Increased STAG2 dosage defines a novel cohesinopathy with intellectual 
disability and behavioral problems

Kumar, R.; Corbett, M. A.; Van Bon, B. W.; Gardner, A.; Woenig, J. A.; Jolly, L. A.; Douglas, E.; Friend, K.; Tan, C.; Van Esch, H.; Holvoet, M.; Raynaud, M.; Field, M.; Leffler, M.; Budny, B.; Wisniewska, M.; Badura-Stronka, M.; Latos-Bielenska, A.; Batanian, J.; Rosenfeld, J. A.; Basel-Vanagaite, L.; Jensen, C.; Bienek, M.; Froyen, G.; Ullmann, R.; Hu, H.; Love, M. I.; Haas, S. A.; Stankiewicz, P.; Cheung, S. W.; Baxendale, A.; Nicholl, J.; Thompson, E. M.; Haan, E.; Kalscheuer, V. M.; Gecz, J.

doi:10.1093/hmg/ddv414

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学術論文

Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

MPS-Authors

Jensen, C.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Bienek, M.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Hu, H.
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Love, M. I.
IMPRS for Computational Biology and Scientific Computing - IMPRS-CBSC (Kirsten Kelleher), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Haas, S. A.
Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Kalscheuer, V. M.
Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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http://www.ncbi.nlm.nih.gov/pubmed/26443594
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引用

Kumar, R., Corbett, M. A., Van Bon, B. W., Gardner, A., Woenig, J. A., Jolly, L. A., Douglas, E., Friend, K., Tan, C., Van Esch, H., Holvoet, M., Raynaud, M., Field, M., Leffler, M., Budny, B., Wisniewska, M., Badura-Stronka, M., Latos-Bielenska, A., Batanian, J., Rosenfeld, J. A., Basel-Vanagaite, L., Jensen, C., Bienek, M., Froyen, G., Ullmann, R., Hu, H., Love, M. I., Haas, S. A., Stankiewicz, P., Cheung, S. W., Baxendale, A., Nicholl, J., Thompson, E. M., Haan, E., Kalscheuer, V. M., & Gecz, J. (2015). Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems. Human Molecular Genetics, 24(25), 7171-7181. doi:10.1093/hmg/ddv414.

引用: https://hdl.handle.net/11858/00-001M-0000-002A-3AC7-E

要旨

Next generation genomic technologies have made a significant contribution to the understanding of the genetic architecture of human neurodevelopmental disorders. Copy number variants (CNVs) play an important role in the genetics of intellectual disability (ID). For many CNVs, and copy number gains in particular, the responsible dosage-sensitive gene(s) have been hard to identify. We have collected 18 different interstitial microduplications and 1 microtriplication of Xq25. There were 15 affected individuals from 6 different families and 13 singleton cases, 28 affected males in total. The critical overlapping region involved the STAG2 gene, which codes for a subunit of the cohesin complex that regulates cohesion of sister chromatids and gene transcription. We demonstrate that STAG2 is the dosage-sensitive gene within these CNVs, as gains of STAG2 mRNA and protein dysregulate disease-relevant neuronal gene networks in cells derived from affected individuals. We also show that STAG2 gains result in increased expression of OPHN1, a known X-chromosome ID gene. Overall, we define a novel cohesinopathy due to copy number gain of Xq25 and STAG2 in particular.