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The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability. Crucially, the gain-of-function mutations could be pharmacologically modulated in vitro using an existing FDA-approved drug, Nitazoxanide, suggesting a possible avenue for treatment, which is currently unavailable for ataxias.

Original publication

DOI

10.1016/j.ajhg.2017.08.005

Type

Journal article

Journal

American Journal of Human Genetics

Publisher

Elsevier (Cell Press): 6 month embargo

Publication Date

07/09/2017

Volume

101

Pages

451 - 458

Addresses

Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.