Jennifer A. Kearney, Ph.D.,
Research in our laboratory is focused on studying genetic modifiers of neurological disease. Within Mendelian disorders there can be considerable variability in the clinical phenotype among family members carrying the same mutation. This variable expressivity may be due to differences in the inheritance of genetic modifier alleles. The role of genetic modifiers in influencing clinical severity has become increasingly important for understanding disease susceptibility and pathophysiology. Variable expressivity is a common feature in patients with inherited epilepsy caused by sodium channel mutations, since family members carrying the same mutation often exhibit differences in the clinical severity. We are studying genetic modifiers of epilepsy using mouse models with mutations in voltage-gated sodium channels. Currently, we are working on positional cloning of modifier loci in mice with primary mutations in the voltage-gated sodium channels Scn1a and Scn2a. We are also developing and characterizing new mouse knock-in models with human epilepsy mutations targeted in the mouse Scn1a locus. Isolation of susceptibility genes will contribute to understanding the molecular events of epileptogenesis and may suggest novel targets for the treatment of human epilepsy.
Hawkins, NA, Martin, MS, Frankel, WN, Kearney, JA, Escayg, A. Neuronal voltage-gated ion channels are genetic modifiers of generalized epilepsy with febrile seizures plus. Neurobiology of Disease, [Epub ahead of print: doi: 10.1016/j.nbd.2010.11.016], 2010.
Wang, D.W., Mistry, A.M., Kahlig, K.M., Kearney, J.A., Xiang, J., George, A.L. Propranolol Blocks Cardiac and Neuronal Voltage-gated Sodium Channels. Frontiers in Pharmacology of Ion Channel and Channelopathies, in press, 2010.
Bergren, SK, Rutter, ED, Kearney, JA. Fine mapping of an epilepsy modifier gene on mouse chromosome 19. Mamm Genome, 20(6):359-366, 2009.
Holland, KD, Kearney, JA, Glauser, TA, Buck, G, Keddache, M, Blankston, J, Glaaser, I, Kass, RS, Meisler, MH. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neuroscience Letters, 433:65-70, 2008.
Kearney, JA, Wiste, AK, Stephani, U, Trudeau, MM, Siegel, A, RamachandranNair, R, Elterman, RD, Muhle, H, Reinsdorf, J, Shields, WD, Meisler, MH, Escayg, A. Recurrent de novo mutations of SCN1A in severe myoclonic epilepsy of infancy. Pediatr Neurol, 34(2), 116-20, 2006.
Kearney, JA, Yang, Y, Beyer, B, Bergren, SK, Claes, L, Dejonghe, P, Frankel, WN. Severe epilepsy resulting from genetic interaction between Scn2a and Kcnq2. Hum Mol Genet, 15(6), 1043-8, 2006.
Levin, SI, Khaliq, ZM, Aman, TK, Grieco, TM, Kearney, JA, Raman, IM, Meisler, MH. Impaired motor function in mice with cell-specific knockout of sodium channel Scn8a (NaV1.6) in cerebellar purkinje neurons and granule cells. J Neurophysiol, 96(2), 785-93, 2006.
Bergren, SK, Chen, S, Galecki, A, Kearney, JA. Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channel Scn2a. Mamm Genome, 16(9), 683-90, 2005.
Meisler, MH, Kearney, JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest, 115(8), 2010-7, 2005.
Turnbull, J, Lohi, H, Kearney, JA, Rouleau, GA, Delgado-Escueta, AV, Meisler, MH, Cossette, P, Minassian, BA. Sacred disease secrets revealed: the genetics of human epilepsy. Hum Mol Genet, 14 Spec No. 2, 2491-2500, 2005.
Spampanato, J, Kearney, JA, de Haan, G, McEwen, DP, Escayg, A, Aradi, I, MacDonald, BT, Levin, SI, Soltesz, I, Benna, P, Montalenti, E, Isom, LL, Goldin, AL, Meisler, MH. A novel epilepsy mutation in the sodium channel SCN1A identifies a cytoplasmic domain for beta subunit interaction. J Neurosci, 24(44), 10022-34, 2004.
Weiss, LA, Escayg, A, Kearney, JA, Trudeau, M, MacDonald, BT, Mori, M, Reichert, J, Buxbaum, JD, Meisler, MH. Sodium channels SCN1A, SCN2A and SCN3A in familial autism. Mol Psychiatry, 8(2), 186-94, 2003.
Kearney, JA, Buchner, DA, De Haan, G, Adamska, M, Levin, SI, Furay, AR, Albin, RL, Jones, JM, Montal, M, Stevens, MJ, Sprunger, LK, Meisler, MH. Molecular and pathological effects of a modifier gene on deficiency of the sodium channel Scn8a (Na(v)1.6). Hum Mol Genet, 11(22), 2765-75, 2002.
Meisler, MH, Kearney, JA, Sprunger, LK, MacDonald, BT, Buchner, DA, Escayg, A. Mutations of voltage-gated sodium channels in movement disorders and epilepsy. Novartis Found Symp, 241, 72-81; discussion 82-6, 226-32, 2002.
Kearney, JA, Plummer, NW, Smith, MR, Kapur, J, Cummins, TR, Waxman, SG, Goldin, AL, Meisler, MH. A gain-of-function mutation in the sodium channel gene Scn2a results in seizures and behavioral abnormalities. Neuroscience, 102(2), 307-17, 2001.
Meisler MH, Kearney J, Escayg A, MacDonald BT, Sprunger LK. Sodium channels and neurological disease: insights from Scn8a mutations in the mouse. The Neuroscientist, 7, 136-145, 2001.
Meisler MH, Kearney J, Ottman R, Escayg A. Recent progress in identification of epilepsy genes in human and mouse. Annual Review of Genetics, 35, 567-588, 2001.
Albin, RL, Kearney, JA. Alessandro Agnoli Lecture. Models of basal ganglia dysfunction: predictions and pitfalls. Funct Neurol, 15(3), 135-46, 2000.
Kearney, JA, Albin, RL. Intrasubthalamic nucleus metabotropic glutamate receptor activation: a behavioral, Fos immunohistochemical and [14C]2-deoxyglucose autoradiographic study. Neuroscience, 95(2), 409-16, 2000.
Escayg, A, Jones, JM, Kearney, JA, Hitchcock, PF, Meisler, MH. Calcium channel beta 4 (CACNB4): human ortholog of the mouse epilepsy gene lethargic. Genomics, 50(1), 14-22, 1998.