To establish a transcription map of the candidate region.
To characterize and identify the disease gene.
To identify disease causing mutations and perform genotype-phenotype analysis.
To assess the functional consequences of the mutated gene through expression studies in isolated cell systems.
To determine the expression of the P/Q type voltage gated calcium channels as well as other calcium channels in different species and during development.
To develop transgenic and knockout mice models in order to evaluate the direct effect ot therapeutic agents in the transgenic model.
Migraine is one of the most common neurological disorders, affecting approximately 10 % of the population in the European Community. Twin and population-based studies have shown that genetic factors are involved in migraine, but the complex genetics has hampered the identification of candidate genes. Familial hemiplegic migraine (FHM) is a rare, but clearly monogenic autosomal dominant subtype of migraine which can be used as a model to study the common forms of migraine. One of the genes for FHM has been assigned to chromosome 19p13. 2-1, and the involvement of the same locus in normal migraine, has been established by sib-pair analysis. This finding supports the hypothesis of a continuous spectrum encompassing FHM as well as the common types of migraine. Autosomal dominant episodic ataxias occur in two forms, with myokymia (EA-1) and without (EA-2). The disease loci for EA-2 and FHM were independently mapped to the same region on chromosome 19p13.2. The disorders share overlapping clinical features such as episodic nature, cerebellar atrophy, nystagmus and response to flunarazine treatment. The P/Q type voltage gated calcium channel was a strong candidate for both disorders and the gene for the alpha subunit was independently localized to this chromosomal region. Functional studies using transfection and transgenic models will form the basis for screening and rational development of potential prophylactic agents in migraine and episodic ataxia. It is envisaged that characterization of the P type channel will also provide new and important information relevant to the role of calcium channels in neurobiology and pathophysiology in general. Since calcium channels are widely expressed in the nervous system, characterization of the underlying genetic defect in episodic ataxia and FHM may have implications for the understanding of other neurodegenerative disorders. In addition because there are strong associations between migraine and epilepsy, cerebral infarcts, Raynaud phenomena, and major affective and panic disorders, results of this project may also have implications for other episodic neurological, vascular and psychiatric disorders.
Funding SchemeCSC - Cost-sharing contracts
2300 RA Leiden