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A family with Danon disease caused by a splice site mutation in LAMP2 that generates a truncated protein
Nianwei Zhou1, Jie Cui2, Weipeng Zhao1
1Department of Echocardiography, Zhongshan Hospital, Shanghai Institute of Cardiovascular Disease, Shanghai Institute of Medical Imaging, Fudan University, Shanghai, China.
Background:
Danon disease is an X-linked dominant hereditary condition caused by mutations in the gene encoding lysosomal-associated membrane protein 2 (LAMP2), leading to failure of lysosome binding to autophagosomes, accumulation of glycogen in the heart, and abnormal cardiac function.
Methods:
We describe identification of a mutation in LAMP2, c.741+1G>T, in a family with Danon disease by whole exome sequencing.
Results:
Pathology examination of patient skeletal muscle biopsy showed myogenic damage and autophagic vacuoles with sarcolemmal features (AVSF). Numerous autophagic vacuoles accumulated in muscle cells were detected by electron microscopy, indicating abnormal autophagy function.
Conclusion:
The mutation did not result in loss of mRNA exons; rather, a 6-nucleotide (two-codon) insertion, where the latter was a stop codon, leading to early termination of LAMP2 protein translation. The resulting truncated protein lacks an important transmembrane domain, which will impair lysosome/autophagosome fusion, damage autophagy function, and result in the clinical manifestations of Danon disease.
Insights
Danon disease, a genetic disorder affecting the heart, is caused by a specific mutation in the LAMP2 gene. This mutation disrupts protein function, leading to abnormal autophagy and cardiac issues.
Area of Science:
- Genetics
- Molecular Biology
- Cell Biology
Background:
- Danon disease is an X-linked dominant disorder caused by LAMP2 gene mutations.
- It leads to impaired lysosome-autophagosome fusion, glycogen accumulation in the heart, and cardiac dysfunction.
Observation:
- Whole exome sequencing identified a novel LAMP2 mutation (c.741+1G>T) in a Danon disease family.
- Skeletal muscle biopsies revealed myogenic damage and numerous autophagic vacuoles with sarcolemmal features (AVSF).
Findings:
- The identified mutation caused a 6-nucleotide insertion, including a stop codon, leading to premature termination of LAMP2 protein.
- This resulted in a truncated LAMP2 protein lacking a critical transmembrane domain.
Implications:
- The truncated LAMP2 protein impairs lysosome-autophagosome fusion and autophagy.
- This molecular defect underlies the pathogenesis of Danon disease, explaining its cardiac manifestations.
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