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Fulltext Detection of gene deletions by PCR analysis in a Malaysian patient with Duchenne muscular dystrophy

Lee MK, Manonmani V, Arahata K

Med J Malaysia, 1993 Mar;48(1):46-50.
PMID: 8341171

Duchenne muscular dystrophy (DMD), the commonest X-linked disorder, is a progressive, eventually fatal disease. With the advent of molecular genetics, the Duchenne gene and its protein product, dystrophin, have been characterised. Molecular diagnosis of DMD, identification of carriers and antenatal diagnosis are now possible. We describe here the use, in a Malaysian boy with DMD, of a recent innovation, multiplex polymerase chain reaction (PCR), to obtain molecular diagnosis by detection of dystrophin gene deletions.

Matched MeSH terms: Dystrophin/genetics*; Dystrophin/isolation & purification
What are the effects of treatments used to prevent or treat heart complications in Duchenne muscular dystrophy, Becker muscular dystrophy, and X-linked dilated cardiomyopathy? A Cochrane Review summary with commentary

Patrick Engkasan J, Chan SC

Dev Med Child Neurol, 2020 07;62(7):776-777.
PMID: 32427344 DOI: 10.1111/dmcn.14568
Matched MeSH terms: Dystrophin
Fulltext Screening of dystrophin gene deletions in Malaysian patients with Duchenne muscular dystrophy

Marini M, Salmi AA, Watihayati MS, SMardziah MD, Zahri MK, Hoh BP, et al.

Med J Malaysia, 2008 Mar;63(1):31-4.
PMID: 18935728 MyJurnal

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive genetic disorder characterized by rapidly progressive muscle weakness. The disease is caused by deletion, duplication or point mutation of the dystrophin gene, located on the X chromosome (Xp21). Deletion accounts for 60% of the mutations within the 79 exons of the dystrophin gene. Seven exons (43, 44, 45, 46, 49, 50, and 51) were found to be most commonly deleted among the Asian patients. To detect the frequency of deletion of these 7 exons in Malaysian DMD patients, we carried out a molecular genetic analysis in 20 Malaysian DMD patients. The mean age of initial presentation was 60 months (SD 32 months, range 5-120 months). Fourteen patients were found to have deletion of at least one of the seven exons. The remaining six patients did not show any deletion on the tested exons. Deletions of exons 49, 50 and 51 were the most frequent (71.43%) and appear to be the hot spots in our cohort of patients.

Matched MeSH terms: Dystrophin/genetics*
Two closely spaced nonsense mutations in the DMD gene in a Malaysian family

Rani AQ, Malueka RG, Sasongko TH, Awano H, Lee T, Yagi M, et al.

Mol Genet Metab, 2011 Jul;103(3):303-4.
PMID: 21514860 DOI: 10.1016/j.ymgme.2011.04.002

In Duchenne muscular dystrophy (DMD), identification of one nonsense mutation in the DMD gene has been considered an endpoint of genetic diagnosis. Here, we identified two closely spaced nonsense mutations in the DMD gene. In a Malaysian DMD patient two nonsense mutations (p.234S>X and p.249Q>X, respectively) were identified within exon 8. The proband's mother carried both mutations on one allele. Multiple mutations may explain the occasional discrepancies between genotype and phenotype in dystrophinopathy.

Matched MeSH terms: Dystrophin/genetics*
Genetic polymorphism in DTNBP1 gene is associated with methamphetamine-induced panic disorder

Sim MS, Hatim A, Diong SH, Mohamed Z

J Addict Med, 2014 Nov-Dec;8(6):431-7.
PMID: 25303981 DOI: 10.1097/ADM.0000000000000075

The dysbindin-1 (dystrobrevin-binding protein-1 [DTNBP-1]) gene has repeatedly been shown to be associated with psychotic disorder across diverse populations. In this study, we attempted to investigate the association of the rs3213207 (P1635) genetic polymorphism of the DTNBP1 gene with methamphetamine dependence and with methamphetamine-induced psychosis, manic episodes, and panic disorder in a male Malaysian population.

Matched MeSH terms: Dystrophin-Associated Proteins/genetics*
Mutation spectrum of dystrophin gene in malaysian patients with Duchenne/Becker muscular dystrophy

Rani AQ, Sasongko TH, Sulong S, Bunyan D, Salmi AR, Zilfalil BA, et al.

J. Neurogenet., 2013 Jun;27(1-2):11-5.
PMID: 23438214 DOI: 10.3109/01677063.2012.762580

We undertook the clinical feature examination and dystrophin analysis using multiplex ligation-dependent probe amplification (MLPA) and direct DNA sequencing of selected exons in a cohort of 35 Malaysian Duchenne/Becker muscular dystrophy (DMD/BMD) patients. We found 27 patients with deletions of one or more exons, 2 patients with one exon duplication, 2 patients with nucleotide deletion, and 4 patients with nonsense mutations (including 1 patient with two nonsense mutations in the same exon). Although most cases showed compliance to the reading frame rule, we found two unrelated DMD patients with an in-frame deletion of the gene. Two novel mutations have been detected in the Dystrophin gene and our results were compatible with other studies where the majority of the mutations (62.8%) are located in the distal hotspot. However, the frequency of the mutations in our patient varied as compared with those found in other populations.

Matched MeSH terms: Dystrophin/genetics*
Genetic disruption of the inflammasome adaptor ASC has minimal impact on the pathogenesis of Duchenne muscular dystrophy in mdx mice

Lau YS, Zhao L, Zhang C, Li H, Han R

Life Sci, 2020 Jul 10.
PMID: 32659370 DOI: 10.1016/j.lfs.2020.118069

AIM: Up-regulation of inflammasome proteins was reported in dystrophin-deficient muscles. However, it remains to be determined whether inflammasome activation plays a role in the pathogenesis of Duchenne muscular dystrophy. This study was therefore set out to investigate whether genetic disruption of the inflammasome pathway impacts the disease progression in mdx mice.
MAIN METHODS: Mice deficient in both dystrophin and ASC (encoded by Pycard [PYD And CARD Domain Containing]) were generated. The impact of ASC deficiency on muscular dystrophy of mdx mice were assessed by measurements of serum cytokines, Western blot, real-time PCR and histopathological staining.
KEY FINDINGS: The pro-inflammatory cytokines such as TNF-α, IL-6, KC/GRO and IL-10 were markedly increased in the sera of 8-week-old mdx mice compared to WT. Western blotting showed that P2X7, caspase-1, ASC and IL-18 were upregulated. Disruption of ASC and dystrophin expression in the mdx/ASC-/- mice was verified by Western blot analysis. Histopathological analysis did not find significant alterations in the muscular dystrophy phenotype in mdx/ASC-/- mice as compared to mdx mice.
SIGNIFICANCE: Taken together, our results show that disruption of the central adaptor ASC of the inflammasome is insufficient to alleviate muscular dystrophy phenotype in mdx mice.

Matched MeSH terms: Dystrophin
Fulltext Four nucleotide deletions of exon 47 in Dystrophin gene: a case report of a Kelantanese Duchenne Muscular Dystrophy patient

Fatimah Azman, Rose Adzrianee Adnan, Norhafizah Che Abdul Razak, Nazihah Mohd Yunus, Sarina Sulong, Rozita Abdullah, et al.

Journal of Biomedical and Clinical Sciences, 2017;2(202):11-13.
MyJurnal

Muscular dystrophy is a group of diseases that result in progressive muscle weakness and atrophy. Duchenne Muscular Dystrophy (DMD) is classified as dystrophinopathy and is an X-linked recessive disease. It is caused by alterations in the dystrophin gene at Xp21.2 encoding 79 exons [1]. It is characterised by progressive muscle wasting that begins at 3 to 5 years, delay in motor development and eventually wheelchair confinement followed by premature death at about 30 years from cardiac or respiratory complications [2]. Genetic etiology of cases of DMD in Malaysia are still scarcely reported. Here, we report the genetic cause in the case of an 11-year-old Kelantanese Malay boy who has progressive muscle weakness since 5 years old. He has difficulty in getting up from sitting and supine position also in climbing up stairs until 1st floor. He has a strong family history of DMD and musculoskeletal problems. His younger brother was diagnosed with DMD by molecular analysis and his maternal uncle died at the age of 16 with musculoskeletal problems but was never investigated. Physical examination revealed no dysmorphic features, positive Gower sign with absent tounge fasciculation. On neurological examination, tendon reflexes and muscle tone for limbs were normal. Muscle power for bilateral upper limbs were normal, however, bilateral lower limbs showed slight reduction in muscle power with calf hypertrophy.

Matched MeSH terms: Dystrophin
Therapeutic potential of combined viral transduction and CRISPR/Cas9 gene editing in treating neurodegenerative diseases

Kuruvilla J, Sasmita AO, Ling APK

Neurol Sci, 2018 Nov;39(11):1827-1835.
PMID: 30076486 DOI: 10.1007/s10072-018-3521-0

BACKGROUND AND PURPOSE: The central nervous system (CNS) faces unique difficulties in attaining permanent therapy for neurodegenerative disorder (ND). Genomic level forms of therapy have garnered interest in the recent decade, with the novel CRISPR/Cas9 gene editing tool continuing to be explored due to its efficiency, safety, and adaptability to varying conditions. With the aid of viral vectors as transport vectors, the gene editing tool has produced promising in vitro and in vivo findings in study models. Thus, this review focuses on the recent advancements and update of CRISPR/Cas9 to combat neurodegenerative diseases.
METHODS: Articles detailing potential applications of CRISPR/Cas9 in neurodegenerative settings were retrieved from PubMed and Google Scholar with the keywords "CRISPR," "gene editing," and "neurodegenerative diseases." Relevant information was collected and critically reviewed.
RESULTS: The utility of CRISPR/Cas9 coupled with viral transduction ranges from the disruption of amyloid precursor protein (APP) production at a genomic level in Alzheimer's disease (AD) to the deletion of varying exon portions of the Dmd gene in Duchenne muscular dystrophy (DMD) which would increase dystrophin expression. This usage of CRISPR/Cas9 also extends to experimentally ameliorate the neurodegenerative effects caused by viral infections.
CONCLUSION: The CRISPR/Cas9 gene editing tool is a powerful arsenal in the field of gene therapy and molecular medicine; hence, more research should be called to focus on the ample potential this tool has to offer in the field of neurodegenerative diseases.

Matched MeSH terms: Dystrophin
Fulltext Dystrophin gene expression and intracellular calcium changes in the giant freshwater prawn, Macrobrachium rosenbergii, in response to white spot symptom disease infection

Noor AF, Soo TCC, Ghani FM, Goh ZH, Khoo LT, Bhassu S

Heliyon, 2017 Dec;3(12):e00446.
PMID: 29322096 DOI: 10.1016/j.heliyon.2017.e00446

Background: Dystrophin, an essential protein functional in the maintenance of muscle structural integrity is known to be responsible for muscle deterioration during white spot syndrome virus (WSSV) infection among prawn species. Previous studies have shown the upregulation of dystrophin protein in Macrobrachium rosenbergii (the giant freshwater prawn) upon white spot syndrome virus (WSSV) infection. The literature has also suggested the important role of calcium ion alterations in causing such muscle diseases. Thus, the interest of this study lies within the linkage between dystrophin functioning, intracellular calcium and white spot syndrome virus (WSSV) infection condition.
Methods: In this study, the dystrophin gene from M. rosenbergii (MrDys) was first characterised followed by the characterization of dystrophin gene from a closely related shrimp species, Penaeus monodon (PmDys). Dystrophin sequences from different phyla were then used for evolutionary comparison through BLAST analysis, conserved domain analysis and phylogenetic analysis. The changes in mRNA expression levels of dystrophin and the alteration of intracellular calcium concentrations in WSSV infected muscle cells were then studied.
Results: A 1246 base pair long dystrophin sequence was identified in the giant freshwater prawn, Macrobrachium rosenbergii (MrDys) followed by 1082 base pair long dystrophin sequence in P. monodon (PmDys). Four conserved domains were identified from the thirteen dystrophin sequences compared which were classified into 5 different phyla. From the phylogenetic analysis, aside from PmDys, the characterised MrDys was shown to be most similar to the invertebrate phylum of Nematoda. In addition, an initial down-regulation of dystrophin gene expression followed by eventual up-regulation, together with an increase in intracellular calcium concentration [Ca2+]
i
were shown upon WSSV experimental infection.
Discussion: Both the functionality of the dystrophin protein and the intracellular calcium concentration were affected by WSSV infection which resulted in progressive muscle degeneration. An increased understanding of the role of dystrophin-calcium in MrDys and the interactions between these two components is necessary to prevent or reduce occurrences of muscle degeneration caused by WSSV infection, thereby reducing economic losses in the prawn farming industry from such disease.

Matched MeSH terms: Dystrophin
Fulltext Perturbation of PI3K/Akt signaling affected autophagy modulation in dystrophin-deficient myoblasts

Yazid MD, Hung-Chih C

Cell Commun Signal, 2021 10 27;19(1):105.
PMID: 34706731 DOI: 10.1186/s12964-021-00785-0

BACKGROUND: The absence of dystrophin has gave a massive impact on myotube development in Muscular Dystrophy pathogenesis. One of the conserved signaling pathways involved in skeletal muscle differentiation is the PI3K/Akt/mTOR pathway that plays a vital role in autophagy regulation. To further understand and establish targeted therapy in dystrophin-deficient myoblasts, protein expression profiling has been determined which provides information on perturbed autophagy modulation and activation.
METHODS: In this study, a dystrophin-deficient myoblast cell line established from the skeletal muscle of a dystrophic (mdx) mouse was used as a model. The dfd13 (dystrophin-deficient) and C2C12 (non-dystrophic) myoblasts were cultured in low mitogen conditions for 10 days to induce differentiation. The cells were subjected to total protein extraction prior to Western blotting assay technique. Protein sub-fractionation has been conducted to determine protein localization. The live-cell analysis of autophagy assay was done using a flow cytometer.
RESULTS: In our culture system, the dfd13 myoblasts did not achieve terminal differentiation. PTEN expression was profoundly increased in dfd13 myoblasts throughout the differentiation day subsequently indicates perturbation of PI3K/Akt/mTOR regulation. In addition, rictor-mTORC2 was also found inactivated in this event. This occurrence has caused FoxO3 misregulation leads to higher activation of autophagy-related genes in dfd13 myoblasts. Autophagosome formation was increased as LC3B-I/II showed accumulation upon differentiation. However, the ratio of LC3B lipidation and autophagic flux were shown decreased which exhibited dystrophic features.
CONCLUSION: Perturbation of the PTEN-PI3K/Akt pathway triggers excessive autophagosome formation and subsequently reduced autophagic flux within dystrophin-deficient myoblasts where these findings are of importance to understand Duchenne Muscular Dystrophy (DMD) patients. We believe that some manipulation within its regulatory signaling reported in this study could help restore muscle homeostasis and attenuate disease progression. Video Abstract.

Matched MeSH terms: Dystrophin/genetics