A gene-targeted mouse model for chorea-acanthocytosis.
Chorea-acanthocytosis (CHAC) is a hereditary neurodegenerative disorder with autosomal recessive transmission, in which selective degeneration of striatum has been reported in brain pathology. Clinically, CHAC shows Huntington's disease-like neuropsychiatric symptoms and red blood cell acanthocytosis. Recently, we identified the gene, CHAC, encoding a novel protein, chorein, in which a deletion mutation was found in Japanese families with CHAC. In the present study, we have identified the mouse CHAC cDNA sequence and the exon-intron structures of the gene and produced a CHAC model mouse introducing no. 60-61 exon deletion corresponding to a human disease mutation by a gene-targeting technique. The mice began to show acanthocytosis and motor disturbance in old age. In behavioral observations, locomotor activity was significantly decreased and the contact time at social interaction test was decreased significantly in the model mice. In the brain pathology, many apoptotic cells were observed in the striatum of the mutant mice. In neurochemical determinations, the dopamine metabolite, homovanillic acid, concentration decreased significantly in the portion including the midbrain of the mutant mice. These findings are consistent with the human results reported elsewhere and indicate that the CHAC model mice showed a mild phenotype with late adult onset. The CHAC model mouse therefore provides a good model system to study the human disease.
Tomemori
Yuko
Y
Department of Psychiatry, Kagoshima University Graduate School of Medical and Ental Sciences, Kagoshima, Japan.
Ichiba
Mio
M
Kusumoto
Akira
A
Mizuno
Emiko
E
Sato
Daisuke
D
Muroya
Shinji
S
Nakamura
Masayuki
M
Kawaguchi
Hiroaki
H
Yoshida
Hiroki
H
Ueno
Shu-ichi
S
Nakao
Kazuki
K
Nakamura
Kenji
K
Aiba
Atsu
A
Katsuki
Motoya
M
Sano
Akira
A
D000050:Acanthocytes / Q000473:pathology; D000818:Animals; D002819:Chorea / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D013577:Syndrome; D033921:Vesicular Transport Proteins
D018076:DNA, Complementary; D009419:Nerve Tissue Proteins; D011506:Proteins; C429654:VPS13A protein, human; D033921:Vesicular Transport Proteins; C497828:Vps13a protein, mouse