Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy

Anaya-Segura, Mónica Alejandra; Rangel-Villalobos, Héctor; Martínez-Cortés, Gabriela; Gómez-D́iaz, Benjamín; Coral‐Vázquez, Ramón Mauricio; Zamora-González, Edgar Oswaldo; García, Silvia; López-Hernández, Luz Berenice

doi:10.3390/ijms17081334

Cited by 12 publications

(12 citation statements)

References 35 publications

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“…It has previously been reported that the myomiR miR‐206‐3p is elevated in human female DMD carriers . We therefore decided to first investigate ex‐miRNA abundance in heterozygous female carrier mice.…”

Section: Resultsmentioning

confidence: 99%

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology

Tle.

Lomonosova

Coenen-Stass

et al. 2019

J cachexia sarcopenia muscle

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Background Duchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex-miRNAs) are putative, minimally invasive biomarkers of DMD. Specific ex-miRNAs (e.g. miR-1, miR-133a, miR-206, and miR-483) are highly up-regulated in the serum of DMD patients and dystrophic animal models and are restored to wild-type levels following exon skipping-mediated dystrophin rescue in mdx mice. As such, ex-miRNAs are promising pharmacodynamic biomarkers of exon skipping efficacy. Here, we aimed to determine the degree to which ex-miRNA levels reflect the underlying level of dystrophin protein expression in dystrophic muscle. Methods Candidate ex-miRNA biomarker levels were investigated in mdx mice in which dystrophin was restored with peptide-PMO (PPMO) exon skipping conjugates and in mdx-Xist Δhs mice that express variable amounts of dystrophin from birth as a consequence of skewed X-chromosome inactivation. miRNA profiling was performed in mdx-Xist Δhs mice using the FirePlex methodology and key results validated by small RNA TaqMan RT-qPCR. The muscles from each animal model were further characterized by dystrophin western blot and immunofluorescence staining. Results The restoration of ex-myomiR abundance observed following PPMO treatment was not recapitulated in the high dystrophin-expressing mdx-Xist Δhs group, despite these animals expressing similar amounts of total dystrophin protein (~37% of wild-type levels). Instead, ex-miRNAs were present at high levels in mdx-Xist Δhs mice regardless of dystrophin expression. PPMO-treated muscles exhibited a uniform pattern of dystrophin localization and were devoid of regenerating fibres, whereas mdx-Xist Δhs muscles showed non-homogeneous dystrophin staining and sporadic regenerating foci. Conclusions Uniform dystrophin expression is required to prevent ex-miRNA release, stabilize myofiber turnover, and attenuate pathology in dystrophic muscle.

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Section: Resultsmentioning

confidence: 99%

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology

Tle.

Lomonosova

Coenen-Stass

et al. 2019

J cachexia sarcopenia muscle

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“…2 ). For instance, the characterization of circulating cell-free miRNAs in serum helps in concluding diagnostic and prognostic assessments, based on the fact that disease-specific miRNAs can be identified in extracellular body fluids (such as serum, plasma, and saliva), supporting their potential as biomarkers [ 24 – 27 , 30 , 33 – 35 ]. The presence of miRNAs in body fluids is based on the fact that extracellular miRNAs are protected by exosome-like structures and small intraluminal vesicles released by a large variety of cells [ 36 , 37 ].…”

Section: Non-coding Rnas As Possible Targets In Theranostics Of Genetmentioning

confidence: 99%

MicroRNAs and Long Non-coding RNAs in Genetic Diseases

et al. 2019

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Since the discovery and classification of non-coding RNAs, their roles have gained great attention. In this respect, microRNAs and long non-coding RNAs have been firmly demonstrated to be linked to regulation of gene expression and onset of human diseases, including rare genetic diseases; therefore they are suitable targets for therapeutic intervention. This issue, in the context of rare genetic diseases, is being considered by an increasing number of research groups and is of key interest to the health community. In the case of rare genetic diseases, the possibility of developing personalized therapy in precision medicine has attracted the attention of researchers and clinicians involved in developing “orphan medicinal products” and proposing these to the European Medicines Agency (EMA) and to the Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) in the United States. The major focuses of these activities are the evaluation and development of products (drugs, biologics, devices, or medical foods) considered to be promising for diagnosis and/or treatment of rare diseases or conditions, including rare genetic diseases. In an increasing number of rare genetic diseases, analysis of microRNAs and long non-coding RNAs has been proven a promising strategy. These diseases include, but are not limited to, Duchenne muscular dystrophy, cystic fibrosis, Rett syndrome, and β-thalassemia. In conclusion, a large number of approaches based on targeting microRNAs and long non-coding RNAs are expected in the field of molecular diagnosis and therapy, with a facilitated technological transfer in the case of rare genetic diseases, in virtue of the existing regulation concerning these diseases.

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“…Recent studies have shown that circulating miRNAs can be used as potential diagnostic biomarkers for female DMD/BMD carriers (4,11). Therefore, we evaluated the ability of these seven serum myomiRs and CK to diagnose MD-carriers using ROC curve analysis.…”

Section: Discussionmentioning

confidence: 99%

“…It is estimated that ~2.5–40.0% of female carriers will have manifestations of muscular dystrophy (MD) such as muscle weakness or heart disease later on in their life, but these people rarely show symptoms during childhood ( 2 – 4 ). In addition, multiple studies have shown that ~45–76% of female carriers have increased serum creatine kinase (CK) levels, while others are normal ( 5 – 7 ).…”

Section: Introductionmentioning

confidence: 99%

“…Li et al ( 22 ) found that the serum levels of a group of miRNAs including miR-1, miR-133, miR-206, miR-208a, miR-208b, and miR-499 have important diagnostic and prognostic values for DMD patients. Anaya-Segura et al ( 4 ) further researched and concluded that up-regulated serum miR-206 could be used to detect DMD female carriers. Mousa et al ( 23 ) also confirmed that plasma miR-499 was significantly up-regulated and had the ability to identify female carriers.…”

Section: Introductionmentioning

confidence: 99%

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Serum MyomiRs as Biomarkers for Female Carriers of Duchenne/Becker Muscular Dystrophy

Zhang

Zhong

et al. 2020

Front. Neurol.

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Background: Duchenne/Becker muscular dystrophy (DMD/BMD) is an X-linked recessive lethal neuromuscular disease. MicroRNAs expressed in striated muscle, myomiRs, have been proposed as its potential biomarkers. Serum creatine kinase (CK) is commonly used as a biomarker in clinical practice, but it is not reliable. The aim of this study was to assess whether serum levels of myomiRs has diagnostic value for detection of female DMD/BMD carriers with normal or elevated CK. Methods: Thirty four female carriers and 33 age-matched healthy female controls were enrolled. Peripheral blood samples were collected and serum miRNAs were extracted for measurement of miR-1, miR-133a, miR-133b, miR-206, miR-208a, miR-208b, and miR-499 by quantitative real-time polymerase chain reaction. Results: MiR-1, miR-133a, miR-133b, miR-206, miR-208a, miR-208b, and miR-499 were upregulated in all female carriers in comparison to healthy controls. MiR-1 (Spearman's rho = +0.406, p = 0.017) was correlated with CK in the female carrier group. Receiver operating characteristic curve analysis of all seven myomiRs showed that the area under the curve (AUC) for miR-499, miR-133b, miR-1, miR-208b, and miR-133a exceeded 70.0%, and for miR-206 and miR-208a exceeded 60.0%. MiR-133b and miR-499 were significantly increased in all female carriers, even those with normal CK. AUC for the combination of all seven miRNAs was 87.2%. CK (OR 0.406, 95% CI 0.000-0.001, p < 0.0001) and miR-499 (OR 0.323, 95% CI 0.023-0.106, p = 0.003) were considered to be independent predictors for female carriers presence in the multivariable regression analysis model. Conclusions: MiR-133b and miR-499 are potentially useful biomarkers for female carriers with DMD/BMD (including those with normal CK). The combination of all seven serum miRNAs and their respective combinations with CK have better diagnostic value for female carriers than either CK or any separate miRNA.

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Serum Levels of MicroRNA-206 and Novel Mini-STR Assays for Carrier Detection in Duchenne Muscular Dystrophy

Cited by 12 publications

References 35 publications

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology

Uniform sarcolemmal dystrophin expression is required to prevent extracellular microRNA release and improve dystrophic pathology

MicroRNAs and Long Non-coding RNAs in Genetic Diseases

Serum MyomiRs as Biomarkers for Female Carriers of Duchenne/Becker Muscular Dystrophy

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