IMPC phenotypes (gene matching)
B6(Cg)-Fustm1.1Emcf/H
| Status | Available to order |
| EMMA ID | EM:11106 |
| International strain name | B6(Cg)-Fustm1.1Emcf/H |
| Alternative name | FUS Delta14. |
| Strain type | Targeted Mutant Strains : Knock-in |
| Allele/Transgene symbol | Fustm1.1Emcf |
| Gene/Transgene symbol | Fus |
Information from provider
| Provider | Elizabeth Fisher |
| Provider affiliation | Neurodegenerative Disease, University College London |
| Genetic information | To create a mouse model that expresses mutant FUS (fused in sarcoma) at physiological levels, we targeted a human frameshift mutation (FUS p.G466VfsX14) into the mouse Fus locus. The frameshift arises from an A to G point mutation in the splice acceptor site of exon 14. This results in skipping of exon 14 during splicing and exon 15 (the last exon) being translated out of frame, creating a novel frame-shifted C-terminus. Thus we introduced the identical point mutation, g.13845 A to G (p.G459VfsX14) into the splice acceptor site of exon 14 of the endogenous mouse Fus locus. The human coding sequence of exon 15 was also knocked in to ensure the frameshift peptide sequence produced was identical to that of the human patient (14 residues long), because the mouse coding sequence lacks an early STOP codon and would produce a frameshift peptide that is 64 amino acids in length. The new strain was originally designated B6N;B6J-Fustm1Emcf/H, referred to here as FUS Delta14. FUS Delta14 mice were generated by homologous recombination in the C57BL/6N mouse embryonic stem cell (ESC) line JM8-F6, using standard procedures. Briefly, a construct of 8kb, introduced an A-to-G splice mutation at g.13845 and humanised the coding sequence of exon 15 through the following sequence changes: g.14230 C to T, g.14232 A to T, g.14234 C to G, g.14260 A to G and g.14266 ATTA insertion. Correct clones were initially identified through long-range PCR and copy number qPCR and validated by RT-PCR and Western blot for the truncated RNA/protein product, followed by DNA sequence verification. Mice were generated by injection of modified ESCs into B6(Cg)-Tyrc-2J/J (B6-albino) donor embryos, with the resultant chimeric male offspring crossed to B6-albino females to obtain germline transmission (GLT). GLT was confirmed by copy number qPCR. The FRT-flanked neo cassette was removed by crossing to the flpo recombinase-expression line B6(C3)-Tg(Pgk1-FLPo)10Sykr/J, which is maintained on the C57BL/6J background. The neo-negative line was backcrossed for a minimum of three generations onto the C57BL/6J background before experimental cohorts were bred. |
| Phenotypic information | Homozygous:Late embryonic lethal in homozygotes on C57BL/6J background.Heterozygous:Progressive motor neuron loss in both sexes, but still only a mild phenotype by 18 months. Mild weight loss in males, in heterozygous animals. |
| References |
|
| Homozygous fertile | no |
| Homozygous viable | no |
| Homozygous matings required | not known |
| Immunocompromised | no |
Information from EMMA
| Archiving centre | Mary Lyon Centre at MRC Harwell, Oxford, United Kingdom |
| Animals used for archiving | heterozygous 0 |
| Breeding at archiving centre | The mice have been maintained as het x wt matings on DBA/2JCrl background |
Disease and phenotype information
MGI allele-associated human disease models
Orphanet associated rare diseases, based on orthologous gene matching
- Amyotrophic lateral sclerosis / Orphanet_803
- Juvenile amyotrophic lateral sclerosis / Orphanet_300605
MGI phenotypes (gene matching)
- small thymus / MGI
- motor neuron degeneration / MGI
- decreased motor neuron number / MGI
- abnormal neuromuscular synapse morphology / MGI
- small testis / MGI
- decreased body weight / MGI
- decreased body size / MGI
- abnormal gait / MGI
- abnormal suckling behavior / MGI
- impaired limb coordination / MGI
- increased mortality induced by gamma-irradiation / MGI
- postnatal growth retardation / MGI
- reduced female fertility / MGI
- male infertility / MGI
- decreased litter size / MGI
- premature death / MGI
- no abnormal phenotype detected / MGI
- lymphoid hypoplasia / MGI
- abnormal immunoglobulin level / MGI
- no phenotypic analysis / MGI
- abnormal chromosome morphology / MGI
- aneuploidy / MGI
- chromosome breakage / MGI
- decreased lymphocyte cell number / MGI
- decreased B cell number / MGI
- abnormal male meiosis / MGI
- abnormal hippocampus pyramidal cell morphology / MGI
- postnatal lethality, incomplete penetrance / MGI
- neonatal lethality, complete penetrance / MGI
Literature references
- Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in 'FUSDelta14' knockin mice.;Devoy Anny, Kalmar Bernadett, Stewart Michelle, Park Heesoon, Burke Beverley, Noy Suzanna J, Redhead Yushi, Humphrey Jack, Lo Kitty, Jaeger Julian, Mejia Maza Alan, Sivakumar Prasanth, Bertolin Cinzia, Soraru Gianni, Plagnol Vincent, Greensmith Linda, Acevedo Arozena Abraham, Isaacs Adrian M, Davies Benjamin, Fratta Pietro, Fisher Elizabeth M C, ;2017;Brain : a journal of neurology;140;2797-2805; 29053787