Miriam Meisler, Ph.D.

Michigan Neuroscience Institute Affiliate
Myron Levine Distinguished University Professor
Professor of Human Genetics
Professor of Neurology

4808 Med Sci II
1241 E. Catherine St. SPC 5618
Ann Arbor, MI 48109-5618

734-763-5546

Areas of Interest

My laboratory studies human genetic disorders and mouse models 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 identifying a novel splice factor (Science, 2004). Analysis of an engineered mouse model led to the 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 600 patient mutations have since been identified. We have generated a mouse model that recapitulates the seizures and sudden death and examined cardiac and neuronal function in the mice and pharmacological responses to new and standard anti-epileptic drugs. We also functionally characterized ten 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 the 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 both human and mouse subjects. 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

  • Basic Science Research Award,  American Epilepsy Society (2020)
  • Outstanding Scientist Award, EBS, University of Michigan (2020)
  • Rackham Distinguished Graduate Mentor Award, University of Michigan (2017)
  • Distinguished University Professor, University of Michigan (2011)

Credentials

  • Ph.D., Ohio State University, Biological Chemistry (1968)
  • B. A., Queens College, CUNY. B. A., Chemistry and Biology (1963)

Published Articles or Reviews

  • 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.

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