LAMP2 Microdeletions in Patients With Danon Disease
- 1 April 2010
- journal article
- case report
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation: Cardiovascular Genetics
- Vol. 3 (2), 129-137
- https://doi.org/10.1161/circgenetics.109.901785
Abstract
Background—Danon disease is an X-linked dominant disorder characterized by the clinical triad of hypertrophic cardiomyopathy, skeletal myopathy, and variable mental retardation. Pathologically, autophagic vacuoles are noted in both skeletal and cardiac muscle. It exhibits an X-linked dominant mode of inheritance, and male carriers are severely affected, whereas female carriers develop milder and later-onset cardiac symptoms. Danon disease has been associated with mutations in the lysosome-associated membrane glycoprotein 2 (LAMP2) gene located at Xq24, typically resulting in splicing defects or protein truncation affecting the LAMP2. Because of its rarity, the full spectrum of genetic mutation resulting in Danon disease has not been elucidated.Methods and Results—We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selectedLAMP2exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novelAlu-mediated 34-kb microdeletion encompassing the entire 5′-untranslated region and exon 1 ofLAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)nsimple repeats present in intron 3, which determined a 64-kb and a 58-kb deletion, respectively, thereby ablating exons 4 to 10. Western blot analysis confirmed the absence of LAMP2 in protein extract from lymphocytes of index case 2.Conclusion—This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.Keywords
This publication has 38 references indexed in Scilit:
- Danon disease: Case report and detection of new mutationJournal of Inherited Metabolic Disease, 2009
- Molecular analysis of PRKAG2, LAMP2, and NKX2‐5 genes in a cohort of 125 patients with accessory atrioventricular connectionAmerican Journal of Medical Genetics Part A, 2009
- Cardiovascular magnetic resonance findings in a case of Danon diseaseJournal of Cardiovascular Magnetic Resonance, 2009
- Danon disease: A novel LAMP2 mutation affecting the pre-mRNA splicing and causing aberrant transcripts and partial protein expressionNeuromuscular Disorders, 2008
- Molecular mimicry in pauci-immune focal necrotizing glomerulonephritisNature Medicine, 2008
- Premature ovarian failure in a patient with a complex chromosome rearrangement involving the critical region Xq24, characterized by analysis using fluorescence in situ hybridization by chromosome microdissectionFertility and Sterility, 2007
- Danon Disease as a Cause of Autophagic Vacuolar MyopathyCongenital Heart Disease, 2007
- Danon disease presenting with dilated cardiomyopathy and a complex phenotypeJournal of Human Genetics, 2007
- Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2geneEuropean Journal of Pediatrics, 2005
- Breakpoint analysis of the pericentric inversion distinguishing human chromosome 4 from the homologous chromosome in the chimpanzee (Pan troglodytes)Human Mutation, 2004