Laboratory for Neurogenetics

The objective of our laboratory is to understand the molecular pathomechanisms of neurological diseases including epilepsy, autism, and mental retardation, and to develop diagnostic methods and therapies for those diseases. To do this, we are identifying and characterizing the genes responsible for those diseases by suing more than 4000 patients' materials, developing animal disease models, and testing therapeutic methodologies including gene therapy. The epilepsy project includes juvenile myoclonic epilepsy and sodium channelopathy such as generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) that associates with severe mental decline. We also analyzing cases with epilepsy associated with autism by using full genome analyses. The mental retardation project includes Down syndrome that is the most frequent mental retardation and is caused by trisomy 21. We are characterizing partial trisomy 16 mice as DS animal models, analyzing histological, immunohistochemical, biochemical, behavioral abnormalities and testing potential therapies.

Research Subjects

• Investigation of the pathomechanism of Down syndrome
• Investigation of epilepsy and autism by identification and characterization of responsible genes

Publications

1. Amano K, Fujii M, Arata S, Tojima T, Ogawa M, Shimohata A, Furuichi T, Itohara S, Kamiguchi H, Korenberg J.R, Arata A, Yamakawa K.
   "DSCAM deficiency causes loss of pre-inspiratoru neuron synchroneity and perinatal death."
   The Journal of Neuroscience 29:2984-2996(2009).
2. Suzuki T, Miyamoto H, Nakahari T, Inoue I, Suemoto T, Jiang B, Hirota Y, Itohara S, Saido TC, Tsumoto T, Sawamoto K, Hensch TK, Delgado-Escueta AV, and Yamakawa K.
   "Efhc1 deficiency causes spontaneous myoclonus and increased seizure susceptibility."
   Human Molecular Genetics 18:1099-1109(2009).
3. Ogiwara I, Miyamoto H, Morita N, Atapour N, Mazaki E, Inoue I, Takeuchi T, Itohara S, Yanagawa Y, Obata K, Furuichi T, Hensch TK, Yamakawa K.
   "Nav1.1 Localizes to Axons of Parvalbumin-Positive Inhibitory Interneurons: a Circuit Basis for Epileptic Seizures in Mice Carrying an Scn1a Gene Mutation"
   The Journal of Neuroscience 27(22):5903-5914(2007).
4. Shukkur EA, Shimohata A, Akagi T, Yu W, Yamaguchi M, Murayama M, Chui D, Takeuchi T, Amano K, Harve Subramhanya K, Hashikawa T, Sago H, Epstein CJ, Takashima A, Yamakawa K.
   "Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome"
   Human Molecular Genetics 15: 2752-2762(2006).
5. Suzuki, T., Delgado-Escueta, AV., Aguan, K., Alonso, ME., Shi, J., Hara, Y., Nishida, M., Numata, T., Medina, MT., Takeuchi, T., Morita, R., Bai, D., Ganesh, S., Sugimoto, Y., Inazawa, J., Bailey, JN., Ochoa, A., Jara-Prado, A., Rasmussen, A., Ramos-Peek,Cordova S, Rubio-Donnadieu F, Inoue Y, Osawa M, Kaneko S, Oguni H, Mori Y, Yamakawa K
   "Mutations in EFHC1 cause juvenile myoclonic epilepsy"
   Nature Genettics 36, 842-849 (2004).
6. Amano, K., Sago, H., Uchikawa, C., Suzuki, T., Kotliarova, SE., Nukina, N., Epstein, CJ., and Yamakawa, K.
   "Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome"
   Human Molecular Genetics 13, 1333-1340 (2004).
7. Kamiya, K., Kaneda, M., Sugawara, T., Mazaki, E., Okamura, N., Montal, M., Makita, N., Tanaka, M., Fukushima, K., Fujiwara, T., Inoue, Y., and Yamakawa, K.
   "A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline"
   The Journal of Neuroscience 24, 2690-2698 (2004).
8. Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y, Akagi T, Gomi H, Suzuki T, Amano K, Agarwala KL, Hasegawa Y, Bai D-S, Ishihara T, Hashikawa T, Itohara S, Cornford EM, Niki H, Yamakawa K
   "Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration , ataxia, myoclonus epilepsy and impaired behavioral response in mice."
   Human Molecular Genetics 11:1251-1262 (2002)
9. Ganesh S, Delgado-Escueta AV, Suzuki T, Francheschetti S, Riggio C, Avanzini G, Rabinowicz A, Bohlega S, Bailey J, Alonso ME, Rasmussen A, Thomson AE, Ochoa A, Prado AJ, Medina MT, Yamakawa K
   "Genotype-phenotype correlations for EPM2A mutations in Lafora's progressive myoclonus epilepsy: Exon 1 mutations associate with an early onset cognitive deficit subphenotype."
   Human Molecular Genetics 11:1263-1271 (2002)
10. Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, Nagafuji H, Noda M, Imoto K, Wada K, Mitsudome A, Kaneko S, Montal M, Nagata K, Hirose S, Yamakawa K
    "A missense mutation of the Na+ channel subunit gene Nav1.2 in a patient with febrile and afebrile seizures causes channel dysfunction."
    Proc. Natl. Acad. Sci. USA 98: 6384-6389 (2001)