Neurodegeneration in Lurcher mice caused by mutation in delta2 glutamate receptor gene.
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.
Zuo
J
J
Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10021, USA.
De Jager
P L
PL
Takahashi
K A
KA
Jiang
W
W
Linden
D J
DJ
Heintz
N
N
D000595:Amino Acid Sequence; D000818:Animals; D002874:Chromosome Mapping; D004594:Electrophysiology; D005091:Exons; D066298:In Vitro Techniques; D007438:Introns; D051379:Mice; D008815:Mice, Inbred Strains; D008818:Mice, Neurologic Mutants; D008969:Molecular Sequence Data; D009410:Nerve Degeneration; D009422:Nervous System Diseases / Q000235:genetics*; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011689:Purkinje Cells / Q000502:physiology*; D017470:Receptors, Glutamate / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis
D017470:Receptors, Glutamate; D011994:Recombinant Proteins; C107913:glutamate receptor delta 2