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. 2023 Nov 17:11:148.
doi: 10.12688/f1000research.73476.3. eCollection 2022.

Mutation spectrum analysis of DMD gene in Indonesian Duchenne and Becker muscular dystrophy patients

Ery Kus Dwianingsih  1   2   3 , Kristy Iskandar  1   4   5 , Sunartini Hapsara  4   5 , Chun Ping Liu  6 , Rusdy Ghazali Malueka  1   2   7 , Gunadi  1   2   8 , Masafumi Matsuo  9 , Poh San Lai  6
Affiliations

Mutation spectrum analysis of DMD gene in Indonesian Duchenne and Becker muscular dystrophy patients

Ery Kus Dwianingsih et al. F1000Res. .

Abstract

Background: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the DMD gene. The full mutation spectrum of the DMD gene in Indonesian patients is currently unknown. Mutation-specific therapies are currently being developed, such as exon skipping or stop codon read-through therapy. This study was conducted with the aim of identifying the mutation spectrum of the DMD gene in Indonesia to guide future development and application of feasible therapeutic strategies.

Methods: This study is a cross sectional study that enrolled 43 male patients with a clinical suspicion of DMD or BMD. Multiplex ligation-dependent probe amplification (MLPA) reaction was performed to screen for the common mutations in the DMD gene.

Results: Out of 43 subjects, deletions accounted for 69.77% (n=30) cases, while duplications were found in 11.63% (n=5) cases. One novel duplication spanning exons 2 to 62 was identified. Deletion mutations clustered around the distal (66.67%) and proximal (26.67%) hot spot regions of the DMD gene while duplication mutations were observed solely at the proximal region. Two false positive cases of single exon deletion detected through MLPA were attributed to sequence mutations affecting primer ligation sites, confirming the need to validate all single exon deletions when using this screening method. Analysis of available maternal DNA samples showed that the rate of de novo mutations (48.15%) appears higher than expected in this population. Out of 31 patients who were classified as DMD based on clinical and genotype characterizations, 60.47% (n=26) of cases were suitable for exon skipping therapy.

Conclusion: This is the first comprehensive study showing the feasibility of implementing the MLPA method for routine screening of DMD patients in Indonesia. This is also the first study showing the potential applicability of exon skipping therapy in the majority of DMD cases in the country.

Keywords: Becker muscular dystrophy; DMD gene; Duchenne muscular dystrophy; Indonesia; MLPA; mutation analysis.

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Conflict of interest statement

No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Frequencies of deletion of DMD gene exons in Indonesian Duchenne muscular dystrophy/Becker muscular dystrophy patients (n=28).
Figure 2.
Figure 2.. Distribution pattern of exon deletions in Indonesian Duchenne muscular dystrophy/Becker muscular dystrophy patients (n=28).
Most exon deletions occurred in rod domain of DMD gene. Out-frame deletions indicated in orange boxes, while in-frame deletions indicated in blue boxes.
Figure 3.
Figure 3.. Frequencies of duplication of DMD gene exons in Indonesian Duchenne muscular dystrophy/Becker muscular dystrophy patients (n=5).
Figure 4.
Figure 4.. Distribution pattern of exon duplications in Indonesian Duchenne muscular dystrophy/Becker muscular dystrophy patients (n=5).
All exon duplications occurred in the rod domain of the DMD gene and revealed as out-frame mutations (indicated in orange boxes). In-frame duplication was not detected.
See this image and copyright information in PMC

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