title: Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice.
abstract: A new spontaneous mouse mutant was characterized by closed eyelids at weaning and without apparent eyes (provisional gene name, eyeless; provisional gene symbol, eyl). The mutation follows a recessive pattern of inheritance and was mapped to the region of chromosome 19 containing Pitx3. Genetic complementation tests using Pitx3 ( ak/+ ) mice confirmed eyl as a new allele of Pitx3 (Pitx3 ( eyl )). Sequencing of the Pitx3 gene in eyl mutants identified an inserted G after cDNA position 416 (416insG; exon 4). The shifted open reading frame is predicted to result in a hybrid protein still containing the Pitx3 homeobox, but followed by 121 new amino acids. The novel Pitx3 ( eyl/eyl ) mutants expressed ophthalmological and brain defects similar to Pitx3 ( ak/ak ) mice: microphthalmia or anophthalmia and loss of dopamine neurons of the substantia nigra. In addition, we observed in the homozygous eyeless mutants increased extramedullary hematopoiesis in the spleen, frequently liver steatosis, and reduced body weight. There were also several behavioral changes in the homozygous mutants, including reduced forelimb grip strength and increased nociception. In addition to these alterations in both sexes, we observed in female Pitx3 ( eyl/eyl ) mice increased anxiety-related behavior, reduced locomotor activity, reduced object exploration, and increased social contacts; however, we observed decreased anxiety-related behavior and increased arousal in males. Most of these defects identified in the new Pitx3 mutation are observed in Parkinson patients, making the Pitx3 ( eyl ) mutant a valuable new model. It is the first mouse mutant carrying a point mutation within the coding region of Pitx3.
authors.affiliation: Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rosemann
authors.forename: Alesia
authors.initials: A
authors.lastname: Ivashkevich
authors.forename: Jack
authors.initials: J
authors.lastname: Favor
authors.forename: Claudia
authors.initials: C
authors.lastname: Dalke
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Ildikó
authors.initials: I
authors.lastname: Rácz
authors.forename: Ines
authors.initials: I
authors.lastname: Bolle
authors.forename: Martina
authors.initials: M
authors.lastname: Klempt
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Svetoslav
authors.initials: S
authors.lastname: Kalaydjiev
authors.forename: Thure
authors.initials: T
authors.lastname: Adler
authors.forename: Antonio
authors.initials: A
authors.lastname: Aguilar
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Marion
authors.initials: M
authors.lastname: Horsch
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Julia
authors.initials: J
authors.lastname: Calzada-Wack
authors.forename: Sandra
authors.initials: S
authors.lastname: Kunder
authors.forename: Beatrix
authors.initials: B
authors.lastname: Naton
authors.forename: Valerie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Holger
authors.initials: H
authors.lastname: Schulz
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: J Peter H
authors.initials: JP
authors.lastname: Burbach
authors.forename: Marten P
authors.initials: MP
authors.lastname: Smidt
authors.forename: Leticia
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Markus
authors.initials: M
authors.lastname: Ollert
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.forename: Martin Hrabé
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Michael
authors.initials: M
authors.lastname: Atkinson
authors.forename: Ulrich
authors.initials: U
authors.lastname: Heinzmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000853:Anophthalmos / Q000235:genetics; D001483:Base Sequence; D001522:Behavior, Animal; D015519:Bone Density; D001847:Bone Diseases / Q000235:genetics / Q000503:physiopathology; D002874:Chromosome Mapping; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D008171:Lung Diseases / Q000235:genetics / Q000503:physiopathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains / Q000235:genetics*; D008850:Microphthalmos / Q000235:genetics*; D008969:Molecular Sequence Data; D010146:Pain / Q000235:genetics*; D020734:Parkinsonian Disorders / Q000235:genetics*; D017354:Point Mutation; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; D014446:Tyrosine 3-Monooxygenase