title: LAMP2 microdeletions in patients with Danon disease.
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.
  
  
  RESULTS
  We analyzed 3 male cases with clinical and pathological findings consistent with Danon disease. Comprehensive mutational analysis failed to yield detectable products for selected LAMP2 exons, and genomic DNA deletion was suspected. Genomic junction fragment polymerase chain reaction analysis in case 1 identified a novel Alu-mediated 34-kb microdeletion encompassing the entire 5'-untranslated region and exon 1 of LAMP2. In case 2 and 3, junctional polymerase chain reaction and Southern blot analyses mapped the breakpoint to an MIRb and (TA)(n) simple 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.
  
  
  CONCLUSIONS
  This article is the first report of Danon disease caused by microdeletions at Xq24, which functionally ablate LAMP2. The microdeletion mechanism appears to involve 1 Alu-mediated unequal recombination and 2 chromosomal breakage points involving TA-rich repeat sequences.
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: Birgit H
authors.initials: BH
authors.lastname: Funke
authors.forename: Linda H
authors.initials: LH
authors.lastname: Cripe
authors.forename: G Wesley
authors.initials: GW
authors.lastname: Vick
authors.forename: Debora
authors.initials: D
authors.lastname: Mancini-Dinardo
authors.forename: Liana S
authors.initials: LS
authors.lastname: Peña
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Kanter
authors.forename: Brenda
authors.initials: B
authors.lastname: Wong
authors.forename: Brandy H
authors.initials: BH
authors.lastname: Westerfield
authors.forename: Jaquelin J
authors.initials: JJ
authors.lastname: Varela
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Fan
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
mesh_terms: D000293:Adolescent; D000328:Adult; D041321:Chromosomes, Human, X; D004562:Electrocardiography; D005091:Exons; D052120:Glycogen Storage Disease Type IIb / Q000235:genetics*; D006801:Humans; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008297:Male; D017384:Sequence Deletion
chemical_list: C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins