B6.Cg-Tg(FXN*)1Sars Fxn^tm1Mkn/J

Stock number: 008586
Product name: Tg(FXN);Fxn-
Research areas: Neurobiology Research

Description

This strain harbors a human frataxin transgene and a mouse frataxin knock-out, and may be useful in studies of Friedreich's Ataxia.

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Detailed description

Mice that are hemizygous for the transgene and homozygous for the targeted mutation are viable, normal in size and do not display any gross physical or behavioral abnormalities. The Donating Investigator reports that no other behavioral or histological phenotype has been observed. FISH and karyotyping shows one copy of the transgene inserted on Chromosome 5.

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

Development

These Tg(FXN);Fxn- mice harbor the the FXN*500GAA transgene (Tg(FXN)1Sars) and frataxin knockout allele (Fxn^tm1Mkn).

The FXN*500GAA transgene, created by Dr. Joseph Sarsero, was designed with a bacterial artificial chromosome (BAC) containing the entire human frataxin (FXN) gene with an interrupted 500 GAA trinucleotide repeat inserted into intron 1. This transgene was injected into C57BL/6J donor eggs. FISH and karyotyping of mice from founder line 1 shows one copy of the transgene inserted on Chromosome 5. Founder animals were bred as described below.

The frataxin knockout allele (Frda^- or Frda^del4) was designed by Drs. Michel Koenig and Helene Puccio by replacing exon 4 of the frataxin gene on chromosome 19 with a loxP-flanked PGK-neomycin resistance cassette. Fxn^tm1Mkn mice on the 129/Sv-ter, or mixed C57BL/6J and 129/Sv-ter background were obtained by Dr. Sarsero and used as described below.

To generate this Tg(FXN);Fxn- line (Stock No. 008586), FXN*500GAA transgenic mice from founder line 1 were bred to mice carrying the Fxn^tm1Mkn allele on the 129/Sv-ter, or mixed C57BL/6J and 129/Sv-ter background. Dr. Sarsero reported that double mutant mice were backcrossed to C57BL/6J mice using a speed congenic protocol (see SNP note below), and then sent to The Jackson Laboratory Repository.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 1 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

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: Tg(FXN*)1Sars
Name: transgene insertion 1, Joseph Sarsero
MGI accession ID: MGI:5432794
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(FXN*)1Sars
Marker name: transgene insertion 1, Joseph Sarsero
Chromosome: 5
Strain of origin: C57BL/6J
Expressed genes: FXN,frataxin,human
Molecular note: The transgene contained a bacterial artificial chromosome (BAC) with the entire human frataxin (FXN) gene with a 500 GAA trinucleotide repeat inserted into intron 1. Line 1 contained a single copy of the transgene inserted into chromosome 5.