B6.Cg-Fxn^tm1Mkn Fxn^tm1Pand/J

Stock number: 014162
Product name: KIKO
Research areas: Neurobiology Research

Description

Frataxin levels and pancreatic iron levels are reduced in these knock-in/knockout mice. However, unlike Friedreich's Ataxia patients, no detectable change in GAA repeat size is observed. This mutant mouse may be useful in studies of Friedreich's Ataxia.

Detailed description

These frataxin knock-in/knockout (KIKO) mice harbor one allele of the frataxin (GAA)₂₃₀ expansion mutation (Fxn^tm1Pand) on one chromosome, and one allele of the frataxin exon 4-deleted mutation (Fxn^tm1Mkn) on the homologous chromosome. KIKO mice are viable and fertile. Analysis of frataxin levels in tissues from KIKO mice demonstrate a reduction of frataxin to 25-36% of wildtype controls. KIKO animals up to 1 year of age perform equivalent to wildtype controls on rotarod test. Total iron concentrations were similar in all tested tissues of KIKO and wildtype mice except in pancreas: KIKO mice demonstrate lower iron levels in pancreatic tissues. No iron deposits and only mild collagen staining around the vessels of the heart were observed in both year old KIKO mice and wildtype controls. In contrast to Friedreich's Ataxia patients, no detectable change in GAA repeat size was found over six studied generations. Moreover, no evidence of somatic cell instability was noted as GAA repeat expansion size was the same in all analyzed tissues. However, characterization of KIKO mice performed at The Jackson Laboratory revealed that starting at 6 months of age, these animals exhibit an abnormal "weaving" gait when subjected to a forced treadmill walk. This phenotype occurs with increasing penetrance as the mice age. This mutant mouse may be useful in studies of Friedreich's Ataxia.

Importation of this model was supported by the Friedreich's Ataxia Research Alliance (FARA).

Development

To generate these frataxin knock-in/knockout animals (KIKO), mice heterozygous for the frataxin (GAA)₂₃₀ expansion mutation (Fxn^tm1Pand) were bred with mice heterozygous for the frataxin exon 4-deleted mutation (Fxn^tm1Mkn). Progeny bearing both the GAA expansion (knock-in) allele and the exon 4-deleted (knockout) allele were bred together, and given the Stock No. 014162. These KIKO mice no longer harbor the Tg(FXN)YG8Pook transgene.

For a description of the frataxin (GAA)₂₃₀ expansion mutation (Fxn^tm1Pand), please see Stock No. 008470.

For a description of the frataxin exon 4-deleted mutation (Fxn^tm1Mkn), please see the compound mutant Stock No. 012253.

Allele

Symbol: Fxn^tm1Mkn
Name: targeted mutation 1, Michel Koenig
MGI accession ID: MGI:2177162
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Fxn
Marker name: frataxin
Chromosome: 19
Strain of origin: 129/Sv
Expressed genes: Fxn,frataxin,mouse, laboratory
Molecular note: A loxP-flanked PGK-neomycin resistance cassette replaced a genomic DNA fragment containing exon 4, which is highly conserved and often mutated in humans. An additional line was also produced in which the loxP flanked neomycin cassette was removed by Cre mediated recombination, but no distinction was made between these alleles in the original reference. From J:90098: The presence of a human FRDA transgene in hemizygous form in a Frda^tm1Mkn homozygous null background rescues the embryonic lethal phenotype and complements for the loss of endogenous mouse frataxin.

Allele

Symbol: Fxn^tm1Pand
Name: targeted mutation 1, Massimo Pandolfo
MGI accession ID: MGI:3641251
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Fxn
Marker name: frataxin
Chromosome: 19
Strain of origin: 129/Sv
Molecular note: A targeting vector was designed to insert a GAA230 repeat expansion and a floxed neomycin resistance cassette into intron 1 of the locus. Western blot demonstrated that mutants expressed frataxin protein at 75% of wild-type levels in all tissues examined.