title: Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome.
abstract: Using Down syndrome as a model for complex trait analysis, we sought to identify loci from chromosome 21q22.2 which, when present in an extra dose, contribute to learning abnormalities. We generated low-copy-number transgenic mice, containing four different yeast artificial chromosomes (YACs) that together cover approximately 2 megabases (Mb) of contiguous DNA from 21q22.2. We subjected independent lines derived from each of these YAC transgenes to a series of behavioural and learning assays. Two of the four YACs caused defects in learning and memory in the transgenic animals, while the other two YACs had no effect. The most severe defects were caused by a 570-kb YAC; the interval responsible for these defects was narrowed to a 180-kb critical region as a consequence of YAC fragmentation. This region contains the human homologue of a Drosophila gene, minibrain, and strongly implicates it in learning defects associated with Down syndrome.
authors.affiliation: Human Genome Center, Lawrence Berkeley National Laboratory, California 94720, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Smith
authors.forename: M E
authors.initials: ME
authors.lastname: Stevens
authors.forename: S P
authors.initials: SP
authors.lastname: Sudanagunta
authors.forename: R T
authors.initials: RT
authors.lastname: Bronson
authors.forename: M
authors.initials: M
authors.lastname: Makhinson
authors.forename: A M
authors.initials: AM
authors.lastname: Watabe
authors.forename: T J
authors.initials: TJ
authors.lastname: O'Dell
authors.forename: J
authors.initials: J
authors.lastname: Fung
authors.forename: H U
authors.initials: HU
authors.lastname: Weier
authors.forename: J F
authors.initials: JF
authors.lastname: Cheng
authors.forename: E M
authors.initials: EM
authors.lastname: Rubin
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000473:pathology; D018244:Chromosomes, Artificial, Yeast; D004314:Down Syndrome / Q000235:genetics*; D004594:Electrophysiology; D005123:Eye / Q000473:pathology; D018628:Gene Dosage; D006801:Humans; D007858:Learning / Q000502:physiology*; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D008969:Molecular Sequence Data; D009043:Motor Activity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011505:Protein-Tyrosine Kinases; D012689:Sequence Homology, Nucleic Acid; D019076:Transgenes; D000097603:Dyrk Kinases
chemical_list: D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases