA analysis/complete sequencing of the DMD gene in a group of Bulgarian Duchenne/Becker muscular dystrophy patients

Neuromuscular Disorders ◽

10.1016/j.nmd.2008.06.369 ◽

2008 ◽

Vol 18 (8) ◽

pp. 667-670 ◽

Cited By ~ 16

Author(s):

Albena Todorova ◽

Tihomir Todorov ◽

Bilyana Georgieva ◽

Michaela Lukova ◽

Velina Guergueltcheva ◽

...

Keyword(s):

Muscular Dystrophy ◽

Becker Muscular Dystrophy ◽

Complete Sequencing ◽

Dmd Gene

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Becker muscular dystrophy due to an inversion of exons 23 and 24 of the DMD gene

Muscle & Nerve ◽

10.1002/mus.22226 ◽

2011 ◽

Vol 44 (5) ◽

pp. 822-825 ◽

Cited By ~ 4

Author(s):

Kevin M. Flanigan ◽

Diane Dunn ◽

C. Aaron Larsen ◽

Livija Medne ◽

Carsten B. Bönnemann ◽

...

Keyword(s):

Muscular Dystrophy ◽

Becker Muscular Dystrophy ◽

Dmd Gene

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Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

International Journal of Endocrinology ◽

10.1155/2015/867273 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 27

Author(s):

Maricela Rodríguez-Cruz ◽

Raúl Sanchez ◽

Rosa E. Escobar ◽

Oriana del Rocío Cruz-Guzmán ◽

Mardia López-Alarcón ◽

...

Keyword(s):

Insulin Resistance ◽

Muscular Dystrophy ◽

Glucose Metabolism ◽

Molecular Mechanisms ◽

Becker Muscular Dystrophy ◽

Body Fat Mass ◽

Metabolic Alterations ◽

Underweight Patients ◽

Dmd Gene ◽

Muscle Biopsies

Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR.Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69) and 50 (OR = 8.73; 95% CI = 1.17–65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue.Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR.

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The lncRNA 44s2 Study Applicability to the Design of 45-55 Exon Skipping Therapeutic Strategy for DMD

Biomedicines ◽

10.3390/biomedicines9020219 ◽

2021 ◽

Vol 9 (2) ◽

pp. 219

Author(s):

Elena Gargaun ◽

Sestina Falcone ◽

Guilhem Solé ◽

Julien Durigneux ◽

Andoni Urtizberea ◽

...

Keyword(s):

Muscular Dystrophy ◽

Gene Mutations ◽

Exon Skipping ◽

Becker Muscular Dystrophy ◽

Protein Stabilization ◽

Progressive Muscular Dystrophy ◽

Dilatative Cardiomyopathy ◽

Proliferation And Differentiation ◽

Dmd Gene ◽

Dystrophin Protein

In skeletal muscle, long noncoding RNAs (lncRNAs) are involved in dystrophin protein stabilization but also in the regulation of myocytes proliferation and differentiation. Hence, they could represent promising therapeutic targets and/or biomarkers for Duchenne and Becker muscular dystrophy (DMD/BMD). DMD and BMD are X-linked myopathies characterized by a progressive muscular dystrophy with or without dilatative cardiomyopathy. Two-thirds of DMD gene mutations are represented by deletions, and 63% of patients carrying DMD deletions are eligible for 45 to 55 multi-exons skipping (MES), becoming BMD patients (BMDΔ45-55). We analyzed the genomic lncRNA presence in 38 BMDΔ45-55 patients and characterized the lncRNA localized in introns 44 and 55 of the DMD gene. We highlighted that all four lncRNA are differentially expressed during myogenesis in immortalized and primary human myoblasts. In addition, the lncRNA44s2 was pointed out as a possible accelerator of differentiation. Interestingly, lncRNA44s expression was associated with a favorable clinical phenotype. These findings suggest that lncRNA44s2 could be involved in muscle differentiation process and become a potential disease progression biomarker. Based on these results, we support MES45-55 therapy and propose that the design of the CRISPR/Cas9 MES45-55 assay consider the lncRNA sequences bordering the exonic 45 to 55 deletion.

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