Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

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Sensitivity and Frequencies of Dystrophin Gene Mutations in Thai DMD/BMD Patients As Detected by Multiplex PCR

Disease Markers ◽

10.1155/2008/521568 ◽

2008 ◽

Vol 25 (2) ◽

pp. 115-121 ◽

Cited By ~ 5

Author(s):

Thanyachai Sura ◽

Jakris Eu-ahsunthornwattana ◽

Sarinee Pingsuthiwong ◽

Manisa Busabaratana

Keyword(s):

Muscular Dystrophy ◽

Multiplex Pcr ◽

Gene Mutations ◽

Dystrophin Gene ◽

Index Patient ◽

Becker Muscular Dystrophy ◽

Large Size ◽

Different Populations ◽

The Mean ◽

Deletion Frequency

Background: Duchenne muscular dystrophy (DMD), a lethal X-linked disease affecting 1 in 3500 male births, and its more benign variant, Becker muscular dystrophy (BMD), are caused by mutations in the dystrophin gene. Because of its large size, analysing the whole gene is impractical. Methods have been developed to detect the commonest mutations i.e. the deletions of the exons. Although these tests are highly specific, their sensitivity is inherently limited by the prevalence of deletions, which differs among different populations.Methods: We reviewed our database for the detection of Dystrophin gene mutation by means of 31-exon multiplex PCR in Thai males, diagnosed clinically and biochemically with DMD or BMD from July 1994 to November 2006. One index patient was chosen from each family for statistical analysis. The overall sensitivity of the test, the number of fragment deleted, and the deletion frequency of each fragment were calculated, along with their 95% confidence intervals (C.I.).Results: We found deletions in 99 out of the 202 index patients (49%; Bayesian 95% C.I. = 42%–56%). 51% of these had deletion in only one of the 31 exons tested, while the patient with the most extensive deletions had 14 exons deleted. The mean number of deleted exons were 2.84 (BCabootstrap 95% C.I. = 2.37–3.48), or 5.02 (3.81–6.85) if all the untested exons adjacent to the confirmed deleted exons were assumed to be deleted. The region spanning exons 44-52 was the most frequently deleted. These were similar to those reported in the Japanese.Conclusion: The multiplex PCR detected deletions only in about half of the Thai patients. The diseases therefore should not be excluded solely on the negative result if DMD/BMD is strongly suspected.

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Unexpected DMD Gene Mutations Detected by CMA and CNV-seq in amniotic Fluid and Aborted Fetus Samples

10.21203/rs.3.rs-376139/v1 ◽

2021 ◽

Author(s):

Qiuhua Wu ◽

Lihui Yang ◽

Qiujie Jin ◽

Rui Wang ◽

Wen Zhai ◽

...

Keyword(s):

Prenatal Diagnosis ◽

Muscular Dystrophy ◽

Amniotic Fluid ◽

Spontaneous Abortion ◽

Gene Mutations ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Hereditary Diseases ◽

Muscle Dysfunction ◽

Dmd Gene

Abstract Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are common X chromosome-linked recessive hereditary diseases. The mechanism is that the exon mutations of anti-myatrophy protein gene (Dystrophin gene) and lead to muscle dysfunction. Prenatal diagnosis can prevent the birth of children with defects and have good clinical significance. Methods: CMA and CNV-seq were used to detect the amniotic fluid after amniocentesis,. CNV-seq was used to detect spontaneous abortion tissue. The DMD gene mutations were found in 6 amniotic fluid samples and one spontaneous abortion sample. DMD gene mutations were confirmed by MLPA and new DMD mutations were found.Results: CMA found DMD mutations :1.Xp21.1, 75.5kb del (E52-53); 2.Xp21.2, 334.92kb dup (E61-79); 3.Xp21.2, 292.25kb dup (E58-74); 4.Xp21.1, 374.20 kb dup (E45-51). CNV-seq found DMD mutations: 5.X p21.2, E64-79 dup; 6.X p21.1, E1-7dup; 7.Xp21.1, E 44-52 del. Conclusions: 4 fetuses harboring DMD gene mutations were found by CMA, 2 fetuses and 1 induced abortion carrying DMD gene mutations was detected by CNV-seq. CMA/CNV-seq jointed with MLPA test can provide more comprehensive evidence for prenatal diagnosis.

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Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy

Disease Models & Mechanisms ◽

10.1242/dmm.044701 ◽

2020 ◽

Vol 13 (9) ◽

pp. dmm044701

Author(s):

Naomi Teramoto ◽

Hidetoshi Sugihara ◽

Keitaro Yamanouchi ◽

Katsuyuki Nakamura ◽

Koichi Kimura ◽

...

Keyword(s):

Muscular Dystrophy ◽

Gene Mutations ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Severe Form ◽

Independent Manner ◽

Glycoprotein Complex ◽

Dystrophin Expression ◽

Pathological Evaluation ◽

Dystrophin Glycoprotein Complex

ABSTRACTDystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

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Deletion of Exon in the Dystrophin Gene in a Case of Becker Muscular Dystrophy with Cardiac Involvement

Korean Circulation Journal ◽

10.4070/kcj.1998.28.5.805 ◽

1998 ◽

Vol 28 (5) ◽

pp. 805 ◽

Cited By ~ 1

Author(s):

Kwang Il Kim ◽

Byung-Hee Oh ◽

Moo-Yong Rhee ◽

In-Ho Chae ◽

Sue Shin ◽

...

Keyword(s):

Muscular Dystrophy ◽

Cardiac Involvement ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy

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Association between specific dystrophin gene mutations and myocardial fibrosis by cardiovascular magnetic resonance imaging in patients with Duchenne and Becker muscular dystrophy

Journal of Cardiovascular Magnetic Resonance ◽

10.1186/1532-429x-16-s1-p325 ◽

2014 ◽

Vol 16 (S1) ◽

Author(s):

Marly C Silva ◽

Carlos H Rassi ◽

Zilda M Meira ◽

Juliana G Giannetti ◽

Mariz Vainzof ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Cardiovascular Magnetic Resonance ◽

Magnetic Resonance ◽

Muscular Dystrophy ◽

Myocardial Fibrosis ◽

Cardiovascular Magnetic Resonance Imaging ◽

Gene Mutations ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Resonance Imaging

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Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models

JRSM Cardiovascular Disease ◽

10.1177/2048004019879581 ◽

2019 ◽

Vol 8 ◽

pp. 204800401987958

Author(s):

HR Spaulding ◽

C Ballmann ◽

JC Quindry ◽

MB Hudson ◽

JT Selsby

Keyword(s):

Skeletal Muscle ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Disease Progression ◽

Gene Mutations ◽

Dystrophin Gene ◽

Mdx Mice ◽

Dystrophin Deficiency ◽

Muscle Wasting Disease ◽

Dystrophin Protein

Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.

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