First Author | Zuo J | Year | 1997 |
Journal | Nature | Volume | 388 |
Issue | 6644 | Pages | 769-73 |
PubMed ID | 9285588 | Mgi Jnum | J:42431 |
Mgi Id | MGI:1095746 | Doi | 10.1038/42009 |
Citation | Zuo J, et al. (1997) Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene [see comments]. Nature 388(6644):769-73 |
abstractText | Lurcher (Lc) is a spontaneous, semidominant mouse neurological mutation(1). Heterozygous Lurcher mite (Lc/+) display ataxia as a result of a selective, coil-autonomous and apoptotic death of cerebellar Purkinje cells during postnatal develoment(2-4). Homozygous Lurcher mice (Lc/Lc) die shortly after birth because of a massive loss of mid- and hindbrain neurons during late embryogenesis(5). 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 delta 2 glutamate receptor gene (GluR delta 2). 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 delta 2(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. |