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

Mol Brain. 2011 Jun 10;4:24. doi: 10.1186/1756-6606-4-24.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Gene Dosage*
  • Genetic Testing
  • Genome, Human
  • Humans
  • Male
  • Middle Aged
  • Multiple System Atrophy / genetics*
  • Oligonucleotide Array Sequence Analysis
  • Phenotype
  • Shc Signaling Adaptor Proteins*
  • Src Homology 2 Domain-Containing, Transforming Protein 2
  • Twins, Monozygotic / genetics*

Substances

  • SHC2 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 2