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Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy
K Yoshida1, A Nakamura, M Yazaki
1Department of Medicine (Neurology) and Division of Clinical Genetics, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. naokosy@gipac.shinshu-u.ac.jp
Insights
Researchers identified a novel L1 insertion in the DMD gene causing X-linked dilated cardiomyopathy (XLDCM) in Japanese patients. This genetic finding clarifies a cause for XLDCM without skeletal muscle issues.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- X-linked dilated cardiomyopathy (XLDCM) is a dystrophinopathy primarily affecting the heart.
- The genetic basis for XLDCM, particularly cardiospecific mutations in the DMD gene, requires further elucidation.
Purpose of the Study:
- To identify the pathogenic mutations responsible for XLDCM in Japanese patients.
- To investigate the correlation between identified DMD mutations and the XLDCM phenotype.
Main Methods:
- Genetic analysis of three XLDCM patients from two unrelated Japanese families.
- Characterization of a novel de novo L1 insertion in muscle exon 1 of the DMD gene.
Main Results:
- A unique, 5'-truncated L1 insertion was identified in the 5'-untranslated region of muscle exon 1 in the DMD gene.
- This insertion selectively impacted the transcription or stability of muscle dystrophin transcripts, sparing brain and Purkinje cell forms.
Conclusions:
- The identified L1 insertion in the DMD gene is a likely cause of XLDCM in a subset of Japanese patients.
- This finding provides a specific genetic mechanism for XLDCM presenting without overt skeletal myopathy.
Abstract:
X-linked dilated cardiomyopathy (XLDCM) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt clinical signs of skeletal myopathy. To date, several mutations in the Duchenne muscular dystrophy gene, DMD , have been identified in patients with XLDCM, but a pathogenic correlation of these cardiospecific mutations in DMD with the XLDCM phenotype has remained to be elucidated. We report here the identification of a unique de novo L1 insertion in the muscle exon 1 in DMD in three XLDCM patients from two unrelated Japanese families. The insertion was a 5'-truncated form of human L1 inversely integrated in the 5'-untranslated region in the muscle exon 1, which affected the transcription or the stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form, probably due to its unique site of integration. We speculate that this insertion of an L1 sequence in DMD is responsible for some of the population of Japanese patients with XLDCM.