Study to Explore Rare Gene Mutation Found in Spinocerebellar Ataxia

A study supported by a research grant from the National Ataxia Foundation (NAF) will explore the underlying mutation of the recently described spinocerebellar ataxia, type 41 (SCA41). In addition to producing new insights into spinocerebellar ataxia mechanisms, the study could contribute to improved diagnostics.

Only one case with spinocerebellar ataxia and a mutation in the TRPC3 gene has so far been described, although researchers earlier showed that a mouse model of spinocerebellar ataxia also carries a mutation in the gene. The research group demonstrated that the human mutation behaved like its mouse counterpart, and likely caused disease.

TPRC3 is an ion channel located in the membrane of cells in the cerebellum, and contributes to cell communication through the transport of positively charged ions. Considering the potential of the TRPC3 mutation to cause human disease, Brent L. Fogel from the University of California, Los Angeles, and Esther B. E. Becker from the University of Oxford, U.K., will investigate SCA41 by developing a model of human cerebellum cells to study TRPC3 and characterize its mutations.

For this, they will make use of induced pluripotent stem cells obtained from the skin of both healthy individuals and the SCA41 patient. These cells will be turned into neurons of the type that exist in the cerebellum.

With these cells, Drs. Fogel and Becker will study the mutated TRPC3 to tease out those aspects of channel function affected by the mutation. The team will also introduce other mutations, including known mouse ataxia mutations, in the cultured cells to study all the crucial regions of the protein. They hope to predict which changes are likely to cause ataxia in people — findings that may improve ways of diagnosing the disease.

The cultured cerebellar cells can also be used to test new drug therapies affecting the function of the TPRC3 channel.

Another part of the study will have a more clinical focus, as Drs. Fogel and Becker plan to screen patients for mutations in the gene. They will sequence both the coding parts of the genome, and particular genes in families with a dominant type of ataxia whose cause has not been determined. Sporadic ataxia patients will also be screened to identify rare or new mutations in TRPC3.

Suspected mutations will then be analyzed to determine if they cause disease, a process that might be aided by the use of the cerebellar cell cultures.

These research processes might lead to new ways of verifying new mutations in other ataxia genes.