title: Regulation of the dopaminergic system in a murine model of aromatic L-amino acid decarboxylase deficiency.
abstract: Aromatic l-amino acid decarboxylase (AADC) is responsible for the syntheses of dopamine and serotonin. Children with AADC deficiency exhibit compromised development, particularly with regard to their motor functions. Currently, no animal model of AADC deficiency exists. We inserted an AADC gene mutation (IVS6+4A>T) and a neomycin-resistance gene into intron 6 of the mouse AADC (Ddc) gene. In the brains of homozygous knock-in (KI) mice (Ddc(IVS6/IVS6)), AADC mRNA lacked exon 6, and AADC activity was <0.3% of that in wild-type mice. Half of the KI mice were born alive but grew poorly and exhibited severe dyskinesia and hindlimb clasping after birth. Two-thirds of the live-born KI mice survived the weaning period, with subsequent improvements in their growth and motor functions; however, these mice still displayed cardiovascular dysfunction and behavioral problems due to serotonin deficiencies. The brain dopamine levels in the KI mice increased from 9.39% of the levels in wild-type mice at 2weeks of age to 37.86% of the levels in wild-type mice at 8weeks of age. Adult KI mice also exhibited an exaggerated response to apomorphine and an elevation of striatal c-Fos expression, suggesting post-synaptic adaptations. Therefore, we generated an AADC deficient mouse model, in which compensatory regulation allowed the mice to survive to adulthood. This mouse model will be useful both for developing gene therapies for AADC deficiency and for designing treatments for diseases associated with neurotransmitter deficiency.
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital and National Taiwan University College of Medicine: 8 Chung-Shan South Road, Taipei 10041, Taiwan. ncleentu@ntu.edu.tw
authors.forename: Ni-Chung
authors.initials: NC
authors.lastname: Lee
authors.forename: Yih-Dar
authors.initials: YD
authors.lastname: Shieh
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Tzen
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.forename: Pin-Wen
authors.initials: PW
authors.lastname: Chen
authors.forename: Min-Hsiu
authors.initials: MH
authors.lastname: Hu
authors.forename: Meng-kai
authors.initials: MK
authors.lastname: Hu
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ichinose
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D020820:Dyskinesias / Q000235:genetics / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D051379:Mice; D017072:Neostriatum / Q000378:metabolism*
chemical_list: D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine