Microphthalmia, parkinsonism, and enhanced nociception in Pitx3 ( 416insG ) mice.
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.
Rosemann
Michael
M
Institute of Radiation Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Ivashkevich
Alesia
A
Favor
Jack
J
Dalke
Claudia
C
Hölter
Sabine M
SM
Becker
Lore
L
Rácz
Ildikó
I
Bolle
Ines
I
Klempt
Martina
M
Rathkolb
Birgit
B
Kalaydjiev
Svetoslav
S
Adler
Thure
T
Aguilar
Antonio
A
Hans
Wolfgang
W
Horsch
Marion
M
Rozman
Jan
J
Calzada-Wack
Julia
J
Kunder
Sandra
S
Naton
Beatrix
B
Gailus-Durner
Valerie
V
Fuchs
Helmut
H
Schulz
Holger
H
Beckers
Johannes
J
Busch
Dirk H
DH
Burbach
J Peter H
JP
Smidt
Marten P
MP
Quintanilla-Martinez
Leticia
L
Esposito
Irene
I
Klopstock
Thomas
T
Klingenspor
Martin
M
Ollert
Markus
M
Wolf
Eckhard
E
Wurst
Wolfgang
W
Zimmer
Andreas
A
de Angelis
Martin Hrabé
MH
Atkinson
Michael
M
Heinzmann
Ulrich
U
Graw
Jochen
J
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
D050483:Dopamine Plasma Membrane Transport Proteins; D018398:Homeodomain Proteins; D014446:Tyrosine 3-Monooxygenase