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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.

Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K - Mol Brain (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. h-isasak@med.hokudai.ac.jp

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.

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Related in: MedlinePlus

Structure of copy number loss in the 350-kb subtelomeric region on 19p13.3 resolved by high-density tiling microarray. The moving average log2 ratio (y-axis) is plotted against the genomic position along the chromosome (x-axis). HK06, HK12, HK15, HK19, HK23, and HK28 represent 6 patients with MSA and HK60c and HK78c represent controls. The dark lines indicate the copy number loss. The light lines and dotted lines indicate the normal range and median of the average log2 ratios for probes among normal individuals (n = 25), respectively.
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Figure 4: Structure of copy number loss in the 350-kb subtelomeric region on 19p13.3 resolved by high-density tiling microarray. The moving average log2 ratio (y-axis) is plotted against the genomic position along the chromosome (x-axis). HK06, HK12, HK15, HK19, HK23, and HK28 represent 6 patients with MSA and HK60c and HK78c represent controls. The dark lines indicate the copy number loss. The light lines and dotted lines indicate the normal range and median of the average log2 ratios for probes among normal individuals (n = 25), respectively.

Mentions: After confirming the absence of statistical differences in age and gender distribution, we further analyzed the distal 350-kb region showing copy number loss on the 19p subtelomere in the 33 patients with MSA against an additional set of 25 control subjects (second set of controls, Table 1) by using the same custom-made tiling array as for the MZ twins. Again, we found frequent heterozygous copy number loss in this region in 10 of the 33 patients but not in any of the 25 control subjects. Figure 4 demonstrates the moving average pattern of the distal 350-kb region with copy number loss on 19p13.3 in 6 of the 10 patients, and Figure 5 shows a deletion map of this region in the 10 patients.


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.

Sasaki H, Emi M, Iijima H, Ito N, Sato H, Yabe I, Kato T, Utsumi J, Matsubara K - Mol Brain (2011)

Structure of copy number loss in the 350-kb subtelomeric region on 19p13.3 resolved by high-density tiling microarray. The moving average log2 ratio (y-axis) is plotted against the genomic position along the chromosome (x-axis). HK06, HK12, HK15, HK19, HK23, and HK28 represent 6 patients with MSA and HK60c and HK78c represent controls. The dark lines indicate the copy number loss. The light lines and dotted lines indicate the normal range and median of the average log2 ratios for probes among normal individuals (n = 25), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3141657&req=5

Figure 4: Structure of copy number loss in the 350-kb subtelomeric region on 19p13.3 resolved by high-density tiling microarray. The moving average log2 ratio (y-axis) is plotted against the genomic position along the chromosome (x-axis). HK06, HK12, HK15, HK19, HK23, and HK28 represent 6 patients with MSA and HK60c and HK78c represent controls. The dark lines indicate the copy number loss. The light lines and dotted lines indicate the normal range and median of the average log2 ratios for probes among normal individuals (n = 25), respectively.
Mentions: After confirming the absence of statistical differences in age and gender distribution, we further analyzed the distal 350-kb region showing copy number loss on the 19p subtelomere in the 33 patients with MSA against an additional set of 25 control subjects (second set of controls, Table 1) by using the same custom-made tiling array as for the MZ twins. Again, we found frequent heterozygous copy number loss in this region in 10 of the 33 patients but not in any of the 25 control subjects. Figure 4 demonstrates the moving average pattern of the distal 350-kb region with copy number loss on 19p13.3 in 6 of the 10 patients, and Figure 5 shows a deletion map of this region in the 10 patients.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan. h-isasak@med.hokudai.ac.jp

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.

Show MeSH
Related in: MedlinePlus