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[Cardiologic study of 10 patients with Duchenne muscular dystrophy(DMD): personal experience].

Duchenne (DMD) and Becker (BMD) muscular dystrophies are an heterogeneous group of diseases characterized by a progressive muscular degeneration. The locus involved is localized on short arm of chromosome X (2.1) and the gene product has been called dystrophin. The total dystrophin deficiency leads to DMD while the reduction of dystrophin expression to BMD. The dystrophin has an elevated molecular weight (427 Kd) with different isoforms expressed in skeletal muscular system, central nervous system and myocardium tissue. The cardiovascular involvement is up to the muscular dystrophy: in the DMD patients it is secondary to the progressive course and it usually seen in wheel-chair patients. We have retrospectively evaluated through electrophysiology (EKG) and Echo (M-mode and 2 dimensional) studies 10 DMD patients to define the heart involvement.

Adolescent↗
PubMed1989

Molecular and phenotypic analysis of patients with deletions within the deletion-rich region of the Duchenne muscular dystrophy (DMD) gene.

Eighty unrelated individuals with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) were found to have deletions in the major deletion-rich region of the DMD locus. This region includes the last five exons detected by cDNA5b-7, all exons detected by cDNA8, and the first two exons detected by cDNA9. These 80 individuals account for approximately 75% of 109 deletions of the gene, detected among 181 patients analyzed with the entire dystrophin cDNA. Endpoints for many of these deletions were further characterized using two genomic probes, p20 (DXS269; Wapenaar et al.) and GMGX11 (DXS239; present paper). Clinical findings are presented for all 80 patients allowing a correlation of phenotypic severity with the genotype. Thirty-eight independent patients were old enough to be classified as DMD, BMD, or intermediate phenotype and had deletions of exons with sequenced intron/exon boundaries. Of these, eight BMD patients and one intermediate patient had gene deletions predicted to leave the reading frame intact, while 21 DMD patients, 7 intermediate patients, and 1 BMD patient had gene deletions predicted to disrupt the reading frame. Thus, with two exceptions, frameshift deletions of the gene resulted in more severe phenotype than did in-frame deletions. This is in agreement with recent findings by Baumbach et al. and Koenig et al. but is in contrast to findings, by Malhotra et al., at the 5' end of the gene.

Chromosome Aberrations↗
PubMed1989

Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications.

We have studied 34 Becker and 160 Duchenne muscular dystrophy (DMD) patients with the dystrophin cDNA, using conventional blots and FIGE analysis. One hundred twenty-eight mutations (65%) were found, 115 deletions and 13 duplications, of which 106 deletions and 11 duplications could be precisely mapped in relation to both the mRNA and the major and minor mutation hot spots. Junction fragments, ideal markers for carrier detection, were found in 23 (17%) of the 128 cases. We identified eight new cDNA RFLPs within the DMD gene. With the use of cDNA probes we have completed the long-range map of the DMD gene, by the identification of a 680-kb SfiI fragment containing the gene's 3' end. The size of the DMD gene is now determined to be about 2.3 million basepairs. The combination of cDNA hybridizations with long-range analysis of deletion and duplication patients yields a global picture of the exon spacing within the dystrophin gene. The gene shows a large variability of intron size, ranging from only a few kilobases to 160-180 kb for the P20 intron.

Chromosome Deletion↗
PubMed1996

Preliminary study on the molecular structure of 3' region of Duchenne muscular dystrophy (DMD) gene in Chinese.

Number and order of HindIII exon-containing fragments (Hd) at 3' region of DMD gene were studied systematically using 16 partly-overlapping cDNA subprobes which were produced from dystrophin cDNA 9-14 with each of 9 restriction endonucleases. There are 25 Hd fragments corresponding to cDNA 9-14 in DMD gene. Since then, the exact length and the new order of Hd fragments are established. A new 2.1 kb fragment (Hd 55) is revealed; a 5.2 kb fragment (formerly designated as Hd 59) is excluded and the existence of a controversial 3.2 kb fragment (Hd 64) is confirmed. Besides, three new exons were revealed by comparing the PvuII and the XbaI hybridization patterns with the HindIII hybridization patterns for these cDNA subprobes. It is concluded that there are at least 66 Hd fragments, or 79 exons in DMD gene basing on the discovery of three additional exons. The corresponding relationship between the 66 Hd fragments and the SfiI large scale physical map has been studied, and at least 17 Hd fragments or 19 exons were shown to be distributed in the last fragment (IJ fragment) of the SfiI map of DMD gene.

DNA, Complementary↗
PubMed2025

Rethinking the pathogenicity of intragenic DMD duplications detected by carrier screening: High prevalence of nontandem duplications revealed by long-read sequencing.

PURPOSE: The pathogenicity of intragenic duplications depends on their structural configuration. Tandem duplications often disrupt reading frames and cause gene loss of function, whereas interspersed (nontandem) duplications are largely benign. When the configuration cannot be determined, current guidelines presume a tandem structure, leading to some laboratories automatically classifying such variants as likely pathogenic or pathogenic. This study evaluates the validity of this presumption for DMD, in patients with and without clinical indications of dystrophinopathy. METHODS: We performed high-coverage long-read genome sequencing on 15 patients with intragenic DMD duplications. A total of 4 patients had clinically indicated dystrophinopathy testing, whereas in the remaining 11 patients, the duplications were detected without clear indications of dystrophinopathy (eg, through carrier screening). RESULTS: All 4 patients with clinical indications had tandem duplications. In contrast, 64% (7/11) of the cases without such indications had interspersed duplications, with 4 subsequently reclassified as likely benign, 2 (likely) pathogenic, and 1 uncertain. These duplications were often complex, involving coduplications or codeletions with other regions. CONCLUSION: Our findings challenge the presumption that intragenic DMD duplications are predominantly in tandem. This highlights the need for a cautious variant interpretation approach, particularly in carrier screening and other settings in which variants are identified without indications of dystrophinopathy.

Humans↗
PubMed1999

Pitfalls in prenatal diagnosis of DMD due to placental mosaicism of the X-chromosomes: prenatal and postnatal findings in a fetus with a deletion of exons 67-71 of the dystrophin gene.

Prenatal diagnosis of Duchenne and Becker muscular dystrophy (DMD) is performed as a routine procedure in many laboratories. The major potential problem is an incorrect diagnosis that could be obtained due to contamination with maternal tissue. We report a case of mosaicism of the X-chromosomes confined to the placenta as a possible source of confusing results in prenatal diagnosis of DMD. To the best of our knowledge, this is the first reported case of this problem in a prenatal DMD diagnosis.

Abortion, Induced↗
PubMed1995

Somatic mosaicism for a DMD gene deletion.

Mosaicism is a mixed state, with two cell populations of different genetic origins caused by a cell mutation occurring after fertilization. In the present case, DNA analysis of lymphocytes led to a DMD diagnosis before death. Postmortem immunocytochemical and DNA analysis showed somatic mosaicism. At age 18 years, blood lymphocyte DNA analysis showed a DMD gene deletion, upstream from exon 7 to the 5' end containing both muscle and brain promoters. As the patient's mother and elder sister had no deletions, he was considered to have a new mutation. Immunocytochemical studies of postmortem tissues showed that dystrophin was absent from the tongue, deltoid, intercostal, psoas and rectus femoris muscles, but there was a mix of dystrophin-positive and negative fibers in the rectus abdominis, cardiac, temporalis and sternocleidomastoid muscles. All diaphragm cells were dystrophin positive. Polymerase chain reaction (PCR) amplification from all tissues except the temporalis and sternocleidomastoid muscles, diaphragm and kidney, in which no deletion was found, showed the deletion from at least exon 6 to the 5' end containing both muscle and brain promoters. In this case, a genomic deletion of the DMD gene contributed to the formation of tissues derived from both ectoderm and endoderm, and cells of mesodermal origin showed genotypic and phenotypic heterogeneity. Our results indicate a mutation of the present case may have occurred just before the period of germ layer formation.

Brain Chemistry↗
PubMed2006

Duplications in the DMD gene.

The detection of duplications in Duchenne (DMD)/Becker Muscular Dystrophy (BMD) has long been a neglected issue. However, recent technological advancements have significantly simplified screening for such rearrangements. We report here the detection and analysis of 118 duplications in the DMD gene of DMD/BMD patients. In an unselected patient series the duplication frequency was 7%. In patients already screened for deletions and point mutations, duplications were detected in 87% of cases. There were four complex, noncontiguous rearrangements, with two also involving a partial triplication. In one of the few cases where RNA was analyzed, a seemingly contiguous duplication turned out to be a duplication/deletion case generating a transcript with an unexpected single-exon deletion and an initially undetected duplication. These findings indicate that for clinical diagnosis, duplications should be treated with special care, and without further analysis the reading frame rule should not be applied. As with deletions, duplications occur nonrandomly but with a dramatically different distribution. Duplication frequency is highest near the 5' end of the gene, with a duplication of exon 2 being the single most common duplication identified. Analysis of the extent of 11 exon 2 duplications revealed two intron 2 recombination hotspots. Sequencing four of the breakpoints showed that they did not arise from unequal sister chromatid exchange, but more likely from synthesis-dependent nonhomologous end joining. There appear to be fundamental differences therefore in the origin of deletions and duplications in the DMD gene.

Cohort Studies↗
PubMed2007

Protein- and mRNA-based phenotype-genotype correlations in DMD/BMD with point mutations and molecular basis for BMD with nonsense and frameshift mutations in the DMD gene.

Straightforward detectable Duchenne muscular dystrophy (DMD) gene rearrangements, such as deletions or duplications involving an entire exon or more, are involved in about 70% of dystrophinopathies. In the remaining 30% a variety of point mutations or "small" mutations are suspected. Due to their diversity and to the large size and complexity of the DMD gene, these point mutations are difficult to detect. To overcome this diagnostic issue, we developed and optimized a routine muscle biopsy-based diagnostic strategy. The mutation detection rate is almost as high as 100% and mutations were identified in all patients for whom the diagnosis of DMD and Becker muscular dystrophy (BMD) was clinically suspected and further supported by the detection on Western blot of quantitative and/or qualitative dystrophin protein abnormalities. Here we report a total of 124 small mutations including 11 nonsense and frameshift mutations detected in BMD patients. In addition to a comprehensive assessment of muscular phenotypes that takes into account consequences of mutations on the expression of the dystrophin mRNA and protein, we provide and discuss genomic, mRNA, and protein data that pinpoint molecular mechanisms underlying BMD phenotypes associated with nonsense and frameshift mutations.

Adolescent↗
PubMed2007

Tandem duplication of DMD exon 18 associated with epilepsy, macroglossia, and endocrinologic abnormalities.

We describe a patient with Duchenne muscular dystrophy (DMD) who additionally suffered from intractable seizures, severe mental retardation, and a marked macroglossia. He also had endocrinologic abnormalities consisting of growth hormone deficiency, delayed puberty, and adrenal hypoplasia. We detected a duplication of DMD exon 18 and flanking introns that caused a frame-shift and was not removed by corrective splicing. A coincident mutation in the FKRP gene was excluded by direct sequencing. Complex DNA rearrangements, deletions, and duplications >100 kb were excluded through microarray-comparative genomic hybridization (CGH), although we were not able to exclude a second coincident mutation with certainty. In conclusion, we present a case of DMD that conflicts with current understanding of genotype-phenotype relations and discuss putative pathogenetic mechanisms for this uncommon phenotype.

Adrenal Insufficiency↗
PubMed1991

X-irradiation improves mdx mouse muscle as a model of myofiber loss in DMD.

The mdx mouse, although a genetic and biochemical homologue of human Duchenne muscular dystrophy (DMD), presents a comparatively mild histopathological and clinical phenotype. These differences are partially attributable to the greater efficacy of regeneration in the mdx mouse than in DMD muscle. To lessen this disparity, we have used a single dose of X-irradiation (16 Gy) to inhibit regeneration in one leg of mdx mice. The result is an almost complete block of muscle fiber regeneration leading to progressive loss of muscle fibers and their replacement by loose connective tissue. Surviving fibers are mainly peripherally nucleated and, surprisingly, of large diameter. Thus, X-irradiation converts mdx muscle to a model system in which the degenerative process can be studied in isolation from the complicating effect of myofiber regeneration. This system should be of use for testing methods of alleviating the myofiber degeneration which is common to mdx and DMD.

Animals↗
PubMed1990

The DMD gene promoter: a potential role in gene therapy.

The studies I've outlined here are obviously at a preliminary stage but do offer some insight into the complexity of DMD gene regulation and do suggest that an understanding of this regulation may have some potential benefit in gene therapy for this disease. The high promoter activity found was unexpected and suggests that in vivo the activity of the endogenous gene may be repressed by elements not present within this region. Of course, other interpretations are possible. The transcripts in vivo may turn over very quickly, or the very large size of the DMD gene may in itself limit the rate of transcription. Alternatively, the gene may be actively transcribed only during the early stages of differentiation. A more detailed analysis of developmental expression and of DNA sequences surrounding exon one is required to address these alternatives, but the possibility for augmenting dystrophin synthesis during myoblast therapy clearly exists. The high level of activity and the tissue and developmental specificity exhibited by the HP2 construct suggest this may be the promoter of choice in future gene therapy experiments. The high degree of specificity shown by this promoter would reduce the need to target gene constructs to muscle cells and would reduce the potential complications of uncontrolled gene expression. Of course, before any of these benefits could be realized much more work must be done both in analysing DMD gene expression and in testing potential gene therapy constructs both in culture and in animal models of this disease.

Chromosome Mapping↗
PubMed2005

A new technique for the quantitative assessment of 8-oxoguanine in nuclear DNA as a marker of oxidative stress. Application to dystrophin-deficient DMD skeletal muscles.

This is the first report on the development of an immunohistochemical technique, combined with quantitative image analysis, for the assessment of oxidative stress quantitatively in nuclear DNA in situ, and its application to measure DNA damage in Duchenne muscular dystrophic (DMD) muscles. Three sequential staining procedures for cell nuclei, a cell marker, and a product of oxidative DNA damage, 8-oxoguanine (8-oxoG), were performed. First, the nuclei in muscle sections were stained with Neutral Red followed by the capture of their images with an image analysis system used for absorbance measurements. Second, the same sections were then immunostained for laminin in basement membranes as the cell marker. Next, the sections were treated with 2 N HCl to remove the bound Neutral Red and to denature tissue DNA. Third, the sections were immunostained for 8-oxoG in DNA, using diaminobenzidine (DAB) to reveal the antibody complex. This was followed by capture of the images of the immunostained sections as previously. The absorbances at 451.2 nm of bound Neutral Red and DAB polymer oxides, the final product of 8-oxoG immunostaining, were measured in the same myonuclei in the sections. Analysis of these absorbances permitted indices of the 8-oxoG content, independent of the nuclear densities, to be determined in nuclear DNA in single myofibres and myosatellite cells surrounded by basement membranes. We found that the mean index for the myonuclei in biceps brachii muscles of 2- to 7-year-old patients was 14% higher than that in age-matched normal controls. This finding of the increased oxidative stress in the myonuclei in young DMD muscles agrees with the previous reports of increased oxidative stress in the cytoplasm in the DMD myofibres and myosatellite cells. The present technique for the quantitative assessment of oxidative stress in nuclear DNA in situ is applicable not only in biomedical research but also in the development of effective drugs for degenerative diseases related to oxidative stress.

Animals↗
PubMed2006

A nonsense mutation-created intraexonic splice site is active in the lymphocytes, but not in the skeletal muscle of a DMD patient.

Production of semi-functional dystrophin mRNA from the dystrophin gene encoding a premature stop codon has been shown to modify the severe phenotype of Duchenne muscular dystrophy (DMD). In this study, we report the tissue-specific production of semi-functional dystrophin mRNA via activation of a nonsense mutation-created intraexonic splice acceptor site. In a DMD patient a novel nonsense mutation was identified in exon 42. In his lymphocytes semi-functional dystrophin mRNA with a 63-nucleotide deletion in exon 42 (dys-63) was found to be produced. In vitro splicing assay using hybrid minigenes disclosed that the mutation-created intraexonic splice acceptor site was activated. In his skeletal muscle cells, however, only the authentically spliced dystrophin mRNA was found. This finding identifies the modulation of the splicing of muscle dystrophin mRNA in cases of DMD as a potential target for therapeutic strategies to generate a milder phenotype for this disease.

Base Sequence↗
PubMed2006

New insights in the regulation of calcium transfers by muscle dystrophin-based cytoskeleton: implications in DMD.

Calcium mishandling in Duchenne muscular dystrophy (DMD) suggested that dystrophin, a membrane-associated cytoskeleton protein, may regulate calcium-signalling cascades such as calcium entries. Calcium overload in human DMD myotubes is dependent on their contractile activity suggesting the involvement of channels being activated during contraction and/or calcium release. Forced expression of mini-dystrophin in dystrophin-deficient myotubes, reactivates appropriate sarcolemmal expression of dystrophin-associated proteins and restores normal calcium handling in the cytosol. Furthermore, the recombinant mini-dystrophin reduced the store-operated calcium influx across the sarcolemma, and the mitochondrial calcium uptake during this influx. A slow component of calcium release dependent on IP3R, as well as the production of IP3, were also reduced to normal levels by expression of mini-dystrophin. Our studies provide a new model for the convergent regulation of transmembrane calcium influx and IP3-dependent calcium release by the dystrophin-based cytoskeleton (DBC). We also suggest molecular association of such channels with DBC which may provide the scaffold for assembling a multiprotein-signalling complex that modulates the channel activity. This suggests that the loss of this molecular association could participate in the alteration of calcium homeostasis observed in DMD muscle cells.

Animals↗
PubMed1978

X-linked recessive (Duchenne) muscular dystrophy (DMD) and purine metabolism: effects of oral allopurinol and adenylate.

Data are presented which suggest that Duchenne muscular dystrophy (DMD) may have some origin in a severe deficiency of total muscle adenine nucleotides. Using double-blind techniques, this possibility was tested in 16 DMD patients by giving oral allopurinol, a synthetic inhibitor of the purine catabolic enzyme xanthine oxidase. Sublingual procaine adenylate was also briefly tested. Instances of clinical improvement quickly occurred which were statistically significant; they were accompanied by a significant increase in physical strength. These improvements have been maintained for more than 6 mo by administration of a small amount of allopurinol daily. Procaine adenylate had little effect. These results support the above view of DMD and seem to indicate that existing purines, retained and recycled after allopurinol, can sustain such improvement, and that additional adenylate is unnecessary.

Adenosine Monophosphate↗
PubMed1988

An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus.

Deletions giving rise to Duchenne muscular dystrophy (DMD) and the less severe Becker muscular dystrophy (BMD) occur in the same large gene on the short arm of the human X chromosome. We present a molecular mechanism to explain the clinical difference in severity between DMD and BMD patients who bear partial deletions of the same gene locus. The model is based on the breakpoints of intragenic deletions and their effect on the translation of triplet codons into amino acids of the protein product. Deletions identified in three DMD patients are shown to shift the translational open reading frame (ORF) of triplet codons for amino acids, and each deletion is predicted to result in a truncated, abnormal protein product. Deletions identified in three BMD patients are shown to maintain the translational ORF for amino acids and predict a shorter, lower molecular weight protein. The smaller protein product is presumed to be semifunctional and to result in a milder clinical phenotype. The same ORF mechanism is also applicable to potential 5' and 3' intron splice mutations and their effect on protein production and clinical phenotype.

Adolescent↗
PubMed1988

Mapping of Xp21 translocation breakpoints in and around the DMD gene by pulsed field gel electrophoresis.

Balanced translocations with a breakpoint in the Xp21 region are likely to disrupt the giant Duchenne muscular dystrophy (DMD) locus and can be demonstrated in females suffering from the disease. Pulsed field gel electrophoresis allows the positioning of these breakpoints by detecting junction fragments on the derived chromosomes; DNA probes hybridizing to these fragments may be located as many as several hundred kilobases away from the breakpoints. By using this approach, 11 translocation breakpoints from the Xp21 region have been analyzed. The localization of three previously examined breakpoints was confirmed. Six other breakpoints, including a breakpoint flanking the DMD gene and not associated with the DMD phenotype, could be positioned relative to SfiI sites on a 3.5-Mb restriction map of the region.

Cell Line↗