C57BL/6J-Nars1^em1Rwb/RwbJ

Stock number: 034762
Research areas: Neurobiology Research

Description

This Ser472Phe point substitution in asparaginyl-tRNA synthetase 1 is homozygous lethal but causes no detected neurological defect in heterozygotes, unlike a similar point substitution in humans which causes a dominant peripheral axonal neuropathy.

Detailed description

This Ser472Phe point substitution was not found to cause any decrease in transcript level of Nars1 in the spinal cord by qRT-PCR, consistent with a stable mRNA with an amino acid point substitution. Although a human Ser461Phe point mutation has proven dominant in causing a peripheral axonal neuropathy, this parallel Ser472Phe point mutation in the mouse C57BL/6J background causes recessive embryonic lethality in homozygotes but no neurological phenotype was detected in heterozygotes. Of 31 pups born from heterozygous intercrosses none were homozygous. Heterozygotes were assessed with peripheral nerve histology, body weight measurement, the inverted wire grid test for grip strength and latency to falling, and nerve conduction velocity measurements of the sciatic nerve, but no defect was found relative to wild-type controls even at 18 months of age. Additionally, no alteration in expression of stress response ATF4-target genes was found in spinal cord from heterozygotes.

Development

This CRISPR/cas9-mediated TCT to TTT point substitution that results in the replacement of serine at amino acid 472 with phenylalanine was generated in C57BL/6J. After two backcrosses to C57BL/6J isolated this allele from other induced mutations, the heterozygous males at generation N2 were used for sperm cryopreservation.

Allele

Symbol: Nars1^em1Rwb
Name: endonuclease-mediated mutation 1, Robert W Burgess
MGI accession ID: MGI:7310304
Generation method: Endonuclease-mediated
Attributes: Hypomorph
Marker symbol: Nars1
Marker name: asparaginyl-tRNA synthetase 1
Marker synonyms: ASNRS; LRRGT00113; NARS; NEDMILEG; NEDMILG
Chromosome: 18
Strain of origin: C57BL/6J
Molecular note: This C to T substitution in the last codon in exon 13 results in a TCT to TTT codon change that causes an amino acid change at residue 472 from serine to phenylalanine (p.S472F), orthologous to a pathological mutation in human.