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A cross-departmental collaboration involving Associate Professor Esther Becker and Lauren Watson, a research scientist in the Becker group, has led to the publication of an important paper reporting dominant mutations that cause spinocerebellar ataxias. 

Spinocerebellar ataxias are a group of diseases that cause degeneration in the cerebellum, which is the part of the brain responsible for controlling movement. Whilst there many different types of this disorder, each with their own unique symptoms, generally the disorder is characterised by problems with movement that worsen over time. 

The paper, published in the American Journal of Human Genetics, describes a series of mutations in a human gene called GRM1, which produces a glutamate receptor known as mGlur1. mGlur1 is one of the most abundant of its group of receptors in the Central Nervous System and is particularly rich in the group of brain cells in the cerebellum known as Purkinje cells. Disease causing mutations in GRM1 are quite rare.; however, a single family with recessive mutations has been identified as causing cerebellar ataxia and intellectual disability.

This paper has now identified, for the first time, dominant mutations in GRM1 that cause distinct disease symptoms. Two of the mutations led to increased receptor activity and caused slowly progressive ataxia with disease onset between the ages of 20 and 50. These families did not carry any other known spinocerebellar ataxia-causing mutations. The team also identified another mutation occurring in a child, whose parents were unaffected, that led to the production of a shorter form of the protein. This caused intellectual disability and cerebellar ataxia without apparent shrinking of the cerebellum.

The finding of mutations that lead to increased receptor activity are particularly important because drugs are available that have the opposite effect, reducing activity. The researchers tested an approved mGluR1 drug Nitazoxanide against these mutant receptors in laboratory conditions.  Nitazoxanide was indeed shown to inhibit the mutant receptor in these experiments.  This offers the hope that drugs targeting mGlur1 may one day offer therapeutic opportunities in cerebellar ataxias.

To find out more about the work that goes on in the Becker Group, visit their webpage.