Abstract. Background: Multiple system atrophy (MSA) is a sporadic disease. Its pathogenesis may involve multiple genetic and nongenetic factors, but its etiology remains largely unknown. We hypothesized that the genome of a patient with MSA would demonstrate copy number variations (CNVs) in the genes or genomic regions of interest. To identify genomic alterations increasing the risk for MSA, we examined a pair of monozygotic (MZ) twins discordant for the MSA phenotype and 32 patients with MSA. Results: By whole-genome CNV analysis using a combination of CNV beadchip and comparative genomic hybridization (CGH)-based CNV microarrays followed by region-targeting, high-density, custom-made oligonucleotide tiling microarray analysis, we identified disease-specific copy number loss of the (Src homology 2 domain containing)-transforming protein 2 (SHC2) gene in the distal 350-kb subtelomeric region of 19p13.3 in the affected MZ twin and 10 of the 31 patients with MSA but not in 2 independent control populations (p = 1.04 × 10-8, odds ratio = 89.8, Pearson's chi-square test). Conclusions: Copy number loss of SHC2 strongly indicates a causal link to MSA. CNV analysis of phenotypically discordant MZ twins is a powerful tool for identifying disease-predisposing loci. Our results would enable the identification of novel diagnostic measure, therapeutic targets and better understanding of the etiology of MSA. © 2011 Sasaki et al; licensee BioMed Central Ltd.
CITATION STYLE
Sasaki, H., Emi, M., Iijima, H., Ito, N., Sato, H., Yabe, I., … Matsubara, K. (2011). Copy number loss of (src homology 2 domain containing)-transforming protein 2 (SHC2) gene: Discordant loss in monozygotic twins and frequent loss in patients with multiple system atrophy. Molecular Brain, 4(1). https://doi.org/10.1186/1756-6606-4-24
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