The ENU-induced neurological 7 (nur7) allele of aspartoacylase (Aspanur7) results from a Q193X transition generating a nonsense codon and a loss-of-function mutation. Homozygous Aspanur7 mice display a Canavan disease-related pathology and may be useful in studying the axonal pathology caused by central nervous system myelin defects.
Brian Popko, University of ChicagoRead More +
Mice homozygous for this ENU-induced mutation, the neurological 7 (nur7) allele of Aspa (Aspanur7), are viable and fertile, although the donating investigator reports homozygotes are poor breeders. The Aspanur7 mutation encodes a Q193X transition that generates a nonsense codon and results in a predicted 120 amino acid truncation of the protein. While mutant Aspa mRNA expression is reduced by 40% (compared to wildtype), no truncated Aspa protein expression is reported in homozygous oligodendrocytes or brain tissue. Homozygous mice display early-onset spongy degeneration of central nervous system myelin with increased NAA levels similar to that observed in Canavan disease; an Aspa-deficiency-induced fatal childhood autosomal recessive leukodystrophy. Homozygous mice are easily distinguished at 21 days of age by their small body size and a wide-based ataxic gait. Neurological disease progresses with age to tremors and seizures. These Aspanur7 mutant mice may be useful in studying the axonal pathology caused by central nervous system myelin defects.
These mutant mice were created by the laboratory of Dr. Monica Justice (Baylor College of Medicine) using multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice. Genetic screening was utilized to identify mice with a neurological phenotype described as hypoactive in young postnatal mice and trembling during movement in adulthood ("small, lethargic, tremors in adults"). Using a candidate gene approach, a region of chromosome 11 containing the aspartoacylase (Aspa) gene was associated with the mutant phenotype. Sequencing of this gene identified a C->T transition in nucleotide 577 in exon 4 (coding a Q193X mutation that generates a TAA stop/nonsense codon and results in the early termination of the protein). Heterozygous Aspanur7 mice (also harboring the In(11Trp53;11Wnt3)8Brd balancer) were bred together (C57BL/6J genetic background) for many generations. Homozygous Aspanur7 mice (not harboring the In(11Trp53;11Wnt3)8Brd balancer) were sent to The Jackson Laboratory. Upon arrival, mice were bred with C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.
A 27 SNP (single nucleotide polymorphism) panel analysis performed by The Jackson Laboratory revealed 7 of 27 markers that were not C57BL/6 allele-type. These data suggest 129, C3H, or CBA (and perhaps other) genetic contamination prior to arrival at The Jackson Laboratory.
|Allele Name||neurological 7|
|Allele Type||Chemically induced (ENU)|
|Allele Synonym(s)||neurological (nur) 07; nurm07Jus; small lethargic|
|Gene Symbol and Name||Aspa, aspartoacylase|
|Gene Synonym(s)||ACY2; ASP; Acy-2; Acy-2; Acy2; Acy2; aminoacylase 2; neurological 7; nur7; nur7; small lethargic|
|Strain of Origin||C57BL/6J|
|Molecular Note||Exon 4 contains a point mutation of C to T at position 577 that results in an amino acid substitution of a stop codon for glutamine at position 193 (Q193X). The absence of protein expression was confirmed by western blot on brain extracts.|
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