Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice

Michael Roseman, Alesia Ivashkevich, Jack Favor, Claudia Dalke, S M Holter, Lore Becker, Ildiko Racz, Ines Bolle, Martina Kempt, Birgit Rathkolb, Svetoslav Kalaydjiev, Thure Adler, Antonio Aguilar, Wolfgang Hans, Marion Horsch, Jan Rozman, Julia Calzada-Wack, Sandra Kunder, Beatrix Naton, Valerie Gailus-DurnerHelmut Fuchs, Holger Scholz, Johannes Beckers, Dirk Busch, J Peter Burbach, Marten Smidt, Leticia Quintanilla-Martinez, Irene Esposito, Thomas Klopstock, Martin Klingenspor, Markus Ollert, Eckhard Wolf, W Wurst, Andreas Zimmer, Martin de Angelis, Michael Atkinson, Ulrich Heinzmann, Jochem Graw

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32 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)13 - 27
Number of pages15
JournalMammalian Genome
Issue number1-2
Publication statusPublished - 2010
Externally publishedYes

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