LAMP2 Microdeletions in Patients With Danon Disease
| Autor: | Matteo Vatta, Brandy H. Westerfield, Yuxin Fan, Brenda Wong, Zhao Yang, Jaquelin Varela, Ronald J. Kanter, G. Wesley Vick, Birgit Funke, Linda H. Cripe, Debora Mancini-Dinardo, Jeffrey A. Towbin, Liana S. Peña |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male Adolescent Biology Article Electrocardiography Exon Lysosomal-Associated Membrane Protein 2 Genetics medicine Humans Danon disease Genetics (clinical) Sequence Deletion Southern blot Chromosomes Human X LAMP2 Breakpoint Intron Lysosome-Associated Membrane Glycoproteins Exons medicine.disease Molecular biology Glycogen Storage Disease Type IIb genomic DNA RNA splicing Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation: Cardiovascular Genetics. 3:129-137 |
| ISSN: | 1942-3268 1942-325X |
| DOI: | 10.1161/circgenetics.109.901785 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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