Neuropediatrics 2006; 37 - TP120
DOI: 10.1055/s-2006-945714

A MOUSE MODEL OF PAROXYSMAL NON-KINESIGENIC DYSKINESIA (PNKD)

J Nakayama 1, Y Xu 1, HY Lee 1, YH Fu 1, LJ Ptacek 1
  • 1Department of Neurology, University of California San Francisco, San Francisco, CA, United States

Objectives: Paroxysmal non-kinesigenic dyskinesia (PNKD) is an autosomal dominant episodic movement disorder characterized by spontaneous attacks of dystonia, chorea, and athetosis beginning childhood through early adulthood. These attacks are precipitated by alcohol, coffee, stress and fatigue. PNKD has been mapped to chromosome 2q33-q35, and two mutations (Ala7Val and Ala9Val) in the myofibrillogenesis regulator 1 gene (MR-1) were recently identified in PNKD families. The MR-1 protein function is unknown, and it is still not understood how mutations in this gene lead to manifestation of the PNKD phenotype. In order to elucidate the function of the MR-1 protein, we have begun developing animal models.

Methods: We created transgenic mice with a mouse BAC clone (RP24–112K19) containing the wild-type murine ortholog (mMR-1). This BAC clone was modified to introduce the Ala7Val and Ala9Val mutations. Transgene expression in these mice was confirmed by RT-PCR. We also generated mMR-1 knockout mice. These mice were subsequently bred with C57/Bl6 mice. All experiments were conducted in accordance with the guidelines of the Institutional Animal Care and Use Committee.

Results: Three lines of mMR-1 mutant transgenic mice and two lines of mMR-1 knockout mice were generated. Transgenic mice show normal development and neurological reflexes are großly normal. The body weight of transgenic mice was significantly lower (10–15%) than their wild type littermates. Transgenic mice appear to recapitulate the human phenotype as they have dystonic attacks precipitated by caffeine and ethanol. Transgenic mice from all three lines showed these attacks. Homozygous knockout mice were viable and reproductive, and had no groß phenotypic abnormalities. They did not show attacks by either caffeine or ethanol.

Conclusion: Our results suggest that the gain-of-function mutations in MR-1 might be responsible for the PNKD phenotypes. Using the PNKD mouse model, we hope to elucidate the function of the MR- 1 protein and understand the pathophysiology of this disorder.