2. Academic Validation
  3. Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

Dominant Mutations in GRM1 Cause Spinocerebellar Ataxia Type 44

  • Am J Hum Genet. 2017 Sep 7;101(3):451-458. doi: 10.1016/j.ajhg.2017.08.005.
Lauren M Watson 1,  Elizabeth Bamber 1,  Ricardo Parolin Schnekenberg 2,  Jonathan Williams 3,  Conceição Bettencourt 4,  Jennifer Lickiss 5,  Sandeep Jayawant 6,  Katherine Fawcett 7,  Samuel Clokie 5,  Yvonne Wallis 5,  Penny Clouston 3,  David Sims 7,  Henry Houlden 8,  Esther B E Becker 9,  Andrea H Németh 10
Affiliations

Affiliations

  • 1 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK.
  • 2 Nuffield Department of Clinical Neurosciences, University of Oxford, 6th Floor West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK.
  • 3 Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford OX3 7LE, UK.
  • 4 Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK; Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, London WC1N 3BG, UK.
  • 5 West Midlands Regional Genetics Laboratory, Birmingham Women's and Children's NHS Foundation Trust, Birmingham B15 2TG, UK.
  • 6 Department of Paediatrics, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK.
  • 7 MRC Computational Genomics Analysis and Training Programme, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
  • 8 Department of Molecular Neuroscience, Institute of Neurology, University College London, London WC1N 3BG, UK.
  • 9 Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK. Electronic address: [email protected].
  • 10 Nuffield Department of Clinical Neurosciences, University of Oxford, 6th Floor West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford OX3 7HE, UK. Electronic address: [email protected].
PMID: 28886343 DOI: 10.1016/j.ajhg.2017.08.005
Abstract

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.

Keywords

Homer; Purkinje cells; ataxia; atrophy; calcium; cerebellum; glutamate; intellectual disability; mGluR1; nitazoxanide.

Figures