title: Genetic dissection of the Down syndrome critical region.
abstract: Down syndrome (DS), caused by trisomy 21, is the most common chromosomal disorder associated with developmental cognitive deficits. Despite intensive efforts, the genetic mechanisms underlying developmental cognitive deficits remain poorly understood, and no treatment has been proven effective. The previous mouse-based experiments suggest that the so-called Down syndrome critical region of human chromosome 21 is an important region for this phenotype, which is demarcated by Setd4/Cbr1 and Fam3b/Mx2. We first confirmed the importance of the Cbr1-Fam3b region using compound mutant mice, which carry a duplication spanning the entire human chromosome 21 orthologous region on mouse chromosome 16 [Dp(16)1Yey] and Ms1Rhr. By dividing the Setd4-Mx2 region into complementary Setd4-Kcnj6 and Kcnj15-Mx2 intervals, we started an unbiased dissection through generating and analyzing Dp(16)1Yey/Df(16Setd4-Kcnj6)Yey and Dp(16)1Yey/Df(16Kcnj15-Mx2)Yey mice. Surprisingly, the Dp(16)1Yey-associated cognitive phenotypes were not rescued by either deletion in the compound mutants, suggesting the possible presence of at least one causative gene in each of the two regions. The partial rescue by a Dyrk1a mutation in a compound mutant carrying Dp(16)1Yey and the Dyrk1a mutation confirmed the causative role of Dyrk1a, whereas the absence of a similar rescue by Df(16Dyrk1a-Kcnj6)Yey in Dp(16)1Yey/Df(16Dyrk1a-Kcnj6)Yey mice demonstrated the importance of Kcnj6. Our results revealed the high levels of complexities of gene actions and interactions associated with the Setd4/Cbr1-Fam3b/Mx2 region as well as their relationship with developmental cognitive deficits in DS.
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jiang
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Liu
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Physiology and Pathophysiology, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Department of Physiology and Pathophysiology, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Meng
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and.
authors.forename: Pavel V
authors.initials: PV
authors.lastname: Belichenko
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Kleschevnikov
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Pao
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Peresie
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wie
authors.affiliation: Department of Neurosciences, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA and.
authors.forename: William C
authors.initials: WC
authors.lastname: Mobley
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA, Genetics, Genomics and Bioinformatics Program, Department of Cellular and Molecular Biology, Roswell Park Division of Graduate School,State University of New York at Buffalo, Buffalo, NY 14263, USA yuejin.yu@roswellpark.org.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Yu
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D003072:Cognition Disorders / Q000235:genetics*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D017384:Sequence Deletion