Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene

Nature. 1997 Aug 21;388(6644):769-73. doi: 10.1038/42009.


Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation. Heterozygous Lurcher mice (Lc/+) display ataxia as a result of a selective, cell-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal development. Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis. We have used positional cloning to identify the mutations responsible for neurodegeneration in two independent Lc alleles as G-to-A transitions that change a highly conserved alanine to a threonine residue in transmembrane domain III of the mouse delta2 glutamate receptor gene (GluR delta2). Lc/+ Purkinje cells have a very high membrane conductance and a depolarized resting potential, indicating the presence of a large, constitutive inward current. Expression of the mutant GluR delta2(Lc) protein in Xenopus oocytes confirmed these results, demonstrating that Lc is inherited as a neurodegenerative disorder resulting from a gain-of-function mutation in a glutamate receptor gene. Thus the activation of apoptotic neuronal death in Lurcher mice may provide a physiologically relevant model for excitotoxic cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Chromosome Mapping
  • Electrophysiology
  • Exons
  • In Vitro Techniques
  • Introns
  • Mice
  • Mice, Inbred Strains
  • Mice, Neurologic Mutants
  • Molecular Sequence Data
  • Nerve Degeneration
  • Nervous System Diseases / genetics*
  • Point Mutation*
  • Polymorphism, Single-Stranded Conformational
  • Purkinje Cells / physiology*
  • Receptors, Glutamate / genetics*
  • Receptors, Glutamate / physiology
  • Recombinant Proteins
  • Sequence Homology, Amino Acid
  • Xenopus laevis


  • Receptors, Glutamate
  • Recombinant Proteins
  • glutamate receptor delta 2

Associated data

  • GENBANK/D10028
  • GENBANK/D10651
  • GENBANK/D13266
  • GENBANK/L19058
  • GENBANK/M73271
  • GENBANK/M97192
  • GENBANK/U34661
  • GENBANK/X57947