Familial episodic ataxia (EA) syndromes are rare and heterogeneous (EA1-EA7 to date) monogenic disorders, the study of which has illuminated previously unrecognized but important roles of ion channels and transporters in neuronal and cerebellar function. Overlapping features between the EA syndromes and the more common but genetically complex vertigo and ataxia syndromes, particularly those associated with migraine, suggest possibly shared disease mechanisms. We have recruited the largest number of patients with EA under the care of any research group worldwide. We have expanded the clinical and genetic spectrum of EA2 and EA1, defined a new syndrome EA6, and mapped EA7. Furthermore, we performed functional studies to find that the type and location of mutations affect the biophysical and biochemical properties of the abnormal proteins, which correlate with phenotypic variability. The overall goal of the proposed research is to define the genetic causes of episodic ataxia syndromes in our existing database to improve recognition and diagnosis.
The specific aims for this proposal are: 1) To improve the genetic diagnosis in EA. The majority of the subjects in our database has not been genetically diagnosed despite extensive screening. We will search for exonic copy number variants using Multiplex Ligationdependent Probe Amplification (MLPA). We will use array-based IIlumina Genome Analyzers (Solexa sequencing technology) to identify mutations and other nucleotide variations in the known EA genes, as validated by our preliminary analysis. 2) To identify new EA loci and genes. We will search for new disease loci by linkage analysis in large families and identify-by-descent mapping (using IIlumina 300K HumanCyloSNP-12 BeadChip) in small families that are not suitable for linkage analysis and sporadic cases. We will select candidate genes based on function and expression profile and also by position including those in the linked regions with or without well-characterized function. We will test the hypotheSiS that mutations in membrane proteins including but not limited to ion channels that regulate neuronal excitability cause episodic ataxia. Insights gained from the study will lead to improved diagnosis and treatment of familial episodic ataxia and the more common episodic vertigo syndromes.
Designated the episodic ataxia center for the Rare Diseases Clinical Research Network sponsored by the National Institutes of Health, we have been referred patients with episodic ataxia from across the country. We have recruited a large number of patients with episodic ataxia, yet only less than a third has been genetically characterized. Our main goal is apply state of the art research strategies to genetically define our patient population and to find new causes underlying inherited episodic ataxia. Our efforts will improve the diagnosis and treatment of episodic ataxia and related disorders leading to dizziness and imbalance.
| Steffen, Janos; Vashisht, Ajay A; Wan, Jijun et al. (2017) Rapid degradation of mutant SLC25A46 by the ubiquitin-proteasome system results in MFN1/2-mediated hyperfusion of mitochondria. Mol Biol Cell 28:600-612 |
| Wan, Jijun; Steffen, Janos; Yourshaw, Michael et al. (2016) Loss of function of SLC25A46 causes lethal congenital pontocerebellar hypoplasia. Brain 139:2877-2890 |
| Rudnik-Schöneborn, Sabine; Senderek, Jan; Jen, Joanna C et al. (2013) Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations. Neurology 80:438-46 |
| Wan, Jijun; Yourshaw, Michael; Mamsa, Hafsa et al. (2012) Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat Genet 44:704-8 |
