Areas of Interest
My laboratory studies human genetic disorders and mouse models that are relevant to human health. We use classical and molecular genetics to investigate neurological disorders related to phosphoinositol metabolism and sodium channel function. We initially discovered the sodium channel SCN8A/Nav1.6 by positional cloning of a transgene-induced mutant (Nature Genet. 1995). We generated a floxed allele to study the contribution of this channel to the firing patterns of specific types of neurons. Positional cloning of a modifier of an SCN8A splice site mutation led to identification of a novel splice factor (Science, 2004). Analysis of an engineered mouse model led to identification of epileptogenic mutations of human SCN1A (Nat. Genet., 2000), now known to be the most common genetic cause of epilepsy, with more than 1250 known mutations. In 2012, we identified the first human mutation of sodium channel SCN8A in epileptic encephalopathy (EIEE13) (Am. J. Hum. Genet.) and more than 150 patient mutations have since been identified. We have generated a mouse model which recapitulates the seizures and sudden death, and examined cardiac and neuronal function in the mice, as well as pharmacological responses to new and standard anti-epileptic drugs. We also functionally characterized 10 de novo patient mutations in transfected cells, demonstrating a variety of gain-of-function mechanisms. Positional cloning of a spontaneous mouse mutation in the FIG4 gene was the starting point for identification of its causal role in Charcot-Marie-Tooth disease (Nature, 2007). We subsequently identified FIG4 mutations in two other disorders, Yunis-Varón Syndrome (Am. J. Hum. Genet.) and Polymicrogyria with seizures (Neurology). We characterized the pathogenic mechanisms of several mutant alleles of FIG4, PIKFYVE and VAC14 affecting PI(3,5)P2 biosynthesis in human and mouse. Most recently, we identified the first human mutations of VAC14 in two unrelated children with sudden onset of neurological decline. More than 30 predoctoral and postdoctoral trainees have participated in the research.
Honors & Awards
2020 Basic Science Research Award, American Epilepsy Society2016 Outstanding Scientist Award, EBS, University of Michigan
2017 Rackham Distinguished Graduate Mentor Award, University of Michigan
2011 Distinguished University Professor, University of Michigan
2005 Distinguished Biomedical Faculty Lectureship, University of Michigan
2001 AAAS Fellow
1997-99 President, International Mammalian Genetics Society
1995 Sarah Goddard Power Award, University of Michigan
1993 Distinguished Faculty Achievement Award, University of Michigan
1975 Basil O Connor Scholar Award, March of Dimes
1968 Ph. D. Ohio State University, Biological Chemistry
1963 B. A. Queens College, CUNY. B. A., Chemistry and Biology
Lenk, GM, Jafar-Nejad P, Hill SF, Huffman L, Smolen C, Wagnon JL, Petit, H, Giger, R, Rigo F, Meisler MH (2020) Antisense oligonucleotide therapy delays seizure onset and extends survival in a mouse model of SCN8A encephalopathy. Ann. Neurol. 87:339-346.
Yu, W, Hill SF, Xenakis JG, Pardo-Manuel de Villena, F, Wagon JL and Meisler MH. (2020) Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse. Epilepsia 61:2847-2856.
Bunton-Stasyshyn RKA, Wagnon JL, Wengert ER, Barker BS, Faulkner A, Wagley PK, Bhatia K, Jones JM, Maniaci MR, Parent JM, Goodkin HP, Patel MK, Meisler MH (2019) Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. Brain 142: 362-375.
Solé L, Wagnon JL, Akin AJ, Meisler, MH and Tamkun MM (2019) The MAP1B binding domain of Nav1.6 is required for stable expression at the axon initial segment. J. Neurosci 39:4238-4251, 2019.
Wengert ER, Cathrine E. Tronhjem CE, Jacy L. Wagnon JL, Katrine M Johannesen KM, Petit H, Krey I, Anusha I, Saga U, Panchal PS, Strohm SM, Lange J, Kamphausen SB, Rubboli, G Lemke JR, Gardella E,PatelMK, Meisler MH, Møller RS. (2019) Biallelic inherited variants of SCN8A are a rare cause of epileptic encephalopathy. Epilepsia 60:2277-2285.
Wagnon JL, Barker BS, Hounshell, Haaxma C, Shealy A, Moss T, Parikh S, Messer, RD, Patel MK and Meisler MH (2015a) Pathogenic mechanisms of recurrent epileptogenic mutations of SCN8A in epileptic encephalopathy. Annals of Clinical and Translational Neurology. DOI 10.1002/acn3.276.
Wagnon JL, Korn MJ, Parent R, Tarpey TA, Jones JM, Hammer MF, Murphy GG, Parent JM and Meisler MH (2015b) Convulsive seizures and SUDEP in a mouse model of SCN8A related epileptic encephalopathy, Human Molec.Genet. 24:506-516.