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
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
2011 Distinguished University Professor, University of Michigan
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 LD, Smolen CE, Wagnon JL, Petit H, Yu W, Ziobro J, Bhatia K, Parent J, Giger RJ, Rigo F, Meisler MH. Scn8a antisense oligonucleotide is protective in mouse models of SCN8A Encephalopathy and Dravet Syndrome. Ann Neurol. 2020 Jan 14. doi: 10.1002/ana.25676. [Epub ahead of print] PMID: 31943325
Baulac S, Lenk GM, Dufresnois B, Bencheikh BOA, Couarch P, Renard R, Larson PA, Ferguson CJ, Noé E, Poirier K, Hubans C, Ferreira S, Guerrini R, Ouazzani R, El Hachimi KH, Meisler MH and Leguern L (2014) Role of phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria. Neurology 82:1068-75.
Estacion M, O'Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD and Meisler MH (2014) A novel de novo mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiology of Disease 69:117-23, PMCID:PMC4124819
de Kovel CGF, Meisler MH, Brilstra EH, van Berkestijn FM, van 't Slo R, van Lieshout S, Nijman IJ, O'Brien JE; Hammer MF, Estacion M, Waxman SG, Dib-Hajj SD, Koeleman BP (2014) Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Research 108:1511-1521.
Wagnon JL, Korn MJ, Parent R, Tarpey TA, Jones JM, Hammer MF, Murphy GG, Parent JM and Meisler MH (2015) Convulsive seizures and SUDEP in a mouse model of SCN8A related epileptic encephalopathy,Human Molec.Genet.24:506-51
Vaccari I, Carbone A, Previtali SC, Mironova YA, Alberizzi V, Noseda R, Rivellini C, Bianchi F, Del Carro U, D’Antonio M, Lenk GM, Wrabetz L, Giger RJ, Meisler MH, Bolino A (2015) Loss of Fig4 in both Schwann cells and motor neurons contributes to CMT4J neuropathy. Human Molecular Genetics 24:383-396.
Blanchard, MG, Willemsen MH, Walker JB, Dib-Hajj SD, Waxman SG, Jongmans, MCJ, Kleefstra T, van de Warrenburg, BP, Praamstra, P, Nicolai, J, Yntema, HG, Bindels RJM, Meisler MH and Kamsteeg E-J (2015) De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsies. J. Med. Genet. 52:330-337.
Pal D, Jones JM, Wisidagamage S, Meisler MH and Mashour GA (2015) Reduced Nav1.6 sodium channel activity in mice increases in vivo sensitivity to volatile anesthetics. PLOS ONE.
Wagnon JL, Barker BS, Hounshell, Haaxma C, Shealy A, Moss T, Parikh S, Messer, RD, Patel MK and Meisler MH (2016) Pathogenic mechanisms of recurrent epileptogenic mutations of SCN8A in epileptic encephalopathy. Annals of Clinical and Translational Neurology 3:114-123.
Lenk GM, Frei CM, Miller AC, Wallen RC, Mironova YA, Giger RJ, Meisler MH (2016) Rescue of neurodegeneration in the Fig4 null mouse by a catalytically inactive FIG4 transgene.Hum Mol Genet 25:340-347.
Mironova YA, Lenk GM, Lin J-P, Min SH, Abrams CS, Corey JM, Kawaguchi R, Coppola G, Havton L, Twiss J, Shrager P, Meisler MH, Giger RJ (2016) The PI(3,5)P2 Biosynthetic Complex Regulates Intrinsic and Extrinsic Mechanisms of Oligodendrocyte Differentiation and Axon Myelination. eLife Mar 23 PMID 27008179
Jones JM, Dionne L, Dell’Orco J, Parent R, Krueger JN, Cheng X, Dib-Hajj SD, Bunton-Stasyshyn RK, Sharkey LM, Dowling JJ, Murphy GG, Shakkottai VG, Shrager P, Meisler MH (2016) Single amino acid deletion in transmembrane segment DIVS6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol. Disease 89:36-45.
He F, Jones JM, Figueroa-Romero C, Zhang DP, Feldman EL, Goutman SA, Meisler MH and Todd PK (2016) Screening for novel G4C2 hexanucleotide repeat expansions at ALS and FTD-associated loci. Neurology Genetics 2:e71.
Lenk GM, Szymanska K, Debska-Vielhaber G, Rydzanicz M, Walczak A, Bekiesinska- Figatowska M, Vielhaber S, Kerstin Hallmann K, Stawinski P, Buehring S, Hsu DA, Kunz WS, Meisler MH* and Rafal Ploski (2016) Biallelic mutations of VAC14 in pediatric onset neurological disease. Am. J. Hum. Genet. 99:188-194.
Barker B, Ottolini M, Wagnon JL, Hollander R, Meisler MH and Patel M (2016) The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin. Epilepsia 57:1458-1466.
Frasier CR, Wagnon JL, Bao Y, McVeigh L, Lopez-Santiago L, Meisler MH and Isom LL (2016) Cardiac arrhythmia in a mouse model of SCN8A Epileptic Encephalopathy. PNAS 113:12838-12843.
Sprissler RS, Wagnon JL, Bunton-Stasyshyn RK, Meisler MH, Michael F. Hammer MF (2016) Altered gene expression profile in a mouse model of Scn8a epilepsy reveals reactive astrocytosis in response to seizures. Exptl. Neurol. 288:134-141.
Meisler MH, Helman G, Hammer MF, Fureman BE, Gaillard WD, Goldin AL, Hirose S, Ishii A, Kroner BL, Lossin C, Mefford HC, Parent JM, Patel M, Schreiber J, Stewart R, Whittemore V, Wilcox K, Wagnon JL, Pearl PL, Vanderver A, Scheffer IE (2016) SCN8A Encephalopathy: Research Progress and Prospects. Epilepsia, 57:1027-35