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In the Meisler Lab we investigate genetic variation and diversity using the resources of the mouse and human genomes. Currently, we are focused on understanding the molecular mechanisms underlying neurological disease. Mouse genetics provides an entre into human neurological disease through the generation of new mouse models as well as the study of spontaneous mouse mutants. Mouse mutants that we have characterized include wobbler, flailer, mnd2, pale tremor, doubleridge, infantile gliosis, and med (motor endplate disease).

The goal of our laboratory is to elucidate the molecular mechanisms underlying inherited neurological disorders and to evaluate therapeutic interventions. We have generated several mouse models with knock-in of patient mutations that reproduce the human pathophysiology, with a focus on mutations of the sodium channel gene SCN8A (Nav1.6) in developmental encephalopathy and disorders of phosphoinositide biosynthesis such as Charcot-Marie-Tooth Syndrome. We are currently evaluating antisense oligos (ASOs) as an intervention for gain-of-function sodium channel mutations, and identification of modifier genes as alternative therapeutic targets.

Current projects:

• Evaluation of candidate genes for neuropsychiatric disease

• Functional characterization of Scnm1, a putative mRNA splicing factor and modifier in mice

• Role of the endocytic pathway in neurodegeneration

• Behavioral studies of the Scn8a conditional knock-out mouse

• Characterization of the Scn8a promoter

• Alternative splicing of Scn8a

• Genetic modifiers and pathogenesis of inherited epilepsy

• Positional cloning of mouse neurological mutants

• The nuclear-encoded gene OMI and mitochondrial disease

• Functional characterization of pathogenic mutations in sodium channel Scn8a