TardbpQ101X ENU-induced mutant mice possess a nonsense mutation in exon 3 of the Tardbp gene. These mutant mice may be useful in studying the effects of TDP-43 protein regulation on the development of amyotrophic lateral sclerosis and frontotemporal dementia.
Elizabeth MC Fisher, UCL Institute of Neurology
These TardbpQ101X ENU-induced mutant mice possess a nonsense mutation in exon 3 of the TAR DNA binding protein (Tardbp) gene.
The Tardbp gene product, TDP-43, is a protein localized to the nucleus of nerve cells. Ubiquinated accumulations of mutant TDP-43 have been linked to the development of Lou Gehrig's disease (Amyotrophic lateral sclerosis; ALS) and frontotemporal dementia (FTD). Heterozygotes are viable and fertile, homozygotes are embryonic lethal by E6.5. The mutant allele produces a truncated transcript, although no truncated protein is detected. Interestingly, heterozygous mutant mice produce the same amount of wildtype TDP-43 protein as non-mutant-controls (the Tardbp gene is subject to autoregulation mechanisms), yet they exhibit a mild loss-of-function phenotype and behavioral abnormalities. Female mice display a hindlimb limb-clasp defect, with an average onset of 61 weeks, with no abnormal hindlimb neuromuscular function. Males and females also exhibit an abnormal, softer abdominal body tone.
Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder male C57BL/6J mice, a forward genetic screen was utilized to identify mice with a mutation in the TAR DNA binding protein (Tardbp) gene. Males were bred with C3H/HeH females and sperm from F1 males was screened for mutations in Tardbp. A mutation was mapped with Sanger sequencing and a C to T transition in exon 3 of Tardbp resulting in a glutamine to Stop codon nonsense mutation (Q101X). Sperm from TardbpQ101X F1 males was used for in vitro fertilization of C57BL/6J oocytes. These TardbpQ101X mice were bred to C57BL/6J mice for at least 10 times prior to their arrival at The Jackson Laboratory, where they were further bred to C57BL/6J (Stock No. 000664) for at least one generation.
|Allele Name||mutation 1, Harwell|
|Allele Type||Chemically induced (ENU) (Hypomorph)|
|Gene Symbol and Name||Tardbp, TAR DNA binding protein|
|Strain of Origin||C57BL/6J|
|Molecular Note||ENU mutagenesis induced a C to T transition in exon 3 that results in the amino acid substitution of a glutamine to Stop codon nonsense mutation (Q101X).|
When maintaining a live colony, heterozygous mice may be bred to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664). Homozygous mice are embryonic lethal prior to E6.5.
When using the B6(C3H)-Tardbpm1H/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #019899 in your Materials and Methods section.