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Spinocerebellar ataxia 6; SCA6

Disease ID:882
Name:Spinocerebellar ataxia 6; SCA6
Associated with:1 target
Synonyms
Spinocerebellar ataxia
Database Links
Disease Ontology: DOID:1441
OMIM: 183086
Orphanet: ORPHA98758

Targets

Cav2.1
Comments:  SCA6 is a member in the group of neurodegenerative disorders containing expanded CAG (polyglutamine) repeats. Unaffected individuals have CAG repeats numbering between 4 and 16 in the CACNA1A gene, while SCA6 patients have expansions of greater than 21 repeats. The length of the expansion appears to be correlated with age of onset (greater CAG expansion is associated with earlier age of onset) and is associated with severe cerebellar Purkinje cell loss, moderate granule cell and dentate nucleus neuronal loss and mild neuronal loss in the inferior olive. In heterogenous expression systems biophysical analyses of polyglutamine expansions on Cav2.1 properties show a range of effects on voltage- and time-dependant properties with a strong dependence on both auxiliary subunit and Cav2.1 subunit splice variant composition when expressed in heterologous systems. The neuronal loss observed in SCA6 brains may be due to a combination of altered channel properties resulting in abnormal intracellular calcium concentrations and perinuclear and/or nuclear channel protein aggregates resulting in cell death.
References:  1
Mutations:  Cav2.1 is associated with 1 mutation. Click here for details

Ligands

No ligand related data available for Spinocerebellar ataxia 6; SCA6

References

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1. Adams PJ, Snutch TP. (2007) Calcium channelopathies: voltage-gated calcium channels. Subcell. Biochem., 45: 215-51. [PMID:18193639]

2. Ishikawa K, Fujigasaki H, Saegusa H, Ohwada K, Fujita T, Iwamoto H, Komatsuzaki Y, Toru S, Toriyama H, Watanabe M, Ohkoshi N, Shoji S, Kanazawa I, Tanabe T, Mizusawa H. (1999) Abundant expression and cytoplasmic aggregations of [alpha]1A voltage-dependent calcium channel protein associated with neurodegeneration in spinocerebellar ataxia type 6. Hum. Mol. Genet., 8 (7): 1185-93. [PMID:10369863]

3. Kordasiewicz HB, Thompson RM, Clark HB, Gomez CM. (2006) C-termini of P/Q-type Ca2+ channel alpha1A subunits translocate to nuclei and promote polyglutamine-mediated toxicity. Hum. Mol. Genet., 15 (10): 1587-99. [PMID:16595610]

4. Matsuyama Z, Wakamori M, Mori Y, Kawakami H, Nakamura S, Imoto K. (1999) Direct alteration of the P/Q-type Ca2+ channel property by polyglutamine expansion in spinocerebellar ataxia 6. J. Neurosci., 19 (12): RC14. [PMID:10366652]

5. Restituito S, Thompson RM, Eliet J, Raike RS, Riedl M, Charnet P, Gomez CM. (2000) The polyglutamine expansion in spinocerebellar ataxia type 6 causes a beta subunit-specific enhanced activation of P/Q-type calcium channels in Xenopus oocytes. J. Neurosci., 20 (17): 6394-403. [PMID:10964945]

6. Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, Uchihara T, Nagayama S, Osanai M, Mizusawa H, Tanabe T. (2000) Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function. J. Biol. Chem., 275 (15): 10893-8. [PMID:10753886]