Genetic animal models are used to elucidate molecular mechanisms of disease. These models can then be used to adapt existing therapies, design new drugs to target components of disease progression, or screen small molecules for novel therapeutics. The models presented here exploit different powerful genetic systems to explore two human diseases: migraine and Anderson Tawil’s Syndrome (ATS).
Migraine with aura is a complex episodic disorder consisting of a constellation of symptoms: aura, headache, nausea, and hypersensitivity to sensory stimuli. For most patients, during the headache phase, the skin becomes hyper-sensitive to non-noxious stimuli. This condition is called cutaneous allodynia. We have established a system for quantifying one of the components of migraine using mouse behavioral assays to measure dose-dependent nitroglycerin-induced peripheral allodynia. We find that Sumatriptan, a serotonin agonist used for migraine, alleviates nitroglycerin-induced cutaneous allodynia. We use this system to test a new mouse model that expresses a human mutation associated with migraine: a mouse expressing a mutant form of Casein Kinase I ∂.
Andersen-Tawil Syndrome (ATS) is a rare, dominantly inherited episodic disorder that is characterized by periodic paralysis, heart arrhythmia and developmental abnormalities. Mutations in KCNJ2, which encodes the inwardly rectifying potassium channel Kir2.1, cause most ATS cases. Kir channels modulate resting membrane potential, electrolyte recycling in the renal system, and insulin release. Kir family members function as homo/heterotetramers and the presence of one mutant subunit is sufficient to preclude the flow of K+ ions through the channel or alter proper channel trafficking. Under physiological conditions, mutations in Kir2.1 disrupt the outward flow of potassium from the cell and lead to depolarization, ultimately causing the paralysis and arrhythmia associated with ATS. Developmental abnormalities in ATS patients include short stature, broad forehead and nose, abnormal curvature and/or fusion of digits, cleft palate, incomplete dentition and wide-set eyes. This array of developmental abnormalities suggests a link between membrane excitability and development. We will use Drosophila that express mutant Kir channels to examine the role of potassium channels in development.