Phenotypic Mutation 'crawler' (pdf version)
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Mutation Type nonsense
Coordinate64,429,694 bp (GRCm38)
Base Change T ⇒ A (forward strand)
Gene Grid2
Gene Name glutamate receptor, ionotropic, delta 2
Synonym(s) GluRdelta2, tpr, B230104L07Rik
Chromosomal Location 63,255,876-64,704,323 bp (+)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene is a member of the family of ionotropic glutamate receptors which are the predominant excitatory neurotransmitter receptors in the mammalian brain. The encoded protein is a multi-pass membrane protein that is expressed selectively in cerebellar Purkinje cells. A point mutation in the mouse ortholog, associated with the phenotype named 'lurcher', in the heterozygous state leads to ataxia resulting from selective, cell-autonomous apoptosis of cerebellar Purkinje cells during postnatal development. Mice homozygous for this mutation die shortly after birth from massive loss of mid- and hindbrain neurons during late embryogenesis. This protein also plays a role in synapse organization between parallel fibers and Purkinje cells. Alternate splicing results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause cerebellar ataxia in humans. [provided by RefSeq, Apr 2014]
PHENOTYPE: Homozygotes for multiple spontaneous and targeted null mutations exhibit ataxia and impaired locomotion associated with cerebellar Purkinje cell abnormalities and loss, and on some backgrounds, male infertility due to lack of zona penetration by sperm. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_008167; MGI: 95813

Mapped Yes 
Amino Acid Change Tyrosine changed to Stop codon
Institutional SourceBeutler Lab
Gene Model predicted gene model for protein(s): [ENSMUSP00000093536]
SMART Domains Protein: ENSMUSP00000093536
Gene: ENSMUSG00000071424
AA Change: Y679*

Pfam:ANF_receptor 39 404 4.1e-41 PFAM
PBPe 442 807 5.98e-108 SMART
Lig_chan-Glu_bd 452 514 3.76e-24 SMART
transmembrane domain 830 852 N/A INTRINSIC
low complexity region 945 956 N/A INTRINSIC
Predicted Effect probably null
Phenotypic Category
Phenotypequestion? Literature verified References
behavior/neurological 11672610
growth/size 11672610
MCMV susceptibility
nervous system
Alleles Listed at MGI

All Mutations and Alleles(34) : Chemically induced (ENU)(2) Gene trapped(2) Spontaneous(22) Targeted(6) Transgenic(2)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00580:Grid2 APN 6 64345589 missense probably damaging 1.00
IGL00596:Grid2 APN 6 64533704 missense possibly damaging 0.93
IGL01686:Grid2 APN 6 64320196 missense probably benign 0.00
IGL01712:Grid2 APN 6 64665915 missense possibly damaging 0.73
IGL02064:Grid2 APN 6 64063935 missense probably benign 0.29
IGL02216:Grid2 APN 6 64345666 missense probably damaging 0.96
IGL02563:Grid2 APN 6 64345873 missense possibly damaging 0.94
IGL02685:Grid2 APN 6 64345816 missense possibly damaging 0.50
IGL03129:Grid2 APN 6 64063904 missense probably damaging 0.98
IGL03324:Grid2 APN 6 64429822 missense possibly damaging 0.88
IGL03395:Grid2 APN 6 63909069 missense possibly damaging 0.94
swagger UTSW 6 64395280 nonsense
R0133:Grid2 UTSW 6 64320132 missense probably damaging 1.00
R0147:Grid2 UTSW 6 64533587 missense probably benign
R0193:Grid2 UTSW 6 64063953 missense possibly damaging 0.64
R0370:Grid2 UTSW 6 64345734 missense possibly damaging 0.75
R0399:Grid2 UTSW 6 64666052 missense probably benign 0.33
R0600:Grid2 UTSW 6 63503435 missense probably benign 0.38
R0717:Grid2 UTSW 6 64666275 missense possibly damaging 0.96
R1524:Grid2 UTSW 6 64429754 missense possibly damaging 0.92
R1555:Grid2 UTSW 6 64429684 missense possibly damaging 0.87
R1572:Grid2 UTSW 6 64429694 nonsense probably null
R1762:Grid2 UTSW 6 64533654 missense probably damaging 0.98
R1944:Grid2 UTSW 6 63909061 missense probably damaging 1.00
R1961:Grid2 UTSW 6 63908893 missense probably damaging 1.00
R1969:Grid2 UTSW 6 63908918 nonsense probably null
R2138:Grid2 UTSW 6 64345798 missense probably damaging 0.99
R3500:Grid2 UTSW 6 63503399 missense probably damaging 0.97
R3547:Grid2 UTSW 6 64320021 missense probably damaging 0.97
R3845:Grid2 UTSW 6 64345842 missense possibly damaging 0.62
R4124:Grid2 UTSW 6 63503433 missense probably benign 0.41
R4273:Grid2 UTSW 6 63909045 missense probably damaging 1.00
R4591:Grid2 UTSW 6 64320102 missense probably damaging 1.00
R4701:Grid2 UTSW 6 64665915 missense probably benign 0.27
R4721:Grid2 UTSW 6 64666201 missense probably benign 0.33
R4755:Grid2 UTSW 6 63908988 missense probably benign 0.04
R4869:Grid2 UTSW 6 64429740 missense probably damaging 1.00
R5083:Grid2 UTSW 6 64320152 nonsense probably null
R5091:Grid2 UTSW 6 64076878 missense probably benign 0.07
R5117:Grid2 UTSW 6 63256933 missense probably benign 0.15
R5128:Grid2 UTSW 6 64665998 missense probably benign 0.01
R5386:Grid2 UTSW 6 63931105 missense probably damaging 0.99
R5404:Grid2 UTSW 6 63930910 missense probably damaging 0.99
R5534:Grid2 UTSW 6 63503361 missense probably benign
R5626:Grid2 UTSW 6 64076945 critical splice donor site probably null
R5699:Grid2 UTSW 6 63908991 missense probably damaging 0.99
R5700:Grid2 UTSW 6 64094432 missense possibly damaging 0.95
R5876:Grid2 UTSW 6 64663162 missense probably damaging 1.00
R6446:Grid2 UTSW 6 64345593 missense probably damaging 1.00
R6694:Grid2 UTSW 6 63931047 missense possibly damaging 0.92
R6697:Grid2 UTSW 6 63931047 missense possibly damaging 0.92
R6699:Grid2 UTSW 6 63931047 missense possibly damaging 0.92
R6767:Grid2 UTSW 6 63931015 missense probably benign 0.01
R6895:Grid2 UTSW 6 64395299 missense probably damaging 0.99
Mode of Inheritance Autosomal Recessive
Local Stock Live Mice, gDNA
MMRRC Submission 038228-MU
Last Updated 2018-05-22 9:26 AM by Anne Murray
Record Created 2015-03-10 7:11 PM by Jeff SoRelle
Record Posted 2016-12-01
Phenotypic Description

Figure 1. Phenotype of the crawler mice.

The crawler phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R1572, some of which exhibited ataxia and an abnormal gait (Figure 1).

Nature of Mutation

Whole exome HiSeq sequencing of the G1 grandsire identified 120 mutations. Among these the mutation in Grid2 was presumed to be causative because the crawler neurological phenotype mimics other known alleles of Grid2 (see MGI for a list of Grid2 alleles). The mutation in Grid2 is a T to A transversion at base pair 64,429,694 (v38) on chromosome 6, or base pair 1,173,792 in the GenBank genomic region NC_000072 encoding Grid2. The mutation corresponds to residue 2,037 in the NM_008167 mRNA sequence in exon 13 of 16 total exons. 



674  -Q--T--D--I--P--Y--G--T--V--L--D-


The mutated nucleotide is indicated in red.  The mutation results in substitution of tyrosine 679 for a premature stop codon (Y679*) in the GluRδ2 protein.

Protein Prediction

Figure 2. Domain organization (top) and membrane topography of GluRδ2 (bottom). The domains are labeled as explained in the text. The crawler mutation results in substitution of tyrosine 679 for a premature stop codon (Y679*). The SYTANLAAF sequence motif in the M3 transmembrane helix is indicated, with the alanine mutated in Lurcher mice and the tyrosine mutated in swagger mice indicated. The ligand binding pocket formed by the two lobes D1 and D2 is shown as filled with either glycine or D-serine, which have been shown to bind to GluRδ2 with low affinity. Not to scale.

Glutamate receptor ion channels (ionotropic glutamate receptors, iGluR), which are nonselective for monovalent cations (and sometimes Ca2+ permeable), are the major mediators of excitatory synaptic transmission in the central nervous system. iGluRs are tetramers arranged as a dimer of dimers (1-3). Each subunit has a characteristic modular architecture with four domains: the N-terminal domain (NTD), the ligand- or agonist-binding domain (LBD), the transmembrane region, and the C-terminal domain (CTD) (Figure 2) [reviewed in (4;5)]. The extracellular NTD mediates dimer formation and controls heteromer formation among members of the same iGluR subfamily (6). The extracellular LBD is encoded by two polypeptide segments, S1 and S2, which are separated by amino acids that make up part of the transmembrane portion of the protein. The CTD is important for proper delivery of the receptor to the membrane (7;8), for clustering the receptor at the PSD (9;10), and for maintaining stable localization of the receptor at the PSD (11). The transmembrane regions of iGluRs form the ion channel pore, and consist of three α-helices (M1, M3, and M4) and a membrane-inserted pore loop (P or M2).


The crawler mutation occurs within the S2 segment, and converts tyrosine 679 to a stop codon.


For more information about Grid2, please see the record for swagger.

Putative Mechanism

Glutamate is synthesized, stored, released from the presynaptic terminal, and acts through both ligand-gated ion channels (ionotropic glutamate receptors) and G-protein coupled receptors (metabotropic glutamate receptors) on postsynaptic neurons. Activation of these receptors accounts for basal excitatory synaptic transmission and synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) that are thought to underlie learning and memory. 


Lurcher mice have an alanine to threonine point mutation at residue 654 in GluRδ2. Lurcher heterozygotes are smaller than normal at maturity, but are fertile and have a normal lifespan. Lc/+ mice show a swaying of the hindquarters, a jerky up and down movement, and a tendency to fall in their attempts to walk, which are visible by 12 to 14 days of age (12;13). Walking also involves exaggerated hindlimb flexion. GluRδ2-deficient mice display impaired motor coordination, with ataxia observable by postnatal day 12 (14). These mice walk with tottering steps, and lose balance and roll when they rear up on their hind legs. 


The phenotype of crawler mice resembles those of Grid2-/- mice, as well as heterozygous Lurcher mice. Although protein expression of GluRδ2 has not been examined, two reasons suggest that the crawler mutation results effectively in a protein null phenotype rather than a gain-of-function phenotype causing massive Purkinje cell death such as that observed in Lurcher mice. First, the mutation creates a premature stop codon, which is likely to disrupt protein stability and lead to degradation. Second, like the Grid2 null allele and the hotfoot alleles (mainly deletions of portions of the CTD), the crawler mutation is recessive. In contrast, the Lurcher mutation causes death when present in homozygous form. 

Primers PCR Primer

Sequencing Primer
  12. Phillips, R. (1960) 'Lurcher', a New Gene in Linkage Group XI of the House Mouse. J Genet. 57, 35-42.
Science Writers Anne Murray
Illustrators Peter Jurek
AuthorsJeff SoRelle and Bruce Beutler
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