IncreasedSTAG2dosage defines a novel cohesinopathy with intellectual disability and behavioral problems
| Autor: | Martine Raynaud, Raman Kumar, Hilde Van Esch, C Jensen, Bartlomiej Budny, Magdalena Badura-Stronka, Michael I. Love, Guy Froyen, Lachlan A. Jolly, Bregje W.M. van Bon, Jill A. Rosenfeld, Lina Basel-Vanagaite, M Bienek, Alison Gardner, Jillian Nicholl, Sau Wai Cheung, Elizabeth Thompson, Jozef Gecz, Anne Baxendale, Anna Latos-Bielenska, C Tan, Joshua A. Woenig, Stefan A. Haas, Mark A. Corbett, Marzena Wisniewska, Maureen Holvoet, Evelyn Douglas, Eric Haan, Michael Field, Kathryn Friend, Melanie Leffler, Jacqueline R. Batanian, Hao Hu, Pawel Stankiewicz, Reinhard Ullmann, Vera M. Kalscheuer |
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| Rok vydání: | 2015 |
| Předmět: |
Male
DNA Copy Number Variations Cohesin complex Gene regulatory network Cell Cycle Proteins Biology Genome Intellectual Disability Intellectual disability Genetics medicine Humans Copy-number variation Molecular Biology Gene Genetics (clinical) X chromosome Problem Behavior Chromosomes Human X Reverse Transcriptase Polymerase Chain Reaction Antigens Nuclear General Medicine medicine.disease Genetic architecture Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] |
| Zdroj: | Human Molecular Genetics, 24, 7171-81 Human Molecular Genetics, 24, 25, pp. 7171-81 Human Molecular Genetics |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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 one 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. ispartof: Human Molecular Genetics vol:24 issue:25 pages:7171-81 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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