Mosaic tissue distribution of the tandem duplication of LAMP2 exons 4 and 5 demonstrates the limits of Danon disease cellular and molecular diagnostics
Language English Country United States Media print-electronic
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Adult MeSH
- Gene Duplication * MeSH
- Exons * MeSH
- Phenotype MeSH
- Glycogen Storage Disease Type IIb diagnosis genetics MeSH
- Granulocytes cytology MeSH
- Leukocytes cytology MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Lysosomal-Associated Membrane Protein 2 genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mosaicism MeSH
- Mutation MeSH
- Myocardium pathology MeSH
- Flow Cytometry MeSH
- Pedigree MeSH
- Siblings MeSH
- Tissue Distribution MeSH
- DNA Copy Number Variations MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- LAMP2 protein, human MeSH Browser
- Lysosomal-Associated Membrane Protein 2 MeSH
Alu-mediated tandem duplication of exons 4 and 5 (g.15815_22218dup6404) is a novel mutation that has been detected in the LAMP2 gene (Xq24). This exon copy number variation was found in two brothers with the typical phenotype of Danon disease, including characteristic myocardial changes on magnetic resonance imaging. The 6.4 kb duplication was identified in both boys by a combination of exon dosage qPCR analyses and duplication breakpoint/junction mapping. The rearrangement results in a plethora of abnormal LAMP2 splicing variants and also in use of likely cryptic splice sites in the 3' terminus of LAMP2 gene. Although we found minute amounts of normal LAMP2B and LAMP2A mRNAs, no protein was detectable in peripheral blood leukocytes by flow cytometry in both brothers. Uniquely, the fraction of LAMP2-deficient granulocytes (0.06%) assessed by flow cytometry in the patients' asymptomatic mother substantially differed from the random distribution of X-chromosome inactivation in her leukocytes. This discrepancy was later explained by molecular genetic methods as a consequence of mosaic distribution of the mutation in her somatic tissues. Altogether, we report a novel and mosaically distributed exon copy number rearrangement in the LAMP2 gene and comment on obstacles this genetic setup presents to the overall cellular and molecular diagnostic algorithm of Danon disease. Our observations of the mosaicism in the asymptomatic mother suggest that similarly affected females could be a potentially under-diagnosed Danon disease carrier group and that LAMP2 flow cytometry, because of its supreme sensitivity, can be an efficient method for pedigree screening.
See more in PubMed
Neurology. 1981 Jan;31(1):51-7 PubMed
EMBO J. 2007 Jan 24;26(2):313-24 PubMed
Autophagy. 2013 Mar;9(3):403-9 PubMed
Am J Pathol. 2006 Apr;168(4):1309-20 PubMed
J Cell Biol. 1985 Jul;101(1):85-95 PubMed
Nature. 2000 Aug 24;406(6798):906-10 PubMed
Neurology. 2002 Jun 25;58(12):1773-8 PubMed
Methods. 2001 Dec;25(4):402-8 PubMed
Nature. 2000 Aug 24;406(6798):902-6 PubMed
Gene. 2012 Oct 10;507(2):174-6 PubMed
Cardiology. 2012;121(1):27-30 PubMed
Ann Neurol. 2002 Jul;52(1):122-5 PubMed
Gene. 2012 May 1;498(2):183-95 PubMed
Mol Aspects Med. 2006 Oct-Dec;27(5-6):495-502 PubMed
Biochem Biophys Res Commun. 1995 Oct 13;215(2):757-67 PubMed
Hum Genet. 2001 Jul;109(1):121-4 PubMed
Genet Med. 2011 Jun;13(6):563-8 PubMed
Blood. 2005 Jan 1;105(1):61-6 PubMed
Circ Cardiovasc Genet. 2010 Apr;3(2):129-37 PubMed
J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S115-22 PubMed
J Cell Sci. 2000 Dec;113 Pt 24:4441-50 PubMed
