3 years ago

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44
Penny Clouston, Jennifer Lickiss, Ricardo Parolin Schnekenberg, Henry Houlden, Samuel Clokie, Conceição Bettencourt, Jonathan Williams, Lauren M. Watson, Esther B.E. Becker, David Sims, Katherine Fawcett, Andrea H. Németh, Yvonne Wallis, Elizabeth Bamber

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.

Publisher URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30327-0

DOI: 10.1016/j.ajhg.2017.08.005

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