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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*
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*
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*
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*
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