Dataset Information

MiRNome profiling in Duchenne muscular dystrophy; identification of asymptomatic and manifesting female carriers.

ABSTRACT: Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder that occurs due to inactivating mutations in DMD gene, leading to muscular dystrophy. Prediction of pathological complications of DMD and the identification of female carriers are important research points that aim to reduce disease burden. Herein, we describe a case of a late DMD patient and his immediate female family members, who all carry same DMD mutation and exhibited varied degrees of symptoms. In our study, we sequenced the whole miRNome in leukocytes and plasma of the family members and results were validated using real-time PCR. Our results highlighted the role of miR-409-3p, miR-424-5p, miR-144-3p as microRNAs that show correlation with the extent of severity of muscular weakness and can be used for detection of asymptomatic carriers. Cellular and circulating levels of miR-494-3p had shown significant increase in symptomatic carriers, which may indicate significant roles played by this miRNA in the onset of muscular weakness. Interestingly, circulating levels of miR-206 and miR-410-3p were significantly increased only in the severely symptomatic carrier. In conclusion, our study highlighted several miRNA species, which could be used in predicting the onset of muscle and/or neurological complications in DMD carriers.

SUBMITTER: Mousa NO

PROVIDER: S-EPMC8450315 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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miRNome profiling in Duchenne muscular dystrophy; identification of asymptomatic and manifesting female carriers.

Mousa Nahla O NO Sayed Ahmed A AA Fahmy Nagia N Elzayat Mariam G MG Bakry Usama U Abdellatif Ahmed A Zahra Waheed K WK Osman Ahmed A

Bioscience reports 20210901 9

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder that occurs due to inactivating mutations in DMD gene, leading to muscular dystrophy. Prediction of pathological complications of DMD and the identification of female carriers are important research points that aim to reduce disease burden. Herein, we describe a case of a late DMD patient and his immediate female family members, who all carry same DMD mutation and exhibited varied degrees of symptoms. In our study, we sequenced ...[more]

PMID: 34472584

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Project description:Background: Different from males with Duchenne/Becker muscular dystrophy (DMD/BMD) in whom overt myopathy is the rule, muscular dystrophy (MD) female carriers are mostly free of skeletal muscle symptoms. However, similar to MD males, these females are also prone to cardiomyopathy. Since circulating microRNAs (miRNAs) have been proposed as diagnostic biomarkers for various cardiovascular diseases, the aim of the current study was to identify specific circulating miRNAs in the plasma of female DMD/BMD carriers that may allow an early and accurate diagnosis of cardiac involvement in these cases. Methods: Twenty-nine female MD carriers and 24 age-matched healthy female controls were prospectively enrolled. All MD carriers and controls underwent comprehensive cardiovascular magnetic resonance (CMR) studies as well as venous blood sampling on the same day. Results: An impaired left ventricular (LV) systolic function was detected in 4 (14%) MD carriers while late gadolinium enhancement (LGE) indicative of myocardial fibrosis was present in 13 female patients (45%)-with an exclusively non-ischemic pattern. Among the circulating miRNAs examined, six were significantly up-regulated in MD carriers compared to female controls: miR-206 (103-fold increase, p < 0.0001), miR-222 (41-fold, p < 0.0001), miR-26a (fourfold, p = 0.029), miR-342 (27-fold, p < 0.0001), miR-378a-3p (minimum 3,600-fold; almost undetectable in controls, p = 0.013), miR-378a-5p (64-fold, p < 0.0001); only two miRNAs were substantially down-regulated in MD carriers: miR-144 (p < 0.0001) and miR-29a (p = 0.002) (both undetectable in carriers). A significant down-regulation of the miR-29c (<0.001-fold, p = 0.006) was observed in MD carriers with abnormal CMR findings (comprising functional and/or structural abnormalities) compared to those with normal CMR examinations. Univariable analyses regarding the presence of abnormal CMR findings resulted in four significant variables: LV end-diastolic volume index (EDVi), LV end-systolic volume index (ESVi), an elevated plasma creatine kinase (CK), and decreased serum miR-29c levels. In subsequent multivariable analysis, the only independent predictor for an abnormal CMR among MD carriers was circulating miR-29c (OR 0.99, 95% CI 0.98-0.99, p = 0.037). Moreover, an elevated CK and/or a downregulated miR-29c level (<0.05 × 10-3) resulted in an improved AUC value of 0.79 (0.62-0.97, p = 0.007) (79, 80 and 80%, sensitivity, specificity and overall accuracy) for the CMR-based diagnosis of cardiomyopathy in MD carriers when compared to using the two parameters individually. Conclusion: In female MD carriers, down-regulation of circulating miR-29c relates to the presence of functional and/or structural cardiac abnormalities (as detected by CMR) and appears to be a promising novel biomarker-in addition to conventional CK plasma levels-for an early diagnosis of cardiomyopathy.

Project description:BackgroundDuchenne muscular dystrophy (DMD) is an X-linked recessive disease that occurs in males leading to immobility and death in early adulthood. Female carriers of DMD are generally asymptomatic, yet frequently develop dilated cardiomyopathy. This study aims to detect early cardiac manifestation in DMD using cardiovascular magnetic resonance (CMR) and to evaluate its association with clinical symptoms.MethodsClinical assessment of DMD carriers included six minutes walk tests (6MWT), blood analysis, electrocardiography, echocardiography, and CMR using FLASH sequences to detect late gadolinium enhancement (LGE). T1-mapping using the Modified Look-Locker Inversion recovery (MOLLI) sequence was performed quantify extracellular volume (ECV).ResultsOf 20 carriers (age 39.47 ± 12.96 years) 17 (89.5 %) were clinically asymptomatic. ECV was mildly elevated (29.79 ± 2.92 %) and LGE was detected in nine cases (45 %). LGE positive carriers had lower left ventricular ejection fraction in CMR (64.36 ± 5.78 vs. 56.67 ± 6.89 %, p = 0.014), higher bothCK (629.89 ± 317.48 vs. 256.18 ± 109.10 U/l, p = 0.002) and CK-MB (22.13 ± 5.25 vs. 12.11 ± 2.21 U/l, p = 0.001), as well as shorter walking distances during the 6MWT (432.44 ± 96.72 vs. 514.91 ± 66.80 m, p = 0.037). 90.9 % of subjects without LGE had normal pro-BNP, whereas in 66.7 % of those presenting LGE pro-BNP was elevated (p = 0.027). All individuals without LGE were in the NYHA class I, whereas all those in NYHA classes II and III showed positive for LGE (p = 0.066).ConclusionsMyocardial involvement shown as LGE in CMR occurs in a substantial number of DMD carriers; it is associated with clinical and morphometric signs of incipient heart failure. LGE is thus a sensitive parameter for the early diagnosis of cardiomyopathy in DMD carriers.Trial registrationClinicaltrials.gov, NCT01712152 Trial registration: October 19, 2012. First patient enrolled: September 27, 2012 (retrospectively registered).

Project description:Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common pediatric muscular dystrophies, being Duchenne muscular dystrophy (DMD) the most severe form. Despite the fact that there is still no cure for these serious diseases, unprecedented advances are being made for the development of therapies for DMD. Some of which are already conditionally approved: exon skipping and premature stop codon read-through. The present work aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available pharmacogenetic treatments and finally, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with clinical diagnosis of dystrophinopathy, implementing a diagnostic molecular algorithm including: MLPA/PCR/Sanger/Exome and bioinformatics. We also performed a meta-analysis of LA's metrics for DMD available therapies. The employed algorithm resulted effective for the achievement of differential diagnosis, reaching a detection rate of 97%. Because of this, corticosteroid treatment was correctly indicated and validated in 371 patients with genetic confirmation of dystrophinopathy. Also, 20 were eligible for exon skipping of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for premature stop codon read-through therapy. We determined that 87.5% of DMD patients will restore the reading frame with the skipping of only one exon. Regarding nonsense variants, UGA turned out to be the most frequent premature stop codon observed (47%). According to the meta-analysis, only four LA countries (Argentina, Brazil, Colombia and Mexico) provide the complete molecular algorithm for dystrophinopathies. We observed different relations among the available targets for exon skipping in the analyzed populations, but a more even proportion of nonsense variants (∼40%). In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of the standard of care and genetic counseling. Finally, this work contributes with the international efforts to characterize the frequencies and variants in LA, pillars of drug development and theragnosis.

Dataset Information

MiRNome profiling in Duchenne muscular dystrophy; identification of asymptomatic and manifesting female carriers.

Publications

miRNome profiling in Duchenne muscular dystrophy; identification of asymptomatic and manifesting female carriers.

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