Normal mouse and pale tremor mouse

Current Research

The focus of research in the Meisler laboratory has been to develop mouse models of human inherited disorders and use them to access the genes responsible for human disease. This theme has been most completely developed in the context of neurological disease.

During the 1990s, this work was focused on the gene family encoding voltage-gated sodium channels. Positional cloning of the mouse mutant "motor endplate disease" in 1995 resulted in discovery of a novel sodium channel, SCN8A (protein product, Nav1.6) (Burgess et al, 1995). Mutations of SCN8A in the mouse result in a spectrum of motor dysfunctions including ataxia, dystonia, tremor, and paralysis. In 2005 the first human mutation of SCN8A was identified in a family with ataxia and cognitive impairment, suggesting for the first time that ion channel mutations may contribute to cognitive disability (Trudeau et al 2005) [ PDF ]. In addition, analysis of the tissue-specific promoter of SCN8A identified evolutionarily conserved sequence elements whose role in transcription are currently under investigation (Drews et al 2005) [ PDF ].

Voltage-gated Sodium channel structure, Meisler and Kearney (2005) Journal of Clinical Investigation

In 2000, we demonstrated that mutations in the sodium channel SCN1A are responsible for seizure disorders in a mouse model and in human patients with GEFS+ epilepsy (Escayg et al 2000) [ PDF ]. This report led to the identification of more than 200 mutations in SCN1A and the inclusion of this gene in standard work-up of patients with epilepsy.

Severity of inherited disorders can vary among individuals carrying the same disease mutation as a result of variants in modifier genes. In 2003, we identified one of the first cloned modifier genes, one that influences the severity of a sodium channel disorder by altering the in vivo splicing of the sodium channel messenger RNA (Buchner et al 2003) [ PDF ].

In 2007, we identified an endocytic pathway component by positional cloning, of a novel mouse mutant with extensive neurodegeneration (Chow et al 2007). The role of this pathway is now under investigation.

Other accomplishments include the demonstration that mutation of the mitochondrial protease OMI results in neurodegeneration similar to that in Parkinson's Disease (Jones et al 2003) [ PDF ], and the demonstration that mutation of the Wnt inhibitor DKK1 results in abnormal limb development (MacDonald et al 2004) [ PDF ]. The DKK1 mutant is a potential model for human osteoporosis.

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.

Banner Image: Immunofluorescent images of purkinje cells, MN1 cells & hippocampus