title: A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.
abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.
authors.affiliation: German Mouse Clinic, Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany.
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Mary
authors.initials: M
authors.lastname: Stromberg
authors.forename: Marina
authors.initials: M
authors.lastname: Kovalenko
authors.forename: Lillian
authors.initials: L
authors.lastname: Garrett
authors.forename: Lisa
authors.initials: L
authors.lastname: Glasl
authors.forename: Edith
authors.initials: E
authors.lastname: Lopez
authors.forename: Jolene
authors.initials: J
authors.lastname: Guide
authors.forename: Alexander
authors.initials: A
authors.lastname: Götz
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Anja
authors.initials: A
authors.lastname: Schrewed
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wursta
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Hiroko
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Jonathan
authors.initials: J
authors.lastname: Seidman
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Susan
authors.initials: S
authors.lastname: Cotman
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
mesh_terms: D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001341:Autonomic Nervous System / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal; D002318:Cardiovascular Diseases / Q000473:pathology / Q000503:physiopathology; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000378:metabolism; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D007858:Learning; D008168:Lung / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009043:Motor Activity; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D045442:Rotarod Performance Test; D012903:Smell; D012919:Social Behavior; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D005947:Glucose